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Cardiac stem cells: Current knowledge and future prospects

By daniellenierenberg

World J Stem Cells. 2022 Jan 26; 14(1): 140.

Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt

Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt. ge.ude.demxela@annahem.awdar

Radwa A Mehanna, Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt;

Supported by Science and Technology Development Fund, No. 28932; and Cardiovascular Research, Education, Prevention Foundation, CVREP - Dr. Wael Al Mahmeed Grant.

Corresponding author: Radwa A Mehanna, MD, PhD, Academic Research, Professor, Executive President, Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Al Khartoum Square, Azareeta, Alexandria 21500, Egypt. ge.ude.demxela@annahem.awdar

Received 2021 Feb 26; Revised 2021 Jul 2; Accepted 2022 Jan 6.

Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.

Keywords: Cardiac stem and progenitor cells, Cardiac stem cells secretome, Cardiac stem cells niche and metabolism, Nanotechnology, Clinical trials, Combined therapy

Core Tip: With the growing evidence for the existence of regenerating cardiac stem and progenitor cells, studies to evaluate their therapeutic potential have received increasing attention. Although pre-clinical research and clinical trials have demonstrated promising results, yet the latter were often inconsistent in many aspects thus imposing the need for deeper exploration of the molecular biology and relevant pathways regulating cardiogenesis and cardiac muscle repair. This review gives an insight into cardiac stem and progenitor cells regarding their embryological origin, populations, niche, secretome, and metabolism. It overviews the current preclinical research, including medical nanotechnology, and the clinical trials generally applied for cardiac regeneration.

Cardiovascular diseases are the leading cause of death globally, as stated by the latest report 2019 for the World Health Organization, with 17.9 million deaths per year, accounting for 31% of all deaths worldwide.

The heart is one of the least proliferative organs in the human body, and its minimal regenerative capacity has been dogma for decades. Such dogma has been led by the belief that the heart cannot regenerate from ischemic damage. The absence of primary tumors in the heart has further supported the notion of low proliferation. In an alleged post-mitotic organ, it has been debatable whether cardiac cells repair through activation of resident cardiac stem cells (CSCs) and cardiac progenitor cells (CPCs) or by the proliferation of pre-existing cardiomyocytes (CMs). In 2009, Bergmann et al[1] were the first to refute that notion and have reported that the heart can in fact self-renew. Based on the results obtained from their carbon-14-labelled DNA study to track CMs, Bergmann et al[1] stated that about 50% of CMs renew over the lifespan of an adult. Hsieh et al[2] provided further evidence for the origin of newly generated CMs from progenitor cells in an alpha myosin heavy chain (MHC) transgenic model. They estimated that approximately 15% of CMs can regenerate in adult hearts following ischemic damage. With progression of research, lineage tracing of regenerated cardiac tissue confirmed that the newly regenerated CMs develop from a non-CM and possibly from stem cells (SCs)[2].

Further studies have revealed various CSC/CPC candidates that are morphologically and functionally distinct from each other yet act in a complementary fashion and contribute to the regeneration process. This complex cell aggregation is known as the CSC niche that has been a challenge to characterize and locate anatomically[3].

SC applications have been under intensive research interest since the early 20th century. Many types have been isolated, starting from the embryonic, amniotic, and cord blood mesenchymal stem cells (MSCs) and passing through the adult SCs till the induced pluripotent SCs (iPSCs). Adult MSCs are undifferentiated cells with the same potentials as progenitor cells regarding the ability to differentiate into all three germ layer cells[4]. Exogenous MSCs from various sources, including bone marrow, adipose tissue, umbilical cord, placenta, and amniotic fluid[5], have shown promising results in the treatment of cardiovascular diseases. However, the outcome of CSC therapy has shown superior results in experimental studies but to a lesser extent in human clinical trials[6]. The applications of SC therapy for cardiovascular regeneration still hold a plethora of queries to be answered as well as commandment of the molecular and signaling features for CSCs in order to standardize this therapy. Among the aspects that need optimization are the types of SCs and supporting cells to be used, the number of cells, the route of injection, the frequency, and best timing for transplantation. Standardization requires an advanced understanding of the full biological features of CSCs.

SC therapy in cardiac regeneration has dual beneficiary actions. Primarily, the transplanted exogenous SCs would directly differentiate into CMs. Concomitantly, SCs activate the endogenous progenitors through their rich secretome of extracellular vesicles, immunomodulatory and growth factors, protein, and nucleic acid families[7]. These paracrine factors act to activate resident SCs and enhance vascularization to potentiate cardiac repair.

This review aims to provide insight into CSCs/CPCs regarding their embryological origin, populations, niche, metabolism, secretome, and therapeutic potentials. Also discussed is the interplay of nanotechnology with SCs in several aspects, including differentiation, tracking, imaging, and assisted therapy, showing the prospects and limitations of nanoparticle (NP)-based cardiac therapy. Finally, preclinical trials and ongoing, completed, and future clinical trials using CSCs and combined therapy are shown to delineate the potential applications in treating cardiac disease.

The heart is formed of a wide range of cell types originating from the mesodermal precursor cells. They include CMs and endocardial cells forming the inner layer, while epicardial-derived cells (EPDCs) and smooth muscle cells (SMCs) are found on the external layer. Differentiation of the mesodermal cells is initiated by the T-box transcriptional factors Brachyury (Bry) and Eomes. Bry+ cells differentiate into insulin gene enhancer protein islet-1 (ISL1) and T-box transcription factor 5 (TBX5) expressing cells, while Eomes induce expression of mesoderm posterior 1 (MESP1). MESP1+ cells are identified before the first heart field (FHF) and the second heart field (SHF) separations, so MESP1 serves as an indicator of early CPCs for both heart fields[8]. Chemokine receptor type 4 (CXCR4), fetal liver kinase 1 (FLK-1), and platelet derived growth factor receptor A are other surface markers that coincide with MESP1 and are used in combination to isolate CPCs[9,10].

In addition, a novel cell surface marker known as G protein-coupled receptor lysophosphatidic acid receptor 4 is specific to CPCs and determines its functional significance. Interestingly, its transient expression peaks in cardiac progenitors after 3 to 7 d of human (h)PSCs differentiation toward cardiac lineage, then it declines. In vivo, lysophosphatidic acid receptor 4 shows high expression in the initial stages of embryonic heart development and decreases throughout development[11].

The FHF cells are the firstly differentiated myocardial cells that are derived from cells in the anterior lateral plate mesoderm; they give rise to the left ventricle, partially some of the right ventricle population, sinoatrial node, atrioventricular node, and both atria[12]. Meanwhile, the SHF cells originate from the pharyngeal mesoderm to the posterior side of the heart and further divide into anterior and posterior SHF. They contribute to the right ventricle, atria, and the cardiac outflow tract (OFT) formation. Addition of the SHF-derived CMs to the ventricles depend on myocyte enhancer factor 2C (MEF2C). It has been found that MEF2C null mice die at 9.5-d post conception with severe heart defects due to failure of heart looping[13]. In OFT formation, two waves of SHF progenitors and their derivatives have been identified, making a differential contribution to the aorta and pulmonary artery. The early wave of cells is favorably directed to the aorta, while the second wave of cells contributes to the pulmonary artery. Phosphoinositide-dependent kinase-1 critically regulates the second wave of cells, and its deletion results in pulmonary stenosis[14]. The epicardium of the heart is formed of a transient proepicardial organ. Proepicardium is formed from homeobox protein NKx2.5 (NKx2.5) and ISL1+ cells. After epicardial formation, subepicardial mesenchymal space is formed by epithelial to mesenchymal cell transformation of the epicardial cells[15] (Figure ).

Embryonic cardiac progenitors, Brachyury-positive mesoderm precursors and Pax3+ neural crest cells. Brachyury (Bry+) mesoderm precursors give rise to the mesoderm posterior 1+ primordial precursors, which are the origin of the first heart field, second heart field, and proepicardial progenitors, each population of which is responsible for the development of different parts in the heart. Pax3+ neural crest cells are responsible for the development of vascular smooth muscle, outflow tract, valves and the conductive system. Progenitors are tagged with their specific markers. Created with BioRender.com. CPC: Cardiac progenitor cell; LT: Left; RT: Right; FHF: First heart field; SHF: Second heart field; OFT: Outflow tract.

The differentiation in the posterior SHF is regulated by Hoxb1 gene. Stimulation of Hoxb1 in embryonic stem cells (ESCs) halts cardiac differentiation, while Hoxb1-deficiency shows premature cardiac differentiation in embryos. Moreover, an atrioventricular septal defect develops as a result of ectopic differentiation in the posterior SHF of embryos deficient in Hoxb1 and its paralog Hoxa1[16].

Multiple signaling pathways have essential roles in cardiogenesis with a sequential arrangement. The transforming growth factor- (TGF-) superfamily, retinoic acid, Hedgehog, Notch, Wnt, and fibroblast growth factors (FGFs) pathways comprise the chief signaling pathways involved in cardiac development. These pathways, along with transcription factors and epigenetic regulators, regulate cardiac progenitors specification, proliferation, and differentiation into the different cardiac cell lineages[17].

The TGF- superfamily members consist of over 30 structurally associated polypeptide growth factors including nodal and bone morphogenetic proteins (BMP)[18].

Nodal signaling is vital for the formation of sinoatrial node. Nodal inhibition during the cardiac mesoderm differentiation stage downregulates PITX2c, a transcription factor recognized to inhibit the formation of the sinoatrial in the left atrium during cardiac development[19]. Moreover, nodal signaling is dispensable for initiation of heart looping; however, it regulates asymmetries that result in a helical shape at the heart tube poles[20].

BMP signaling, as a member of TGF-, has an important role in the different stages of heart development including the OFT formation, endocardium, and lastly the epicardium. The cardiac neural crest cells have a crucial role in normal cardiovascular development. They give rise to the vascular smooth muscle of the pharyngeal arch arteries, OFT septation, valvulogenesis, and development of the cardiac conduction system[21] (Figure ). The role of BMP in OFT septation mainly depends on their gradient signaling, which arranges neural crest cell aggregation along the OFT; this Dullard-mediated tuning of BMP signaling ensures the fine timed zipper-like closure of the OFT by the neural crest cells[22]. Furthermore, the BMP signaling promotes the development of endocardial cells (ECs) from hPSC-derived cardiovascular progenitors[23]. It is also integrated with Notch signaling for influencing the proepicardium formation, where overexpression of Notch intracellular receptor in the endothelium enhances BMP expression and increases the number of phospho-Smad1/5+ cells for enhancing the formation of the proepicardium[24].

Retinoic acid signaling plays a role in heart development. It is a key factor for efficient lateral mesoderm differentiation into atrial-like cells in a confined time frame. The structural, electrophysiological, and metabolic maturation of CMs are significantly influenced by retinoic acid[25]. However, it is reported that retinoic acid receptor agonists transiently enhance the proliferation of human CPCs at the expense of terminal cardiac differentiation[26].

The downregulation of the retinoic acid responsive gene, ripply transcriptional repressor 3 (RIPPLY3), within the SHF progenitors by histone deacetylase 1 is required during OFT formation[27].

Hedgehog signaling has a role in OFT morphogenesis. Lipoprotein-related protein 2 (LRP2) is a member of the LDL receptor gene family, a class of multifunctional endocytic receptors that play crucial roles in embryonic development. LRP2 is expressed in the anterior SHF cardiac progenitor niche, which leads to the elongation of the OFT during separation into aorta and pulmonary trunk. Loss of LRP2 in mutant mice results in depleting a pool of sonic hedgehog-dependent progenitor cells in the anterior SHF as they migrate into the OFT myocardium due to premature differentiation into CMs. This depletion results in aberrant shortening of the OFT[28].

Four Notch receptors (Notch1Notch4) and five structurally similar Notch ligands [Delta-like (DLL) 1, DLL3, DLL4, Jagged1, and Jagged2] have been detected in mammals[29]. Activation of Notch signaling enhances CM differentiation from human PSCs. However, the CMs derived from Notch-induced cardiac mesoderm are developmentally immature[30]. In vivo, the Notch pathway plays a significant role in CPC biology. An arterial-specific Notch ligand known as DLL4 is expressed by SHF progenitors at critical time-points in SHF biology. The DLL4-mediated Notch signaling is a crucial requirement for maintaining an adequate SHF progenitor pool, in a way that DLL4 knockout results in decreased proliferation and increased apoptosis. Reduced SHF progenitor pool leads to an underdeveloped OFT and right ventricle[31].

The Wnt signaling pathway has an essential role in many developmental stages of embryogenesis. The Wnt family consists of 19 distinct Wnt proteins and other 10 types of Frizzled receptors. On the basis of their primary functions, the Wnt and Frizzled receptors are divided into two major classes, which are the canonical and non-canonical Wnt pathways[32]. Accumulating evidence suggests a role for the dynamic balance between canonical and non-canonical Wnt signaling in cardiac formation and differentiation. Wnt/-catenin signaling is required for proper mesoderm formation and proliferation of CMs but needs to be low for terminal differentiation and cardiac specification. In contrast, for cardiac specification in murine and human ESCs, non-canonical -catenin independent Wnt signaling is essential, while the non-canonical Wnt signaling is necessary for terminal differentiation later in development[33].

The activation of non-canonical Wnt is non-catenin-independent, and the downstream proteins involve several kinases, including protein kinase C, calcium/ calmodulin-dependent kinase, and Jun N terminal kinase (JNK). Wnt11 enhances angiogenesis and improves cardiac function through non-canonical Wnt-protein kinase C-Jun N terminal kinase dependent pathways in myocardial infarction (MI)[34]. In hypoxia, Wnt11 expression preserves the integrity of mitochondrial membrane and facilitates the release of insulin growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF), thus protecting CMs against hypoxia[35]. Canonical dependent Wnt signaling, Wnt 3 Ligand, favors the pacemaker lineage, while its suppression promotes the chamber CM lineage[36].

The regenerative capacity of most organs is contingent on the adult SC populations that exist in their niches and are activated by injury. Adult SC populations vary greatly in their molecular marker expression profile and hence in their possible role in regenerative medicine. The transcriptome is a representation of the gene read-outs, the cellular state, and is imperative for studying all genetic disease and biological processes. The genome-wide profiling using novel sequencing technology has made transcriptome research accessible.

Receptor tyrosine kinase (RTK) c-KIT (also referred to as SC factor receptor or CD117)-expressing CPCs are mainly located in the atria and the ventricular apex, comprising most of the ventricular and atrial myocardium[37]. c-KIT+ cells also express the cardiac transcription factors NKx2.5, GATA binding protein 4 (GATA4), and MEF2C but are negative for the hematopoietic markers CD45, CD3, CD34, CD19, CD16, CD20, CD14, and CD56[38,39]. SC factor ligand attaches to the c-KIT receptor and activates the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and p38 mitogen-activated protein kinase (MAPK) signaling pathways[40]. Both PI3K/AKT and MAPK pathways control various CPCs functions like self-renewal, proliferation, migration, and survival[41]. During embryonic development and the early post-natal time, c-KIT+ CPCs contribute to the generation of new CMs. Such capacity declines in the adult heart with only a few new CMs originating from CPCs[42]. In a rat MI model, the c-KIT+ CPCs have migrated through the collagen type I and type III matrices into the infarcted area. The transplanted CPCs have shown overexpressed matrix metalloproteinases (MMPs; MMP2, MMP9, and MMP14) that degrade extracellular matrix (ECM), concluding that c-KIT+ CPCs hold an invasive capacity[43]. Transplanted CPCs (c-KIT+ CPCs and cardiospheres) also show an endogenous proliferative potential in vivo and additionally activate endogenous CPCs[44].

Stem cell antigen 1 (SCA-1) expressing CPC population exists predominantly in the atrium, intra-atrial septum, and atrium-ventricular boundary and dispersed inside the epicardial layer of adult hearts[45]. SCA-1 is a cell surface protein of the lymphocyte antigen-6 (Ly6) gene family, which has roles in cell survival, proliferation, and differentiation[46]. A population of SCA-1+ cells from murine adult myocardium hold a telomerase activity comparable to that of a neonatal heart. This SCA-1+ population is different from hematopoietic SCs as they lack CD45, CD34, c-KIT, LIM domain only 2, GATA2, VEGF receptor 1, and T-cell acute lymphoblastic leukemia 1/SC leukemia proteins. SCA-1+ cells are also distinct from endothelial progenitor cells and express cardiac lineage transcriptional factors such as GATA4, MEF2C, and translation elongation factor 1 yet lack transcripts for cardiomyocytic structural genes such as BMP1r1 and -, -MHC[47,48]. Although this population exhibits the endothelial marker CD31, it is suggested to be due to the contaminating endothelial CD31+/SCA-1+ cells. In vitro studies have revealed that 5-azacytidine (5-aza), a demethylating agent, pushed SCA-1+ cells to differentiate into CMs[48,49]. Further studies have isolated SCA-1+ cells that lack CD31 and CD45 markers, referring to them as lineage negative (Lin). The SCA-1+/Lin cells display a mesenchymal cell-surface profile (CD34, CD29+, CD90+, CD105+, and CD44+) and are able to differentiate, to a certain extent, into CMs and endothelial and smooth muscle-like cells[50,51].

Human SCA-1+-like cells also express early cardiac transcription factors (GATA4, MEF2C, insulin gene enhancer protein ISL-1, and Nkx-2.5) and can differentiate into contractile CMs[52]. Although a human ortholog of the SCA-1 protein has not been yet identified, an anti-mouse SCA-1 antibody is used to isolate SCA-1+-like cells from the adult human heart.

MESP1 expressing cells mainly contribute to the mesoderm and to the myocardium of the heart tube during development[53]. Transient expression of MESP1 seems to accelerate and enhance the appearance of cardiac progenitor. However, homologous disruption of the MESP1 gene has resulted in aberrant cardiac morphogenesis. MESP1 interacts with the promoter area of main cardiac transcription factors, including heart and neural crest derivatives expressed 2, Nkx2-5, myocardin, and GATA4[54]. These factors induce fibroblasts to express a full battery of cardiac genes, form sarcomeres, develop CM-like electrical activity, and in a few cases elicit beating activity[55]. Several studies have shown that the addition of MESP1 could enhance the efficacy of direct reprogramming of fibroblasts into CMs[56,57]. The transdifferentiation of fibroblasts to CMs via MESP1 suggests that MESP1 chiefly modulates the gene regulatory network for cardiogenesis[52].

Kinase insert domain receptor (KDR), also known as Flk-1, is one of the earliest discovered cardiogenic progenitor cell markers acting during the early stages of cardiac development in human[58]. Nelson et al[59] have reported that Flk-1 has a distinctive transcriptome that has been evident at day 6, immediately after gastrulation but prior to the expression of the cardiac transcription factors. KDR+ population lack the pluripotent octamer-binding transcription factor 4, sex determining region Y-Box transcription factor (SOX) 2, and endoderm SOX17 markers. On the other hand, KDR+ CPCs have shown a noteworthy upregulation in SOX7, a vasculogenic transcription factor, overlapping with the emergence of primordial cardiac transcription factors GATA4, myocardin, and NKx2.5. Moreover, KDR subpopulations that overexpress SOX7 are associated with a vascular phenotype rather than a cardiogenic phenotype. These outcomes offer insights for refining the therapeutic regenerative interventions.

The FHF cells express hyperpolarization activated cyclic nucleotide gated potassium channel 4 and TBX5, while SHF progenitors express TBX1, FGF 8, FGF10, and sine oculis homeobox2 (Figure ). Cells from the SHF exhibit high proliferative and migratory capacities and are mostly responsible for the elongation and winding of the heart tube. Moreover, SHF cells differentiate to CMs, SMCs, fibroblasts, and endothelial cells (ECs) along their journey in the heart tube to form the right ventricle, right ventricular OFT, and most of the atria[60,61]. However, FHF cells hold less proliferative and migratory potentials and differentiate predominantly to CMs that form the left ventricle and small parts of the atria[62]. The cells of the cardiac crescent, theoretically the progeny of FHF CPCs, are terminally differentiated cells expressing the markers of CMs, such as actin alpha cardiac muscle 1 and myosin light chain 7[63,64], hence they are unlikely to be multipotent progenitors. Therefore, it is difficult to identify FHF before Nkx2.5 and TBX5 expressions. Conversely, multipotent SHF CPCs were validated with a clonal tracing experiment and identified by ISL1 expression[65]. However, ISL1 expression is not specific for SHF and has been proposed to represent only the developmental stages[66]. Tampakakis et al[67] generated ESCs by using hyperpolarization activated cyclic nucleotide gated potassium channel 4-green fluorescent protein and TBX1-Cre; Rosa-red fluorescent protein reporters of the FHF and the SHF respectively, and also by using live immunostaining of the cell membrane CXCR4, a SHF marker and the reporters. The ESC-derived progenitor cells have shown functional properties and transcriptome similar to their in vivo equivalents. Thus, chamber-specific cardiac cells have been generated for modelling of heart diseases in vitro.

The EPDCs are important as a signaling source for heart development, cardiac regeneration, and post-MI heart repair. Throughout the development of the heart in mice, EPDCs aid in the formation of various cardiac cell types and secrete paracrine factors for myocardial maturation[68]. In the adult heart, EPDCs are normally dormant and become stimulated following myocardial injury. Transcriptional analysis of the EPDCs derived from human (h)iPSCs cells have revealed several markers of EPDCs including Wilms tumor protein 1, endoglin, thymus cell antigen 1, and aldehyde dehydrogenase 1 family member A2[69] (Figure ). Following MI in mice, EPDCs undergo an epithelial-to-mesenchymal transition, with overexpression of Wilms tumor protein 1, and differentiate mainly into SMCs/fibroblasts[70,71]. EPDC-secreted paracrine factors include VEGF-A, FGF2, and PDGF-C, which support the growth of blood vessels, protect the myocardium, and recover cardiac functions in an acute MI-mouse model[70].

Side population (SP) cells have been detected in the heart and other various tissues and hold enhanced stem and progenitor cell activity[72]. SP cells, when stained in vitro, hold the ability to flush out the DNA Hoechst dye from their nuclei[73]. Gene expression profiling of SP cells after MI has revealed a downregulation of Wnt-related signals coupled with increased SP cell proliferation. This has been validated in vitro by treatment of isolated SP cells with canonical Wnt agonists or recombinant Wnt, where the proliferation of SP cells has been repressed with partial arresting the G1 cell cycle phase[74]. Consistent with this observation, delivery of secreted Frizzled-related proteins (SFRP; the Wnt antagonizer) improves post-MI remodeling[75,76].

SP cells can be identified by surface marker adenosine triphosphate (ATP) binding cassette subfamily G member 2 (ABCG2), also referred to as the breast cancer resistance protein1[77]. ABCG2+ cells have been also observed in the adult heart and can differentiate in vitro into CMs[78]. When SP cells have been injected into the injured hearts of rats, they have been recruited to the injured regions, where they differentiate into CMs, ECs, and SMCs, suggesting that they may be endogenous SP cells[79]. However, ABCG2CreER based genetic lineage tracing has demonstrated that ABCG2+ cells could only differentiate into the multiple cardiac cell lineages during the embryonic stages but not in adulthood[80,81]. The combination of ABCG2+ cells with pre-existing CMs is more likely to stimulate CM proliferation rather than differentiation into CMs directly[82]. Therefore, genetic fate mapping investigations have disproved the SP cells property of the adult endogenous ABCG2+ SP and their in vivo renewing myogenic ability[83].

Cardiospheres contain a combination of stromal, mesenchymal, and progenitor cells that are isolated from cultures of human heart biopsy[39,84]. They represent a niche-like environment, with cardiac-committed cells in the center and supporting cells in the periphery of the spherical cluster[85]. The cardiosphere-derived cells (CDCs) were originally isolated from mouse heart explants and human ventricular biopsies based on their ability to form three-dimensional (3D) spheroids in suspension cultures[86]. CDCs have grabbed much attention due to their proliferation and differentiation abilities by inherent stimulation of cardio-specific differentiation factors [GATA4, MEF2C, Nkx2.5, heart and neural crest derivatives expressed 2, and cardiac troponin T (TNNT2)] using a clustered regularly interspaced short palindromic repeat/dead Cas9 (CRISPR/dCas9) assisted transcriptional enhancement system[87,88]. Sano et al[89] have postulated that the CRISPR/dCas9 system may provide a proficient method of modifying TNNT2 gene activation in SCs. Consequently, CRISPR/dCas9 can improve the therapeutic outcomes of patients with ischemic heart disease by enhancing the transplanted CDCs differentiation capacity within the ischemic myocardium. Heart tissue is usually obtained by endomyocardial biopsy or during open cardiac surgery and grown in explants to form CDCs. CDCs have shown a superior myogenic differentiation potential, angiogenesis, and paracrine factor secretion as compared to other cell types. In heart failure animal models, the injected CDCs potentially differentiated into CMs and vascular cells. Additionally, CDCs have diminished unfavorable remodeling and infarct size, and hence improve cardiac function[90]. Accordingly, cardiospheres and CDCs may be some of the most promising sources of CPCs for cardiac repair.

The niche in the heart integrates several heterogeneous cell types, including CSCs, progenitors, fibroblasts, SMCs, CMs, capillaries, and supporting telocytes (TCs)[91], together with the junctions and cementing ECM that hold the niche together. Such architectural arrangement is essential for protection against external damaging stimuli and for preserving the stemness of the CSCs (Figure ). Without the niche microenvironment, CSCs lose their stemness and initiate differentiation eventually, leading to the exhaustion of the CSC pool. Similarly, in vitro studies require feeder layers and cytokines supplements in the culture media to ensure that SCs remain in their undifferentiated state[37].

Invivo arrangement of the central cardiac stem cells and the surrounding cells that comprise the niche (right side) and the in vitro derived cardio spheres (left side). The key delineates the types of cells identified in the niche and cardio spheres. Created with BioRender. CSC: Cardiac stem cell.

In vitro studies have recapitulated the niche theory using cardiospheres, which are 20150 m spheres (Figure ) of cells generated from the explant outgrowth of heart tissues[92,93]. Cardiospheres consist of CSCs in the core and cells committed to the cardiac lineage such as myofibroblasts, while vascular SMCs and ECs form the outer layer of the spheres. The 3D structure of cardiospheres protects the interiorly located CSCs from oxidative stress as well as maintain their stemness and function[84].

Accurate anatomical identification of CSCs in vivo remains a challenge due to the lack of basal-apical anatomical orientation as seen in epithelial organs such as the intestines[94]. Moreover, the heart does not comprise a specific compartment, where cells form a well-defined lining as seen in the bone marrow osteoblasts[95]. The adult heart epicardial lining anatomically contains several classes of niches, which are not limited to the sub epicardium[96] but dispersed throughout the myocardium, more in the atria and apex away from hemodynamic stress[97]. Some niches have been described in the atrio-ventricular junction of adult mouse and rat hearts[98] and interestingly in the human hearts[99]. The young mouse heart has been studied morphometrically to identify the location of CSCs niche and has been defined as a randomly positioned ellipsoid structure consisting of cellular and extracellular components. Within the niches, undifferentiated CSCs are usually assembled together with early committed cells that express c-KIT on surface, Nkx2.5 in the nucleus, and the contractile protein -sarcomeric actin in the cytoplasmic[97].

CSCs niche consists of clusters of c-kit+, MDR1+, and Sca-1+ cells[98] but lack the expression of the transcription factors and cytoplasmic or membrane proteins of cardiac cells[99,100]. Cardiac c-kit+/CD45- cells comprise about 1% of the CSC niche[97], are self-renewing clonogenic, and possess a cardiac multilineage differentiation potential comprise[101].

Within the niche, gap junctions (connexins) and (cadherins) connect SCs to their supporting cells, myocytes/fibroblasts. Conversely, ECs and SMCs do not act as supporting cells. Hence, the communication between CSCs with CMs and fibroblasts has been investigated by using in vitro assays[102]. The transmission of dyes via gap junctions between CSCs and CMs or fibroblasts was demonstrated previously and verified the functional coupling of these three cell populations[97]. In addition, micro ribonucleic acid (miRNA-499) translocates from CMs to CSCs comprising to the initiation of lineage specification and formation of myocytes[103].

Identification of SC niches is contingent upon the fulfillment of explicit criteria, including the recognition and determination of the affixing of SCs to their supporting cells as well as assuring the existence of an ancestor-progeny association[104]. Chemical and physical signals modulate the behavior of SCs within the niche. Amongst these signals are cytokines, cell surface adhesion molecules, shear forces, oxygen tension, innervation, and ions that serve as major determinants of SCs function[97]. Cell-to-cell signaling mediates the fate of SCs within the niches to promote self-renewal and favors their migration and differentiation. The fine-tuned crosstalk between SCs and their supporting cells regulates the state of the niche regarding quiescence or activity[105].

CSC niches, similar to the bone marrow, characteristically live in low oxygen tension, which favors a quiescent primitive state for SCs[106]. The longstanding perpetuation of the CSC niche requires a hypoxic environment, while physiological normoxia could be required for active cardiomyogenesis[107]. Hypoxic c-KIT+ CSCs within niches have been found throughout the myocardium, especially at the atria and apex. Throughout all ages, bundles of CSCs with low oxygen content coexist with normoxic CSCs niches. Hypoxic CSCs, especially in the atria, are quiescent cells undergoing cell cycle arrest and cannot divide. Normoxic CSCs are pushed into intense proliferation and differentiation with continuous telomere erosion, resulting finally in dysfunctional aged CMs[108]. Additionally, Nkx2.5 and GATA4 expressions are only restricted to the normoxic CSC niche. A balance between the hypoxic and normoxic niche is essential for the preservation of the CSC compartment and for the maintenance of myocardial homeostasis during the organ lifespan. Some factors such as aging cause an imbalance by expanding the hypoxic quiescent CSCs so that less pools of cycling CSCs maintain cell turnover[100]. Hypoxic cardiac niches are abundant in the epicardium and subepicardium in an adult mouse heart, which also fosters a metabolically distinctive population of glycolytic progenitor cells[109].

The pool of CSCs seems to be heterogeneous, incorporating quiescent and actively proliferating cells, migratory and adherent cells, uncommitted and early committed cells, with young and senescent cells. Additional surface epitopes remain to be disclosed to classify pools of CSCs holding specific properties. Surface Notch1 expression distinguishes multipotent CSCs that are poised for lineage commitment, while c-Met and ephrin type-A receptor 2 receptors reveal cells with particular migratory potential out of the niche area. A specific compartment of CSCs, expressing IGF-1 receptor, can be stimulated to regenerate damaged myocardium, while those expressing IGF-2 receptor hold higher probability for senescence and apoptosis. Although this arrangement of cells seems to equip properly the CSC with homeostasis regulation, it does not effectively protect against aging or ischemic injury of the heart[100].

Circulatory angiogenic cells (CACs) are endothelial progenitor cells involved in vasculogenesis, angiogenesis, and stimulating myocardial repair, mainly through paracrine action. Latham et al[110] demonstrated that conditioned medium from CACCSC co-cultures exhibited greatly mobilized CACs, with induction of tubule formation in human umbilical vein endothelial cells, mainly through the upregulation of the angiogenic factors angiogenin, stromal cell-derived factor 1 (SDF-1), and VEGF. Moreover, administration of CACs and CSCs in infarcted hearts of non-obese/severe combined immunodeficient mice restored substantially the left ventricular ejection fraction (LVEF), with reduction of scar formation as revealed by echocardiography. Successful yet modest SMCs, ECs, and CM differentiation has been also reported.

Pericytes (also called Rouget cells, mural cells, or perivascular mesenchymal precursor cells) are mesodermal cells that border the endothelial lining. They are highly proliferative cells and express neural/glial antigen 2, SOX-2, PDGFR-, CD34, and several mesenchymal markers such as CD105, CD90, and CD44. It was previously reported that the transplantation of saphenous vein-derived pericytes (SVPs) into an ischemic limb of an immunodeficient mice restored the local circulatory network via angiogenesis[111]. Moreover, treatment with SVP reduced fibrotic scar, CM death, and vascular permeability in a mouse model of MI via miRNA-132 facilitated angiogenesis[112]. Avolio et al[113] were the first to describe the relationship between SVP and the endogenous CSCs. Combined CSC and SVP transplantation in the infarcted myocardium of severe combined immunodeficient/Beige-immunodeficient mice showed similar results to treatment with CSCs or SVP cells per se, regarding scar size and ventricular function, indicating that SVPs alone are as potent as CSCs.

TCs represent a recently described cell population in the stromal spaces located in many organs, including the heart. They are broadly dispersed throughout the heart and comprise a network in the three cardiac layers, heart valves, and in CSC niches. TCs have been documented also in primary culture from heart tissues[114,115]. The ratio of cardiac TCs (0.5%-1%) exceeds that of CSCs. Although they still represent a minute portion of human cardiac interstitial cells, their extremely long and extensive telopodes allow them to occupy more surface area, forming a 3D platform probably that extends to support other cells[116]. The telopodes act as tracks for the sliding of precursor cells towards mature CMs and their integration into heart architecture[91]. TCs form a tandem with CSCs/CPCs in niches, where they communicate through direct physical contact by atypical junctions or indirect paracrine signaling[115].

TC-CSC co-culturing have suggested that TCs and CSCs act synergistically to control the level of secreted proteins, as shown by the increased levels of monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein1 and 2 (MIP-1 and MIP-2), and interleukin (IL)-13. Whereas, the level of IL-2 decreased compared to the monoculture of CSCs or TCs. IL-6 found in TC culture is behind the upregulation of these chemokines. Chemokines elucidated the role of TCs in directing the formation of CMs. Within the context, MIP-1 and MCP-1 play roles in the formation of SMCs in the airway. Additionally, MCP-1 is also involved in mouse skeletal muscle regeneration by recruiting macrophages. The enhancement of MCP-1 secretion serves as an activator of another cell population, primarily macrophages, which are generally involved in such processes[117].

IL-6 also activates downstream signaling pathways and contributes to cardioprotection and vessel formation in the heart through activation of gp130/signal transducer and activator of transcription 3. The Gp130/signal transducer and activator of transcription 3 is essential for the commitment of cardiac SCA-1+ cells into endothelial lineage[118].

Furthermore, IL-6 targets VEGF and hepatocyte growth factor (HGF) genes. VEGF has a mitogenic effect on CMs[119]. It is known to mobilize bone marrow-derived mesenchymal stem cells (BM-MSCs) into the peripheral blood in MI patients[120]. HGF and its receptor (c-Met) are also involved in cardiogenesis, as it is expressed early during cardiac development[121]. The level of HGF mRNA is normally low in the heart, but it is upregulated for at least 14 d after ischemic insult in rats, enhancing CMs survival under ischemic conditions[122,123]. Moreover, it has the potential to generate an adhesive micro-environment for SCs, as demonstrated in a study of transplantation of HGF transfected BM-MSCs in the infarcted myocardium[124]. HGF is also a powerful angiogenic agent, conducting its mitogenic and morphogenic effects through the expression of its specific receptor in various types of cells, including myocytes. Moreover, HGF exerts antifibrotic and antiapoptotic effects on the myocardium[125,126].

Transcriptomic analysis also has disclosed that TCs express pro-angiogenic miRNAs including let-7e, miRNA-21, miRNA-27b, miRNA-126, miRNA-130, miRNA-143, miRNA-503, and miRNA-100[127]. The TCs and CSCs interact in vitro forming atypical junctions, such as puncta adherentia and stromal synapses. The puncta adherentia consists of cadherincatenin clusters. It controls the symmetry of division by facilitating the proper positioning of centrosomes. Therefore, an increased number of CSCs has been reported to be encountered in the presence of cardiac TCs[128,129].

The paracrine potential of CSCs/CPCs has been recently under focus. CSC-derived cytokines and growth factors include epidermal growth factor (EGF), HGF, IGF-1, IGF-2, IL-6, IL-1, and TGF-1[130,131]. Exosomes appear to harbor relevant reparative signals, which mechanistically underlie the beneficial effects of CSCs transplantation[132].

Structurally, exosomes are lipid bilayer nano-sized organelles, 20-150 nm in diameter, secreted from all cell types, and function as intercellular communicators. Exosomes are highly heterogenic in content, and this stems from the unique packaging process that occurs inside progenitor and SCs. Exosomes carry lipids, proteins, and nucleic acids, with an abundance of miRNAs that hold profound post-transcriptional gene regulatory effects[133].

Amongst the distinctive protein content of cardiac exosomes are the chaperone proteins heat shock protein (HSP) 70 and HSP60. The HSP70 and HSP60, which under normal conditions assist in protein folding processes and deter misfolding and protein aggregation under pathological states induced by stress, also play major roles in apoptosis[134]. Circulating exosomes from healthy individuals have been found to activate cardioprotective pathways in CMs via HSP70 through extracellular signal-regulated kinase and HSP27 phosphorylation[135].

The exosome protein cargo of CPCs is distinct from BM-MSCs, fibroblasts, and other sources as it contains ample amounts of the pregnancy-associated plasma protein-A (PAPP-A). PAPP-A is present on the surface of human exosomes and interacts with IGF binding proteins (IGFBPs) to release IGF-1[136]. The cardioprotective role of CPCs-exosomes has been proven experimentally in in vitro ischemia/reperfusion and MI models and on CMs apoptosis to surpass that of BM-MSC-exosomes owing to their rich content of PAPP-A[137].

Like all exosomes, mouse CPCs-derived exosomes are positive for the surface markers CD63, CD81, and CD9, TSG-101, and Alix, however, they express a high-level of GATA4-responsive-miRNA-451. MiRNA-451 has been shown to inhibit CM apoptosis in an acute mouse myocardial ischemia-reperfusion model through inhibition of the caspases 3/7. The expression of miRNA-21 in the mouse CPCs-exosomes additionally justifies their CM protection against oxidative stress and antiapoptotic effects via inhibition of programmed cell death protein 4 (PDCD4)[138]. Human CPCs-exosomes are enriched with miRNA-210, miRNA-132, and miRNA-146a-3p, which account for the diminished CM apoptosis, enhanced angiogenesis, and improved LVEF[139]. MiRNA-146a-5p is the most highly upregulated miRNA in human CPCs-exosomes and targets genes involved in inflammatory and cell death pathways[137].

The CDCs contain CD34+ stromal cells of cardiac origin and are multipotent and clonogenic but not self-renewing[140]. CDCs secrete exosomes that induce cardiomyogenesis and angiogenesis, regulate the immune response, downgrade fibrosis, and improve the overall cardiac function[141,142]. Moreover, CDCs homogeneously express CD105 but not CD45 or other hematopoietic markers. They also exhibit a high expression of miRNA-126[143]. Circulating miRNA-126 may participate in cardiac repair during acute MI and has been demonstrated to be downregulated in heart damage[144].

While exosomes are constitutively secreted, changes in the surrounding microenvironment, such as hypoxia, can induce modifications in CPCs- and CM- derived extracellular vesicles. Hypoxic CMs secrete large extracellular vesicles containing long noncoding RNA neat 1 (LNCRNA NEAT1), which is transcriptionally regulated under basal conditions by p53, while during hypoxia it is regulated by the hypoxia inducible factor 2A. An uptake of the hypoxic CM-derived extracellular vesicles by fibroblasts can prompt the expression of profibrotic genes[145]. Oxidative stress may also induce the release of cardiac CPCs exosomes, which in turn inhibit apoptosis when taken up by H9C2 (rat cardiomyoblast cell line)[132]. Furthermore, oxidative stress stimulates secretion of miRNA-21 rich exosomes, which could inhibit H9C2 apoptosis by targeting PDCD4 and hence can be accounted as a new method to treat ischemia-reperfusion[138].

Intercellular communication via exosomes occurs as part of various biological processes, including immune modulation, vasculogenesis, transport of genetic materials, and pathological conditions such as inflammation, apoptosis, and fibrosis, which can lead to cardiovascular disease when altered[146]. Hence, isolation and analysis of cardiac exosomes contents, mainly miRNA and proteins, could offer diagnostic information for several cardiovascular diseases[147] (Figure ).

Schematic diagram elucidating the diverse exosomal contents that serve as biomarkers for several cardiovascular diseases. Created with BioRender.com. HSP: Heat shock protein; lncRNA: Long non-coding RNA; miR: MicroRNA.

Functionally, exosomes mediate several intra-cardiac inter-cellular communications such as:

CPC-CM crosstalk through factors, such as miRNA-146a and PAPP-A, which activate extracellular signal-regulated kinases 1/2 pathway and inhibit apoptosis[139].

CPC-macrophage (M1) crosstalk via miRNA-181b and Y-RNA fragment transforms M1 to M2 macrophages with attenuated proinflammatory cytokines and increased IL-10[148,149] (Figure ).

Possible cardiac reparative effects of cardiac stem cell/cardiosphere-derived cell-derived exosomes in myocardial ischemia and ischemia/reperfusion injury. Created with BioRender.com. CSC: Cardiac stem cell; IL: Interleukin; IR: Ischemia/reperfusion; miRNA: MicroRNA; PI3K: Phosphoinositide 3-kinase; SDF-1: Stromal cell-derived factor 1; VEGF: Vascular endothelial growth factor.

CPC-fibroblast interaction via exosomes primes the fibroblasts and increases expression of VEGF and SDF-1. Experimental injection of fibroblasts primed with CPCs-exosomes into the myocardium of a MI model proved to reduce infarct size and improve cardiac function. In addition, cardiosphere-isolated exosomes have been used to prime inert fibroblasts, leading to an intensification of their angiogenic, cardiomyogenic, antifibrotic, and collective regenerative effects[150] (Figure ).

CPC-self regulatory mechanisms: Exosomes derived from CPCs may play critical roles in maintaining the self-renewal state of CPCs themselves and balance their differentiation, i.e. preserve their stemness[151] (Figure ). The CPC-derived exosomes activate the endogenous CPCs by transferring signal molecules directly within their niche[152].

CPC-derived exosomes release various RNA species in the extracellular space, modulating endogenous SC plasticity and tissue regeneration through their cytoprotective, immunomodulatory, pro-angiogenic, and anti-apoptotic actions[153].

Fibroblasts and pericytes interact after transdifferentiating to myofibroblasts and deposit ECM causing cardiac fibrosis. These fibrotic changes are usually induced by cardiac damage and lead to scar formation. Exosomes serve as messengers for cell-to-cell communication during cardiac fibrosis[154]. Molecular mechanisms of cardiac fibrosis are primarily related to TGF- pathways, IL-11 signaling pathway, nuclear factor- pathway, and Wnt pathways[155]. Accordingly, the bioactive substances targeted at these pathways could hypothetically be applied in the treatment of cardiac fibrosis. Wnt3a, being highly expressed in exosomes, could activate the Wnt/-catenin pathway in cardiac fibroblasts by restricting GSK3 activation[156]. Moreover, tumor necrosis factor contained in exosomes can be transferred between cardiac myocytes. In general activation/inhibition of the exosomes conveying remodeling substance secretion or uptake can control the myocardial remodeling and repair following MI[154,157].

The highlighted complex cell-to-cell communication from endogenous or exogenous CSCs provides an optimal microenvironment for resident CPC proliferation and differentiation (Figure ), rendering the environment receptive to transplanted CPCs. This adaptation is promoted through activation of pro-survival kinases, leading to the induction of a glycolytic switch in recipient CPCs[158].

Data from experimental models suggest that the exosomal component of the CPC secretome can fully recapitulate the effects of cellular therapy on ischemic and non-ischemic heart models[140]. In an ischemia-reperfusion injury rat model, Ciullo and partners[159] have shown that the systemic injection of exosomes (genetically manipulated to overexpress CXCR4ExoCXCR4) improve cardiac function. Additionally, expression of hypoxia-inducible factor 1 (HIF-1) in the infarcted myocardium is upregulated through the stimulation of SDF-1. The latter is one of the CXC chemokine family overexpressed in heart post-MI that readily attaches to the CXCR4 receptor and acts as a potent chemoattractant for CXCR4 expressing circulating progenitor cells. The ExoCXCR4 are more bioactive in the infarcted zone than naturally occurring exosomes injected via tail-vein, confirming their superior homing and cardioprotective properties in the damaged heart.

Gallet et al[160] postulated the safety and efficiency of CDC-derived exosomes in acute and chronic myocardial injury animal models. Within the context of experimental research to validate the paracrine hypothesis for CDCsderived exosomes, it has been proven that human CDC-exosomes can recapitulate CDC therapy and boost cardiac function post-MI in pig models. Intramyocardial injection of human CDC-exosomes has resulted in higher exosome retention and efficacy as compared to intracoronary injection, with great reduction of scar size and increased ejection fraction. This indicates that the route of administration is imperative for full functional capacity of the exosomes. Subsequently, the researchers have devised a randomized preclinical study by means of a NOGA-guided intramyocardial exosome injection. Decreased collagen content in the infarct and border zone and increased neovascularization and Ki67+ CMs are indicative of the reparative functions of CDC-exosomes. Notably, human CDC-exosomes have shown a lack of an immune reaction, as seen by the lack of inflammatory reactions or CM necrosis in pig models. These observations strongly support the view that CDC-exosomes are ready to be tested in clinical trials.

Similar promising outcomes were observed in a Duchenne muscular dystrophy model (mdx), in which intramyocardial injection of CDC-exosomes efficiently recapitulated the effects of CDC injection on cardiac function, leading to recovery of movement. Administration of CPC-derived exosomes has resulted in transient restoration of partial expression of full-length dystrophin in mdx mice[161]. Further studies assessed the therapeutic potential of CPC-exosomes in a doxorubicin cardiotoxicity model and non-ischemic heart disease[162]. In addition, two concluded phase I clinical trials in patients with heart failure and revealed the capacity of CDCs to enhance cardiac function by reducing ventricular remodeling and scar formation. Despite receiving a single injection at the beginning of the study, the improvement in cardiac function was noted after the 1-year follow-up. This finding consequently leads to the proposition that transplanted CDCs mainly have imposed their actions at the site of injury by secreting paracrine factors including exosomes. In other words, CDC-exosomes achieved a biphasic beneficiary regenerative effect involving acute cardio protection coupled with long-term stimulation of endogenous cardiac repair[163].

While the fetal heart obtains most of its ATP supply via glycolysis[164], the adult heart relies mainly on fatty acid oxidation to fulfill the contracting myocardium high energy demand[164,165]. The loss of the regenerative phenotype is related to the oxidative metabolism of glucose and fatty acids[166,167] and is mediated by various physiological changes including increased workload and the demand for growth, which cannot be solely met by glycolysis[168,169], as well as postnatal increase in both circulating levels of free fatty acids and blood oxygen levels[164,165]. Studies have shown the involvement of the HIF-1 signaling pathway[170], peroxisome proliferator-activated receptor (PPAR)[171], and peroxisome proliferator-activated receptor coactivator-1 (PGC-1) in the switch toward oxidative metabolism[172], which is accompanied by dramatic increase in the number of mitochondria in CMs[173].

Notably, similar metabolic reprogramming occurs during differentiation from cardiac SCs to CMs[167]. Studies reported that after differentiation into CMs, there is an increase in the mitochondrial number and activity[174], increased oxidative metabolism[175], and increased respiratory capacity resulting in an increased adenosine diphosphate:ATP ratio[173] after differentiation into CMs.

The fact of the various metabolic changes that accompany the transition from glycolysis to fatty acids oxidation affect cardiac cell maturation[164,167] has mandated the consideration of substrate composition in cardiac differentiation protocols[167].

A study by Malandraki-Miller et al[176] investigated the effect of fatty acid supplementation, which mimics the metabolic switch from glucose to fatty acid oxidation, on adult cardiac progenitors. The study used radiolabeled substrate consumption for metabolic flux to investigate the role of the PPAR/PGC-1 axis during metabolic maturation. Oleic acid stimulated the PPAR pathway, enhanced the maturation of the cardiac progenitor, and increased the expression of MHC and connexin after differentiation. Moreover, total glycolytic metabolism, mitochondrial membrane potential, the expression of glucose, and fatty acid transporter increased. The recorded results contributed greatly in highlighting the role of fatty acids and PPAR in CPC differentiation.

Another study by Correia et al[177] has linked substrate utilization and functional maturation of CMs via studying the effect of the metabolic shift from glucose to galactose and fatty acid-containing medium in the maturation of hPSCs-derived CMs (hPSCs-CMs). The shift accelerated hPSC-CM maturation into adult-like CMs with higher oxidative metabolism, mature transcriptional signatures, higher myofibril density, improved calcium influx, and enhanced contractility. Galactose improved total oxidative capacity with reduction of fatty acid oxidation, thereby protecting the cells from lipotoxicity.

In CDCs, oxidative metabolism and cell differentiation reciprocally affect each other. In vitro cultures for CDCs revealed a PPAR agonist that triggers fatty acid oxidation. Metabolic changes have been characterized as the CDC differentiated towards a cardiac phenotype. Addition of a PPAR agonist at the onset of differentiation has induced a switch towards oxidative metabolism, as shown by changes in gene expression with decreasing glycolytic flux and increasing oxidation of glucose and palmitate. Undifferentiated CDCs have generated high levels of ATP from glycolysis and from oxidation of acetoacetate. Upon differentiation, oxidative metabolism of glucose and fatty acids is upregulated with decreased oxidation of acetoacetate, a metabolic phenotype similar to that of the adult heart[178].

Taken together, the metabolic hallmarks of differentiated CMs vary from their undifferentiated SCs. Energy substrate metabolism during cardiac development and differentiation shows gradual decrease in the contribution of glycolysis to ATP synthesis with simultaneous increase in fatty aciddependent mitochondrial respiration[179].

Common methods for the investigation of substrate metabolism include the measurement of metabolic fluxes using radio-labeled substrates, such as D-U-14C-glucose[180,181] as well as measurement of mitochondrial oxygen consumption rate and extracellular acidification rate using the XF Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA, United States)[182,183].

Recently, a detailed protocol for metabolic characterization of hiPSCs-CMs has been developed. The hiPSCs are obtained from adult somatic cells via novel cell reprogramming approaches, followed by differentiation to CMs. The novel in vitro cardiac cellular model provided new insights into studying cardiac disease mechanisms and therapeutic potentials. The characterization protocol measures small metabolites and combines gas- and liquid-chromatography-mass spectrometry metabolic profiling, lactate/pyruvate, and glucose uptake assays as important tools[184]. Integration between the implemented assays has provided complementary metabolic characteristics besides the already established electrophysiological and imaging techniques, such as monitoring ion channel activities[185], measurement of action potentials, changes in Ca+2 fluxes[186], and mitochondria viability and apoptosis[187].

An alternative pathway for glucose metabolism in CMs involves the entry of glucose-6-phosphate (G6P) in the pentose phosphate pathway, with resultant generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH)[188]. Reduced NADPH helps to regenerate reduced glutathione and thus acts protectively against reactive oxygen species induced cell injury.

The cardioprotective role of the pentose/G6P/NADPH/glutathione pathway has been emphasized by Jain et al[189] who demonstrated that G6P dehydrogenase (G6PD) lacking mice have more severe heart damage induced by the myocardial ischemia reperfusion injury in Langendorff-perfused hearts as compared with wild-type mice.

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Cardiac stem cells: Current knowledge and future prospects

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Stem cell therapies in cardiac diseases: Current status and future …

By daniellenierenberg

Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.

Keywords: Cardiac stem cell; Cardiovascular diseases; Cell therapy; Pluripotent stem cells; Progenitor cardiac cells; Stem cell.

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Stem cell therapies in cardiac diseases: Current status and future ...

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Stem Cell and Regenerative Biology | Johns Hopkins Heart and Vascular …

By daniellenierenberg

The limited regenerative capacity of the heart is a major factor in heart failure and death. Once cardiac cells are diseased, its hard for them to heal like your body would with a cut. Studying how the heart forms in fetuses and then matures is a natural step for researchers interested in generating and regenerating heart cells. Theyre also investigating the effect of stem cell-derived cardiac cells on repairing damaged hearts and their potential to treat heart muscle diseases.

Cardiovascular progenitor cells (CPCs), a type of heart cell, are called building blocks because theyre used to form the heart during fetal development. They hold tremendous therapeutic potential because of their unique ability to develop into several different heart cell types. Researchers are studying how CPC cells can renew themselves in mice. Theyre studying whether this renewal also occurs in humans and whether this is useful for repairing damaged hearts.

Because CPCs regenerate, scientists may be able to grow them in a dish. Its not as easy to grow cells in a lab as it is in the body they often have developmental arrest and dont mature. However, a recent discovery of the pathways that lead a fetal cell into an adult cell will enable researchers to recreate adult heart tissue in the lab, which holds tremendous potential for new heart disease treatment.

Videos Heart tissue grown in a dish

Heart tissue grown in a dish from mouse cardiac progenitor cells (CPCs). The CPCs, and the tissue they built, were engineered to produce a red protein.

View labs and centersAdult Cardiac Catheterization LabCiccarone CenterChulan Kwon LabHeart and Vascular InstituteCardiovascular Stem Cell Program

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Stem Cell and Regenerative Biology | Johns Hopkins Heart and Vascular ...

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Skeletal Muscle Cell Induction from Pluripotent Stem Cells

By daniellenierenberg

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into various types of cells including skeletal muscle cells. The approach of converting ESCs/iPSCs into skeletal muscle cells offers hope for patients afflicted with the skeletal muscle diseases such as the Duchenne muscular dystrophy (DMD). Patient-derived iPSCs are an especially ideal cell source to obtain an unlimited number of myogenic cells that escape immune rejection after engraftment. Currently, there are several approaches to induce differentiation of ESCs and iPSCs to skeletal muscle. A key to the generation of skeletal muscle cells from ESCs/iPSCs is the mimicking of embryonic mesodermal induction followed by myogenic induction. Thus, current approaches of skeletal muscle cell induction of ESCs/iPSCs utilize techniques including overexpression of myogenic transcription factors such as MyoD or Pax3, using small molecules to induce mesodermal cells followed by myogenic progenitor cells, and utilizing epigenetic myogenic memory existing in muscle cell-derived iPSCs. This review summarizes the current methods used in myogenic differentiation and highlights areas of recent improvement.

Duchenne muscular dystrophy (DMD) is a genetic disease affecting approximately 1 in 3500 male live births [1]. It results in progressive degeneration of skeletal muscle causing complete paralysis, respiratory and cardiac complications, and ultimately death. Normal symptoms include the delay of motor milestones including the ability to sit and stand independently. DMD is caused by an absence of functional dystrophin protein and skeletal muscle stem cells, as well as the exhaustion of satellite cells following many rounds of muscle degeneration and regeneration [2]. The dystrophin gene is primarily responsible for connecting and maintaining the stability of the cytoskeleton of muscle fibers during contraction and relaxation. Despite the low frequency of occurrence, this disease is incurable and will cause debilitation of the muscle and eventual death in 20 to 30 year olds with recessive X-linked form of muscular dystrophy. Although there are no current treatments developed for DMD, there are several experimental therapies such as stem cell therapies.

Skeletal muscle is known to be a regenerative tissue in the body. This muscle regeneration is mediated by muscle satellite cells, a stem cell population for skeletal muscle [3, 4]. Although satellite cells exhibit some multipotential differentiation capabilities [5], their primary differentiation fate is skeletal muscle cells in normal muscle regeneration. Ex vivo expanded satellite cell-derived myoblasts can be integrated into muscle fibers following injection into damaged muscle, acting as a proof-of-concept of myoblast-mediated cell therapy for muscular dystrophies [69]. However, severe limitations exist in relation to human therapy. The number of available satellite cells or myoblasts from human biopsies is limited. In addition, the poor cell survival and low contribution of transplanted cells have hindered practical application in patients [6, 8, 9]. Human-induced pluripotent stem cells (hiPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem cell- (ESC-) like state by being forced to express genes and factors important for maintaining the defining properties of ESCs. hiPSCs can be generated from a wide variety of somatic cells [10, 11]. They have the ability to self-renew and successfully turn into any type of cells. With their ability to capture genetic diversity of DMD in an accessible culture system, hiPSCs represent an attractive source for generating myogenic cells for drug screening.

The ESC/iPSC differentiation follows the steps of embryonic development. The origin of skeletal muscle precursor cells comes from the mesodermal lineage, which give rise to skeletal muscle, cardiac muscle, bone, and blood cells. Mesoderm subsequently undergoes unsegmented presomitic mesoderm followed by segmented compartments termed somites from anterior to caudal direction. Dermomyotome is an epithelial cell layer making up the dorsal part of the somite underneath the ectoderm. Dermomyotome expresses Pax3 and Pax7 and gives rise to dermis, skeletal muscle cells, endothelial cells, and vascular smooth muscle [12]. Dermomyotome also serves as a tissue for secreted signaling molecules to the neural tube, notochord, and sclerotome [13, 14]. Upon signals from the neural tube and notochord, the dorsomedial lip of dermomyotome initiates and expresses skeletal muscle-specific transcription factors such as MyoD and Myf5 to differentiate into myogenic cells termed myoblasts. Myoblasts then migrate beneath the dermomyotome to form myotome. Eventually, these myoblasts fuse with each other to form embryonic muscle fibers. ESCs/iPSCs mimic these steps toward differentiation of skeletal muscle cells. Many studies utilize methods of overexpression of muscle-related transcription factors such as MyoD or Pax3 [15], or the addition of small molecules which activate or inhibit myogenic signaling during development. Several studies show that iPSCs retain a bias to form their cell type of origin due to an epigenetic memory [1619], although other papers indicate that such epigenetic memory is erased during the reprogramming processes [2022]. Therefore, this phenomenon is not completely understood at the moment. In light of these developments, we have recently established mouse myoblast-derived iPSCs capable of unlimited expansion [23]. Our data demonstrates that these iPSCs show higher myogenic differentiation potential compared to fibroblast-derived iPSCs. Thus, myogenic precursor cells generated from human myoblast-derived iPSCs expanded ex vivo should provide an attractive cell source for DMD therapy. However, since DMD is a systemic muscle disease, systemic delivery of myoblasts needs to be established for efficient cell-based therapy.

During developmental myogenesis, presomitic mesoderm is first formed by Mesogenin1 upregulation, which is a master regulator of presomitic mesoderm [24]. Then, the paired box transcription factor Pax3 gene begins to be expressed from presomitic mesoderm to dermomyotome [25]. Following Pax3 expression, Pax7 is also expressed in the dermomyotome [26], and then Myf5 and MyoD, skeletal muscle-specific transcription factor genes, begin to be expressed in the dorsomedial lip of the dermomyotome in order to give rise to myoblasts which migrate beneath the dermomyotome to form the myotome. Subsequently, Mrf4 and Myogenin, other skeletal muscle-specific transcription factor genes, followed by skeletal muscle structural genes such as myosin heavy chain (MyHC), are expressed in the myotome for myogenic terminal differentiation (Figure 1) [27, 28]. Pax3 directly and indirectly regulates Myf5 expression in order to induce myotomal cells. Dorsal neural tube-derived Wnt proteins and floor plate cells in neural tube and notochord-derived sonic hedgehog (Shh) positively regulate myotome formation [13, 29]. Neural crest cells migrating from dorsal neural tubes are also involved in myotome formation: Migrating neural crest cells come across the dorsomedial lip of the dermomyotome, and neural crest cell-expressing Delta1 is transiently able to activate Notch1 in the dermomyotome, resulting in conversion of Pax3/7(+) myogenic progenitor cells into MyoD/Myf5(+) myotomal myoblasts [30, 31]. By contrast, bone morphogenetic proteins (BMPs) secreted from lateral plate mesoderm are a negative regulator for the myotome formation by maintaining Pax3/Pax7(+) myogenic progenitor cells [29, 32]. Pax3 also regulates cell migration of myogenic progenitor cells from ventrolateral lip of dermomyotome to the limb bud [33]. Pax3 mutant mice lack limb muscle but trunk muscle development is relatively normal [34]. Pax3/Pax7 double knockout mice display failed generation of myogenic cells, suggesting that Pax3 and Pax7 are critical for proper embryonic myogenesis [35]. Therefore, both Pax3 and Pax7 are also considered master transcription factors for the specification of myogenic progenitor cells. Importantly, MyoD was identified as the first master transcription factor for myogenic specification since MyoD is directly able to reprogram nonmuscle cell type to myogenic lineage when overexpressed [3638]. In addition, genetic ablation of MyoD family gene(s) via a homologous gene recombination technique causes severe myogenic developmental or regeneration defects [3945]. Finally, genetic ablation of combinatory MyoD family genes demonstrates that MyoD/:Myf5/:MRF4/ mice do not form any skeletal muscle during embryogenesis, indicating the essential roles in skeletal muscle development of MyoD family genes [28, 46]. It was proven that Pax3 also possesses myogenic specification capability since ectopic expression of Pax3 is sufficient to induce myogenic programs in both paraxial and lateral plate mesoderm as well as in the neural tube during chicken embryogenesis [47]. In addition, genetic ablation of Pax3 and Myf5 display complete defects of body skeletal muscle formation during mouse embryogenesis [48]. Finally, overexpression of Pax7 can convert CD45(+)Sca-1(+) hematopoietic cells into skeletal muscle cells [49]. From these notions, overexpression of myogenic master transcription factors such as MyoD or Pax3 has become the major strategy for myogenic induction in nonmuscle cells, including ES/iPSCs.

The overexpression of MyoD approach to induce myogenic cells from mESCs was first described by Dekel et al. in 1992. This has been a standard approach for the myogenic induction from pluripotent stem cells (Table 1). Ozasa et al. first utilized Tet-Off systems for MyoD overexpression in mESCs and showed desmin(+) and MyHC(+) myotubes in vitro [50]. Warren et al. transfected synthetic MyoD mRNA in to hiPSCs for 3 days, which resulted in myogenic differentiation (around 40%) with expression of myogenin and MyHC [51]. Tanaka et al. utilized a PiggyBac transposon system to overexpress MyoD in hiPSCs. The PiggyBac transposon system allows cDNAs to stably integrate into the genome for efficient gene expression. After integration, around 70 to 90% of myogenic cells were induced in hiPSC cultures within 5 days [52]. This study also utilized Miyoshi myopathy patient-derived hiPSCs for the MyoD-mediated myogenic differentiation. Miyoshi myopathy is a congenital distal myopathy caused by defective muscle membrane repair due to mutations in dysferlin gene. The patient-derived hiPSC-myogenic cells will be able to provide the opportunity for therapeutic drug screening. Abujarour et al. also established a model of patient-derived skeletal muscle cells which express NCAM, myogenin, and MyHC by doxycycline-inducible overexpression of MyoD in DMD patient-derived hiPSCs [53]. Interestingly, MyoD-induced iPSCs also showed suppression of pluripotent genes such as Nanog and a transient increase in the gene expression levels of T (Brachyury T), Pax3, and Pax7, which belong to paraxial mesodermal/myogenic progenitor genes, upstream genes of myogenesis. It is possible that low levels of MyoD activity in hiPSCs may initially suppress their pluripotent state while failing to induce myogenic programs, which may result in transient paraxial mesodermal induction. Supporting this idea, BAF60C, a SWI/SNF component that is involved in chromatin remodeling and binds to MyoD, is required to induce full myogenic program in MyoD-overexpressing hESCs [54]. Overexpression of MyoD alone in hESC can only induce some paraxial mesodermal genes such as Brachyury T, mesogenin, and Mesp1 but not myogenic genes. Co-overexpression of MyoD and BAF60C was now able to induce myogenic program but not paraxial mesodermal gene expression, indicating that there are different epigenetic landscapes between pluripotent ESCs/iPSCs and differentiating ESC/iPSCs in which MyoD is more accessible to DNA targets than those in pluripotent cells. The authors then argued that without specific chromatin modifiers, only committed cells give rise to myogenic cells by MyoD. These results strongly indicate that nuclear landscapes are important for cell homogeneity for the specific cell differentiation in ESC/iPSC cultures. Similar observations were seen in overexpression of MyoD in P19 embryonal carcinoma stem cells, which can induce paraxial mesodermal genes including Meox1, Pax3, Pax7, Six1, and Eya2 followed by muscle-specific genes. However, these MyoD-induced paraxial mesodermal genes were mediated by direct MyoD binding to their regulatory regions, which was proven by chromatin immunoprecipitation (ChIP) assays, indicating the novel role for MyoD in paraxial mesodermal cell induction [55].

hESCs/iPSCs have been differentiated into myofibers by overexpression of MyoD, and this method is considered an excellent in vitro model for human skeletal muscle diseases for muscle functional tests, therapeutic drug screening, and genetic corrections such as exon skipping and DNA editing. Shoji et al. have shown that DMD patient-derived iPSCs were used for myogenic differentiation via PiggyBac-mediated MyoD overexpression. These myogenic cells were treated with morpholinos for exon-skipping strategies for dystrophin gene correction and showed muscle functional improvement [56]. Li et al. have shown that patient-derived hiPSC gene correction by TALEN and CRISPR-Cas9 systems, and these genetically corrected hiPSCs were used for myogenic differentiation via overexpression of MyoD [57]. This work also revealed that the TALEN and CRISPR-Cas9-mediated exon 44 knock-in approach in the dystrophin gene has high efficiency in gene-editing methods for DMD patient-derived cells in which the exon 44 is missing in the genome.

Along this line of the strategy, Darabi et al. first performed overexpression of Pax3 gene, which can be activated by treatment with doxycycline in mESCs, and showed efficient induction of MyoD/Myf5(+) skeletal myoblasts in EB cultures [15]. Upon removing doxycycline, these myogenic cells underwent MyHC(+) myotubes. However, teratoma formation was observed after EB cell transplantation into cardiotoxin-injured regenerating skeletal muscle in Rag2/:C/ immunodeficient mice [15]. This indicates that myogenic cell cultures induced by Pax3 in mESCs still contain some undifferentiated cells which gave rise to teratomas. To overcome this problem, the same authors separated paraxial mesodermal cells from Pax3-induced EB cells by FACS using antibodies against cell surface markers as PDGFR(+)Flk-1() cell populations. After cell sorting, isolated Pax3-induced paraxial mesodermal cells were successfully engrafted and contributed to regenerating muscle in mdx:Rag2/:C/ DMD model immunodeficient mice without any teratoma formations. Darabi et al. also showed successful myogenic induction in mESCs and hES/iPSCs by overexpression of Pax7 [58, 59]. Pax3 and Pax7 are not only expressed in myogenic progenitor cells. They are also expressed in neural tube and neural crest cell-derived cells including a part of cardiac cell types in developmental stage, suggesting that further purification to skeletal muscle cell lineage is crucial for therapeutic applications for muscle diseases including DMD.

Taken together, overexpression of myogenic master transcription factors such as MyoD or Pax3/Pax7 is an excellent strategy for myogenic induction in hESCs and hiPSCs, which can be utilized for in vitro muscle disease models for their functional test and drug screening. However, for the safe stem cell therapy, it is essential to maintain the good cellular and genetic qualities of hESC/hiPSC-derived myogenic cells before transplantation. Therefore, random integration sites of overexpression vectors for myogenic master transcription factors and inappropriate expression control of these transgenes may diminish the safety of using these induced myogenic cells for therapeutic stem cell transplantation.

Stepwise induction protocols utilizing small molecules and growth factors have been established as alternative myogenic induction approaches and a more applicable method for therapeutic situations. As described above, during embryonic myogenesis, somites and dermomyotomes receive secreted signals such as Wnts, Notch ligands, Shh, FGF, BMP, and retinoic acid (RA) with morphogen gradients from surrounding tissues in order to induce the formation of myogenic cells (Figure 2). The canonical Wnt signaling pathway has been shown to play essential roles in the development of myogenesis. In mouse embryogenesis, Wnt1 and Wnt3a secreted from the dorsal neural tube can promote myogenic differentiation of dorsomedial dermomyotome via activation of Myf5 [31, 32, 60]. Wnt3a is able to stabilize -catenin which associates with TCF/LEF transcription factors that bind to the enhancer region of Myf5 during myogenesis [61]. Other Wnt proteins, Wnt6 and Wnt7a, which emerge from the surface ectoderm, induce MyoD [62]. BMP functions as an inhibitor of myogenesis by suppression of some myogenic gene expressions. In the lateral mesoderm, BMP4 is able to increase Pax3 expression which delays Myf5 expression in order to maintain an undifferentiated myogenic progenitor state [63]. Therefore, Wnts and BMPs regulate myogenic development by antagonizing each other for myogenic transcription factor gene expression [64, 65]. Wnt also induces Noggin expression to antagonize BMP signals in the dorsomedial lip of the dermomyotome [66]. In this region, MyoD expression level is increased, which causes myotome formation. Notch signaling plays essential roles for cell-cell communication to specify the different cells in developmental stages. During myotome formation, Notch is expressed in dermomyotome, and Notch1 and Notch2 are expressed in dorsomedial lip of dermomyotome. Delta1, a Notch ligand, is expressed in neural crest cells which transiently interact with myogenic progenitor cells in dorsomedial lip of dermomyotome via Notch1 and 2. This contact induces expression of the Myf5 or MyoD gene in the myogenic progenitor cells followed by myotome formation. The loss of function of Delta1 in the neural crest displays delaying skeletal muscle formation [67]. Knockdown of Notch genes or use of a dominant-negative form of mastermind, a Notch transcriptional coactivator, clearly shows dramatically decrease of Myf5 and MyHC(+) myogenic cells. Interestingly, induction of Notch intracellular domain (NICD), a constitutive active form of Notch, can promote myogenesis, while continuous expression of NICD prevents terminal differentiation. Taken together, transient and timely activation of Notch is crucial for myotome formation from dermomyotome [30].

Current studies for myogenic differentiation of ESCs/iPSCs have utilized supplementation with some growth factors and small molecules, which would mimic the myogenic development described above in combination with embryoid body (EB) aggregation and FACS separation of mesodermal cells (Table 2). To induce paraxial mesoderm cells from mESCs, Sakurai et al. utilized BMP4 in serum-free cultures [68]. Three days after treatment with BMP4, mESCs could be differentiated into primitive streak mesodermal-like cells, but the continuous treatment with BMP4 turned the ESCs into osteogenic cells. Therefore, they used LiCl after treatment with BMP4 to enhance Wnt signaling, which is able to induce myogenic differentiation. After treatment with LiCl, PDGFR(+) E-cadherin() paraxial mesodermal cells were sorted by FACS. These sorted cells were cultured with IGF, HGF, and FGF for two weeks in order to induce myogenic differentiation. Hwang et al. have shown that treatment with Wnt3a efficiently promotes skeletal muscle differentiation of hESCs [69]. hESCs were cultured to form EB for 9 days followed by differentiation of EBs for additional 7 days, and then PDGFR(+) cells were sorted by FACS. These PDGFR(+) cells were cultured with Wnt3a for additional 14 days. Consequently, these Wnt3a-treated cells display significantly increased myogenic transcription factors and structural proteins at both mRNA and protein levels. An interesting approach to identify key molecules that induce myogenic cells was reported by Xu et al. [70]. They utilized reporter systems in zebrafish embryos to display myogenic progenitor cell induction and myogenic differentiation in order to identify small compounds for myogenic induction. Myf5-GFP marks myogenic progenitor cells, while myosin light polypeptide 2 (mylz2)-mCherry marks terminally differentiated muscle cells. They found that a mixed cocktail containing GSK3 inhibitor, bFGF, and forskolin has the potential to induce robust myogenic induction in hiPSCs. GSK3 inhibitors act as a canonical Wnt signaling activator via stabilizing -catenin protein, which is crucial for inducing mesodermal cells. Forskolin activates adenylyl cyclase, which then stimulates cAMP signaling. cAMP response element-binding protein (CREB) is able to stimulate cell proliferation of primary myoblasts in vitro, suggesting that the forskolin-cAMP-CREB pathway may help myogenic cell expansion [71], However the precise mechanisms for CREB-mediated myogenic cell expansion remain unclear. The adenylyl cyclase signaling cascade leads to CREB activation [71]. During embryogenesis, phosphorylated CREB has been found at dorsal somite and dermomyotome. CREB gene knockout mice display significantly decreased Myf5 and MyoD expressions in myotomes. While activation of Wnt1 or Wnt7a promotes Pax3, Myf5, and MyoD expressions, inhibition of CREB eliminates these Wnt-mediated myogenic gene expressions without altering the Wnt canonical pathway, suggesting that CREB-induced myogenic activation may be mediated through noncanonical Wnt pathways. Several groups also utilized GSK3 inhibitors for inducing mesodermal cells from ESCs and iPSCs [72, 73]. These mesodermal cell-like cells were expanded by treatment with bFGF, and then ITS (insulin/transferrin/selenite) or N2 medium were used to induce myogenic differentiation. Finally, bFGF is a stimulator for myogenic cell proliferation. Caron et al. demonstrated that hESCs treated with GSK3 inhibitor, ascorbic acid, Alk5 inhibitor, dexamethasone, EGF, and insulin generated around 80% of Pax3(+) myogenic precursor cells in 10 days [74]. Treatment with SB431542, an inhibitor of Alk4, 5, and 7, PDGF, bFGF, oncostatin, and IGF was able to induce these Pax3(+) myogenic precursor cells into around 5060% of MyoD(+) myoblasts in an additional 8 days. For the final step, treatment with insulin, necrosulfonamide, an inhibitor of necrosis, oncostatin, and ascorbic acid was able to induce these myoblasts into myotubes in an additional 8 days. Importantly, the same authors utilized ESCs from human facioscapulohumeral muscular dystrophy (FSHD) to demonstrate the myogenic characterization after myogenic induction by using the protocol described above. Hosoyama et al. have shown that hESCs/iPSCs with high concentrations of bFGF and EGF in combination with cell aggregation, termed EZ spheres, efficiently give rise to myogenic cells [75]. After 6-week culture, around 4050% of cells expressed Pax7, MyoD, or myogenin. However, the authors also showed that EZ spheres included around 30% of Tuj1(+) neural cells. Therefore, the authors discussed the utilization of molecules for activation of mesodermal and myogenic signaling pathways such as BMPs and Wnts.

Taken together, it is likely that the induced cell populations from ESCs/iPSCs may contain other cell types such as neural cells or cardiac cells because neural cells share similar transcription factor gene expression with myogenic cells such as Pax3, and cardiac cells also develop from mesodermal cells. To overcome this limitation, Chal et al. treated ESCs/iPSCs with BMP4 inhibitor, which prevents ESCs/iPSCs from differentiating into lateral mesodermal cells [76, 77]. To identify what genes are involved in myogenic differentiation in vivo, they performed a microarray analysis which compared samples of dissected fragments in mouse embryos, which are able to separate tail bud, presomitic mesoderm, and somite regions. From microarray data, the authors focused on Mesogenin1 (Msgn1) and Pax3 genes. Importantly, they utilized three lineage tracing reporters, Msgn1-repV (Mesogenin1-Venus) marking posterior somitic mesoderm, Pax3-GFP marking anterior somitic mesoderm and myogenic cells, and Myog-repV (Myogenin-Venus) marking differentiated myocytes, allowing the authors to readily detect different differentiation stages during ESC/iPSC cultures. Treatment with GSK3 inhibitors and then BMP inhibitors in ESC cultures induced Msgn1(+) somitic mesoderm with 45 to 65% efficiencies, Pax3(+) anterior somitic mesoderm with 30 to 50% efficiencies, and myogenin(+) myogenic cells with 25 to 30% efficiencies. Furthermore, the authors examined differentiation of mdx ESCs into skeletal muscle cells and revealed abnormal branching myofibers. Current protocols were also published and described more details for hiPSC differentiation [77].

Some nonmuscle cell populations such as mesoangioblasts have the potential to differentiate into skeletal muscle [6]. Mesoangioblasts were originally isolated from embryonic mouse dorsal aorta as vessel-associated pericyte-like cells, which have the ability to differentiate into a myogenic lineage in vitro and in vivo [6, 78]. Mesoangioblasts possess an advantage for the clinical cell-based treatment because they can be injected through an intra-arterial route to systemically deliver cells, which is crucial for therapeutic cell transplantation for muscular dystrophies [79]. Tedesco et al. successfully generated human iPSC-derived mesoangioblast-like stem/progenitor cells called HIDEMs by stepwise protocols without FACS sorting [80, 81]. They displayed similar gene expression profiles as embryonic mesoangioblasts. However, HIDEMs do not spontaneously differentiate into skeletal muscle cells, and thus, the authors utilized overexpression of MyoD to differentiate into skeletal muscle cells. Similar to mesoangioblasts, HIDEM-derived myogenic cells could be delivered to injured muscle via intramuscular and intra-arterial routes. Furthermore, HIDEMs have been generated from hiPSCs derived from limb-girdle muscular dystrophy (LGMD) type 2D patients and used for gene correction and cell transplantation experiments for the potential therapeutic application.

Myogenic precursor cells derived from ESCs/iPSCs by various methods may contain nonmuscle cells. Therefore, further purification is mandatory for therapeutic applications. Barberi et al. isolated CD73(+) multipotent mesenchymal precursor cells from hESCs by FACS, and these cells underwent differentiation into fat, cartilage, bone, and skeletal muscle cells [82]. Barberi et al. also demonstrated that hESCs cultured on OP9 stroma cells generated around 5% of CD73(+) adult mesenchymal stem cell-like cells [83]. After FACS, these CD73(+) mesenchymal stem cell-like cells were cultured with ITS medium for 4 weeks and then gave rise to NCAM(+) myogenic cells. After FACS sorting, these NCAM(+) myogenic cells were purified by FACS and transplanted into immunodeficient mice to show their myogenic contribution to regenerating muscle.

It has been shown that many genes are associated with myogenesis. In addition, exhaustive analysis, such as microarray, RNA-seq, and single cell RNA-seq supplies much gene information in many different stages. Chal et al. showed key signaling factors by microarray from presomitic somite, somite, and tail bud cells [76]. They found that initial Wnt signaling has important roles for somite differentiation. Furthermore, mapping differentiated hESCs by single cell RNA-seq analysis is useful to characterize each differentiated stage [84].

As shown above, cell sorting of mesodermal progenitor cells, mesenchymal precursor cells, or myogenic cells is a powerful tool to obtain pure myogenic populations from differentiated pluripotent cells. Sakurai et al. have been able to induce PDGFR(+)Flk-1() mesodermal progenitor cells by FACS followed by myogenic differentiation [85]. Chang et al. and Mizuno et al. have been able to sort SMC-2.6(+) myogenic cells from mouse ESCs/iPSCs [86, 87]. These SMC-2.6(+) myogenic cells were successfully engrafted into mouse regenerating skeletal muscle. However, this SMC-2.6 antibody only recognizes mouse myogenic cells but not human myogenic cells [86, 88]. Therefore, Borchin et al. have shown that hiPSC-derived myogenic cells differentiated into c-met(+)CXCR4(+)ACHR(+) cells, displaying that over 95% of sorted cells are Pax7(+) myogenic cells [72]. Taken together, current myogenic induction protocols utilizing small molecules and growth factors, with or without myogenic transcription factors, have been largely improved in the last 5 years. It is crucial to standardize the induction protocols in the near future to obtain sufficient myogenic cell conversion from pluripotent stem cells.

Recent work demonstrated that cells inherit a stable genetic program partly through various epigenetic marks, such as DNA methylation and histone modifications. This cellular memory needs to be erased during genetic reprogramming, and the cellular program reverted to that of an earlier developmental stage [16, 22, 89]. However, iPSCs retaining an epigenetic memory of their origin can readily differentiate into their original tissues [1619, 90100]. This phenomenon becomes a double-edged sword for the reprogramming process since the retention of epigenetic memory may reduce the quality of pluripotency while increasing the differentiation efficiency into their original tissues. DNA methylation levels are relatively low in the pluripotent stem cells compared to the high levels of DNA methylation seen in somatic cells [101]. Global DNA demethylation is required for the reprogramming process [102]. In the context of these observations, recent work demonstrates that activation-induced cytidine deaminase AID/AICDA contributing to the DNA demethylation can stabilize stem-cell phenotypes by removing epigenetic memory of pluripotent genes. This directly deaminates 5-methylcytosine in concert with base-excision repair to exchange cytosine in genomic DNA [103]. MicroRNA-155 has been identified as a key player for the retention of epigenetic memory during in vitro differentiation of hematopoietic progenitor cell-derived iPSCs toward hematopoietic progenitors [104]. iPSCs that maintained high levels of miR-155 expression tend to differentiate into the original somatic population more efficiently.

Recently, we generated murine skeletal muscle cell-derived iPSCs (myoblast-derived iPSCs) [23] and compared the efficiency of differentiation of myogenic progenitor cells between myoblast-derived iPSCs and fibroblast-derived iPSCs. After EB cultures, more satellite cell/myogenic progenitor cell differentiation occurred in myoblast-derived iPSCs than that in fibroblast-derived-iPSCs (unpublished observation and Figure 3), suggesting that myoblast-derived iPSCs are potential myogenic and satellite cell sources for DMD and other muscular dystrophy therapies (Figure 4). We also noticed that MyoD gene suppression by Oct4 is required for reprogramming in myoblasts to produce iPSCs (Figure 3) [23]. During overexpression of Oct4, Oct4 first binds to the Oct4 consensus sequence located in two MyoD enhancers (a core enhancer and distal regulatory region) [105107] preceding occupancy at the promoter in myoblasts in order to suppress MyoD gene expression. Interestingly, Oct4 binding to the MyoD core enhancer allows for establishment of a bivalent state in MyoD promoter as a poised state, marked by active (H3K4me3) and repressive (H3K27me3) modifications in fibroblasts, one of the characteristics of stem cells (Figure 3) [23, 108]. It should be investigated whether the similar bivalent state is also established in Oct4-expressing myoblasts during reprogramming process from myoblasts to pluripotent stem cells. It remains to be elucidated whether Oct4-mediated myogenic repression only relies on repression of MyoD expression or is just a general phenomenon of functional antagonism between Oct4 and MyoD on activation of muscle genes. Nevertheless, myoblast-derived iPSCs will enable us to produce an unlimited number of myogenic cells, including satellite cells that could form the basis of novel treatments for DMD and other muscular dystrophies (Figure 4).

There are pros and cons of transgene-free small molecule-mediated myogenic induction protocols. In the transgene-mediated induction protocols, integration of the transgene in the host genome may lead to risk for insertional mutagenesis. To circumvent this issue, there is an obvious advantage for transgene-free induction protocols. Some key molecules such as Wnt, FGF, and BMP have used signaling pathways to induce myogenic differentiation of ES/iPSCs. However, these molecules are also involved in induction of other types of cell lineages, which makes it difficult for ES/iPSCs to induce pure myogenic cell populations in vitro. By contrast, transgene-mediated myogenic induction is able to dictate desired specific cell lineages. In any case, it is necessary to intensively investigate these myogenic induction protocols for the efficient and safe stem cell therapy for patients.

For skeletal muscle diseases, patient-derived hiPSCs, which possess the ability to differentiate into myogenic progenitor cells followed by myotubes, can be a useful tool for drug screening and personalized medicine in clinical practice. However, there are still limitations for utilizing hiPSC-derived myogenic cells for regenerative medicine. For cell-based transplantation therapies such as a clinical situation, animal-free defined medium is essential for stem cell culture and skeletal muscle cell differentiation. Therefore, such animal-free defined medium needs to be established for optimal myogenic differentiation from hiPSCs. Gene correction in DMD patient iPSCs by TALENs and CRISPR-Cas9 systems are promising therapeutic approaches for stem cell transplantation. However, there are still problems for DNA-editing-mediated stem cell therapy such as safety and efficacy. Since iPSC-derived differentiated myotubes do not proliferate, they are not suited for cell transplantation. Therefore, a proper culture method needs to be established for hiPSCs in order to maintain cells in proliferating the myogenic precursor cell stage in vitro in order to expand cells to large quantities of transplantable cells for DMD and other muscular dystrophies. For other issues, it is essential to establish methods to separate ES/iPSC-derived pure skeletal muscle precursor cells from other cell types for safe stem cell therapy that excludes tumorigenic risks of contamination with undifferentiated cells. In the near future, these obstacles will be taken away for more efficient and safe stem cell therapy for DMD and other muscular dystrophies.

The authors declare that they have no conflicts of interest.

This work was supported by the NIH R01 (1R01AR062142) and NIH R21 (1R21AR070319). The authors thank Conor Burke-Smith and Neeladri Chowdhury for critical reading.

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Skeletal Muscle Cell Induction from Pluripotent Stem Cells

categoriaCardiac Stem Cells commentoComments Off on Skeletal Muscle Cell Induction from Pluripotent Stem Cells dataDecember 1st, 2022
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Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027 – Yahoo Finance

By daniellenierenberg

ReportLinker

Abstract: Whats New for 2022?? Global competitiveness and key competitor percentage market shares. Market presence across multiple geographies - Strong/Active/Niche/Trivial.

New York, Oct. 10, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Induced Pluripotent Stem Cell (iPSC) Industry" - https://www.reportlinker.com/p05798831/?utm_source=GNW

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Complimentary updates for one yearGlobal Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027- In the changed post COVID-19 business landscape, the global market for Induced Pluripotent Stem Cell ((iPSC) estimated at US$1.4 Billion in the year 2020, is projected to reach a revised size of US$0 Thousand by 2027, growing at a CAGR of -100% over the analysis period 2020-2027. Vascular Cells, one of the segments analyzed in the report, is projected to record a -100% CAGR and reach US$0 Thousand by the end of the analysis period. Taking into account the ongoing post pandemic recovery, growth in the Cardiac Cells segment is readjusted to a revised -100% CAGR for the next 7-year period.- The U.S. Market is Estimated at $629.2 Million, While China is Forecast to Grow at -100% CAGR- The Induced Pluripotent Stem Cell ((iPSC) market in the U.S. is estimated at US$629.2 Million in the year 2020. China, the world`s second largest economy, is forecast to reach a projected market size of US$0 Thousand by the year 2027 trailing a CAGR of -100% over the analysis period 2020 to 2027. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at -100% and -100% respectively over the 2020-2027 period. Within Europe, Germany is forecast to grow at approximately -100% CAGR.Neuronal Cells Segment to Record -100% CAGR- In the global Neuronal Cells segment, USA, Canada, Japan, China and Europe will drive the -100% CAGR estimated for this segment. These regional markets accounting for a combined market size of US$188.9 Million in the year 2020 will reach a projected size of US$0 Thousand by the close of the analysis period. China will remain among the fastest growing in this cluster of regional markets.

Select Competitors (Total 51 Featured)Axol Bioscience Ltd.Cynata Therapeutics LimitedEvotec SEFate Therapeutics, Inc.FUJIFILM Cellular Dynamics, Inc.NcardiaPluricell BiotechREPROCELL USA, Inc.Sumitomo Dainippon Pharma Co., Ltd.Takara Bio, Inc.Thermo Fisher Scientific, Inc.ViaCyte, Inc.

Read the full report: https://www.reportlinker.com/p05798831/?utm_source=GNW

I. METHODOLOGY

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEWInfluencer Market InsightsImpact of Covid-19 and a Looming Global RecessionInduced Pluripotent Stem Cells (iPSCs) Market Gains fromIncreasing Use in Research for COVID-19Studies Employing iPSCs in COVID-19 ResearchStem Cells, Application Areas, and the Different Types: A PreludeApplications of Stem CellsTypes of Stem CellsInduced Pluripotent Stem Cell (iPSC): An IntroductionProduction of iPSCsFirst & Second Generation Mouse iPSCsHuman iPSCsKey Properties of iPSCsTranscription Factors Involved in Generation of iPSCsNoteworthy Research & Application Areas for iPSCsInduced Pluripotent Stem Cell ((iPSC) Market: Growth Prospectsand OutlookDrug Development Application to Witness Considerable GrowthTechnical Breakthroughs, Advances & Clinical Trials to SpurGrowth of iPSC MarketNorth America Dominates Global iPSC MarketCompetitionRecent Market ActivitySelect Innovation/AdvancementInduced Pluripotent Stem Cell (iPSC) - Global Key CompetitorsPercentage Market Share in 2022 (E)Competitive Market Presence - Strong/Active/Niche/Trivial forPlayers Worldwide in 2022 (E)

2. FOCUS ON SELECT PLAYERSAxol Bioscience Ltd. (UK)Cynata Therapeutics Limited (Australia)Evotec SE (Germany)Fate Therapeutics, Inc. (USA)FUJIFILM Cellular Dynamics, Inc. (USA)Ncardia (Belgium)Pluricell Biotech (Brazil)REPROCELL USA, Inc. (USA)Sumitomo Dainippon Pharma Co., Ltd. (Japan)Takara Bio, Inc. (Japan)Thermo Fisher Scientific, Inc. (USA)ViaCyte, Inc. (USA)

3. MARKET TRENDS & DRIVERSEffective Research Programs Hold Key in Roll Out of AdvancediPSC TreatmentsInduced Pluripotent Stem Cells: A Giant Leap in the TherapeuticApplicationsResearch Trends in Induced Pluripotent Stem Cell SpaceWorldwide Publication of hESC and hiPSC Research Papers for thePeriod 2008-2010, 2011-2013 and 2014-2016Number of Original Research Papers on hESC and iPSC PublishedWorldwide (2014-2016)Concerns Related to Embryonic Stem Cells Shift the Focus ontoiPSCsRegenerative Medicine: A Promising Application of iPSCsInduced Pluripotent: A Potential Competitor to hESCs?Global Regenerative Medicine Market Size in US$ Billion for2019, 2021, 2023 and 2025Global Stem Cell & Regenerative Medicine Market by Product(in %) for the Year 2019Global Regenerative Medicines Market by Category: Breakdown(in %) for Biomaterials, Stem Cell Therapies and TissueEngineering for 2019Pluripotent Stem Cells Hold Significance for CardiovascularRegenerative MedicineLeading Causes of Mortality Worldwide: Number of Deaths inMillions & % Share of Deaths by Cause for 2017Leading Causes of Mortality for Low-Income and High-IncomeCountriesGrowing Importance of iPSCs in Personalized Drug DiscoveryPersistent Advancements in Genetics Space and Subsequent Growthin Precision Medicine Augur Well for iPSCs MarketGlobal Precision Medicine Market (In US$ Billion) for the Years2018, 2021 & 2024Increasing Prevalence of Chronic Disorders Supports Growth ofiPSCs MarketWorldwide Cancer Incidence: Number of New Cancer CasesDiagnosed for 2012, 2018 & 2040Number of New Cancer Cases Reported (in Thousands) by CancerType: 2018Fatalities by Heart Conditions: Estimated Percentage Breakdownfor Cardiovascular Disease, Ischemic Heart Disease, Stroke,and OthersRising Diabetes Prevalence Presents Opportunity for iPSCsMarket: Number of Adults (20-79) with Diabetes (in Millions)by Region for 2017 and 2045Aging Demographics Add to the Global Burden of ChronicDiseases, Presenting Opportunities for iPSCs MarketExpanding Elderly Population Worldwide: Breakdown of Number ofPeople Aged 65+ Years in Million by Geographic Region for theYears 2019 and 2030Growth in Number of Genomics Projects Propels Market GrowthGenomic Initiatives in Select CountriesNew Gene-Editing Tools Spur Interest and Investments inGenetics, Driving Lucrative Growth Opportunities for iPSCs:Total VC Funding (In US$ Million) in Genetics for the Years2014, 2015, 2016, 2017 and 2018Launch of Numerous iPSCs-Related Clinical Trials Set to BenefitMarket GrowthNumber of Induced Pluripotent Stem Cells based Studies bySelect Condition: As on Oct 31, 2020iPSCs-based Clinical Trial for Heart DiseasesInduced Pluripotent Stem Cells for Stroke Treatment?Off-the-shelf? Stem Cell Treatment for Cancer Enters ClinicalTrialiPSCs for Hematological DisordersMarket Benefits from Growing Funding for iPSCs-Related R&DInitiativesStem Cell Research Funding in the US (in US$ Million) for theYears 2016 through 2021Human iPSC Banks: A Review of Emerging Opportunities and DrawbacksHuman iPSC Banks Worldwide: An OverviewCell Sources and Reprogramming Methods Used by Select iPSC BanksInnovations, Research Studies & Advancements in iPSCsKey iPSC Research Breakthroughs for Regenerative MedicineResearchers Develop Novel Oncogene-Free and Virus-Free iPSCProduction MethodScientists Study Concerns of Genetic Mutations in iPSCsiPSCs Hold Tremendous Potential in Transforming Research EffortsResearchers Highlight Potential Use of iPSCs for DevelopingNovel Cancer VaccinesScientists Use Machine Learning to Improve Reliability of iPSCSelf-OrganizationSTEMCELL Technologies Unveils mTeSR? PlusChallenges and Risks Related to Pluripotent Stem CellsA Glance at Issues Related to Reprogramming of Adult Cells toiPSCsA Note on Legal, Social and Ethical Considerations with iPSCs

4. GLOBAL MARKET PERSPECTIVETable 1: World Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Geographic Region -USA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld Markets - Independent Analysis of Annual Sales in US$Thousand for Years 2020 through 2025 and % CAGR

Table 2: World 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Geographic Region - Percentage Breakdown ofValue Sales for USA, Canada, Japan, China, Europe, Asia-Pacificand Rest of World Markets for Years 2021 & 2025

Table 3: World Recent Past, Current & Future Analysis forVascular Cells by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 4: World 5-Year Perspective for Vascular Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 5: World Recent Past, Current & Future Analysis forCardiac Cells by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 6: World 5-Year Perspective for Cardiac Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 7: World Recent Past, Current & Future Analysis forNeuronal Cells by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 8: World 5-Year Perspective for Neuronal Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 9: World Recent Past, Current & Future Analysis for LiverCells by Geographic Region - USA, Canada, Japan, China, Europe,Asia-Pacific and Rest of World Markets - Independent Analysisof Annual Sales in US$ Thousand for Years 2020 through 2025 and% CAGR

Table 10: World 5-Year Perspective for Liver Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 11: World Recent Past, Current & Future Analysis forImmune Cells by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 12: World 5-Year Perspective for Immune Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 13: World Recent Past, Current & Future Analysis forOther Cell Types by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 14: World 5-Year Perspective for Other Cell Types byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 15: World Recent Past, Current & Future Analysis forCellular Reprogramming by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 16: World 5-Year Perspective for Cellular Reprogrammingby Geographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 17: World Recent Past, Current & Future Analysis for CellCulture by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 18: World 5-Year Perspective for Cell Culture byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 19: World Recent Past, Current & Future Analysis for CellDifferentiation by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 20: World 5-Year Perspective for Cell Differentiation byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 21: World Recent Past, Current & Future Analysis for CellAnalysis by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 22: World 5-Year Perspective for Cell Analysis byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 23: World Recent Past, Current & Future Analysis forCellular Engineering by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 24: World 5-Year Perspective for Cellular Engineering byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 25: World Recent Past, Current & Future Analysis forOther Research Methods by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 26: World 5-Year Perspective for Other Research Methodsby Geographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 27: World Recent Past, Current & Future Analysis for DrugDevelopment & Toxicology Testing by Geographic Region - USA,Canada, Japan, China, Europe, Asia-Pacific and Rest of WorldMarkets - Independent Analysis of Annual Sales in US$ Thousandfor Years 2020 through 2025 and % CAGR

Table 28: World 5-Year Perspective for Drug Development &Toxicology Testing by Geographic Region - Percentage Breakdownof Value Sales for USA, Canada, Japan, China, Europe,Asia-Pacific and Rest of World for Years 2021 & 2025

Table 29: World Recent Past, Current & Future Analysis forAcademic Research by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 30: World 5-Year Perspective for Academic Research byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 31: World Recent Past, Current & Future Analysis forRegenerative Medicine by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 32: World 5-Year Perspective for Regenerative Medicine byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 33: World Recent Past, Current & Future Analysis forOther Applications by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 34: World 5-Year Perspective for Other Applications byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

III. MARKET ANALYSIS

UNITED STATESInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in the United Statesfor 2022 (E)Table 35: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 36: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 37: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 38: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 39: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 40: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

CANADATable 41: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 42: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 43: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 44: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 45: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 46: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

JAPANInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Japan for 2022 (E)Table 47: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 48: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 49: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 50: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 51: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 52: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

CHINAInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in China for 2022 (E)Table 53: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 54: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 55: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 56: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 57: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 58: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

EUROPEInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Europe for 2022 (E)Table 59: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Geographic Region -France, Germany, Italy, UK and Rest of Europe Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 60: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Geographic Region - Percentage Breakdown ofValue Sales for France, Germany, Italy, UK and Rest of EuropeMarkets for Years 2021 & 2025

Table 61: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 62: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 63: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 64: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 65: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 66: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

FRANCEInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in France for 2022 (E)Table 67: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 68: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 69: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 70: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 71: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 72: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

GERMANYInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Germany for 2022 (E)Table 73: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 74: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 75: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 76: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 77: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 78: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

ITALYTable 79: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 80: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 81: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 82: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 83: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 84: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

UNITED KINGDOMInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in the United Kingdomfor 2022 (E)Table 85: UK Recent Past, Current & Future Analysis for InducedPluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells,Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells andOther Cell Types - Independent Analysis of Annual Sales in US$Thousand for the Years 2020 through 2025 and % CAGR

Table 86: UK 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

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Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027 - Yahoo Finance

categoriaCardiac Stem Cells commentoComments Off on Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027 – Yahoo Finance dataOctober 13th, 2022
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Merck and Moderna Announce Exercise of Option by Merck for Joint Development and Commercialization of Investigational Personalized Cancer Vaccine -…

By daniellenierenberg

October 12, 2022 7:15 am ET

Companies on track to report data from the ongoing Phase 2 trial of mRNA-4157/V940 in combination with KEYTRUDA as adjuvant therapy in high-risk melanoma in 4Q 2022

CAMBRIDGE, M.A. and RAHWAY, N.J., October 12, 2022 Moderna, Inc. (Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, and Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced that Merck has exercised its option to jointly develop and commercialize personalized cancer vaccine (PCV) mRNA-4157/V940 pursuant to the terms of its existing Collaboration and License Agreement. mRNA-4157/V940 is currently being evaluated in combination with KEYTRUDA, Mercks anti-PD-1 therapy, as adjuvant treatment for patients with high-risk melanoma in a Phase 2 clinical trial being conducted by Moderna.

We have been collaborating with Merck on PCVs since 2016, and together we have made significant progress in advancing mRNA-4157 as an investigational personalized cancer treatment used in combination with KEYTRUDA, said Stephen Hoge, M.D., President of Moderna. With data expected this quarter on PCV, we continue to be excited about the future and the impact mRNA can have as a new treatment paradigm in the management of cancer. Continuing our strategic alliance with Merck is an important milestone as we continue to grow our mRNA platform with promising clinical programs in multiple therapeutic areas.

Under the agreement, originally established in 2016 and amended in 2018, Merck will pay Moderna $250 million to exercise its option for personalized cancer vaccines including mRNA-4157/V940 and will collaborate on development and commercialization. The payment will be expensed by Merck in the third quarter of 2022 and included in its non-GAAP results. Merck and Moderna will share costs and any profits equally under this worldwide collaboration.

This long-term collaboration combining Mercks expertise in immuno-oncology with Modernas pioneering mRNA technology has yielded a novel tailored vaccine approach, said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. We look forward to working with our colleagues at Moderna to advance mRNA-4157/V940 in combination with KEYTRUDA as it aligns with our strategy to impact early-stage disease.

About mRNA-4157/V940

Personalized cancer vaccines are designed to prime the immune system so that a patient can generate a tailored antitumor response to their tumor mutation signature to treat their cancer. mRNA-4157/V940 is designed to stimulate an immune response by generating T cell responses based on the mutational signature of a patients tumor.

About KEYNOTE-942 (NCT03897881)

KEYNOTE-942 is an ongoing randomized, open-label Phase 2 trial that enrolled 157 patients with high-risk melanoma. Following complete surgical resection, patients were randomized to mRNA-4157/V940 (9 doses every three weeks) and KEYTRUDA (200 mg every three weeks) versus KEYTRUDA alone for approximately one year until disease recurrence or unacceptable toxicity. KEYTRUDA was selected as the comparator in the trial because it is considered a standard of care for high-risk melanoma patients. The primary endpoint is recurrence-free survival, and secondary endpoints include distant metastasis-free survival and overall survival. The Phase 2 trial is fully enrolled and primary data are expected in the fourth quarter of 2022.

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC.

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Endometrial Carcinoma

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis;Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy;Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss;Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis;Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica;Endocrine: Hypoparathyroidism;Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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Merck and Moderna Announce Exercise of Option by Merck for Joint Development and Commercialization of Investigational Personalized Cancer Vaccine -...

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Regenerative Medicine For Heart Diseases: How It Is Better Than Conventional Treatments | TheHealthSite.co – TheHealthSite

By daniellenierenberg

The future possibilities of regenerative Medicine are endless. Know how regenerative medicine for heart diseases is better than conventional treatments.

Written by Longjam Dineshwori | Updated : October 5, 2022 9:52 AM IST

In the past few days, news of people dying due to cardiac arrest and heart attack during the festivities have been making headlines. Concerningly, increasing number of younger people, precisely adults who are in their 30s, are getting heart problems today. Health experts have been advising people to maintain a healthy lifestyle to prevent heart diseases or at least delay their onset. Also, tremendous advancements have been made in the field of cardiology making treatment of heart ailments more effective and less invasive. One of them is regenerative medicine, which is now being explored for the treatment of several diseases.

Get to more about regenerative medicine and its possibilities for treating heart diseases from Dr Pradeep Mahajan, Regenerative Medicine Researcher, Stem Rx Bioscience Solutions Pvt. Ltd, Navi Mumbai.

An alarming one out of four deaths in our country today is due to heart disease. This is largely due to our sedentary lifestyles, unhealthy eating habits, and stress. Barring the heart conditions that are present from birth (congenital) or that are passed down through the generations (inherited), heart diseases can be prevented or at least the onset can be delayed by maintaining a healthy lifestyle.

The field of cardiology (relating to the heart) has advanced tremendously, and there are several medications and surgical procedures that help patients maintain the functions of the heart. However, these call for invasive treatments and the need for life-long medications. Moreover, the side effects of medicines should also be taken into account.

Enter the field of Regenerative Cardiology! As the word suggests, this branch refers to utilising the natural healing potential of the body to repair and re-grow damaged heart tissues. Stem cells have been researched in several heart diseases to overcome the damage to the heart and facilitate healing. Not just stem cells, but cell-based products like exosomes, molecular chaperones, growth factors etc. have shown promise as well. Do not think about the technicalities, all these molecules are present in our body and researchers and clinicians are now working on how to apply these for the treatment of several diseases.

Commonly, we hear of blocks in the heart, infection, and weak muscles of the heart that do not pump blood properly leading to various diseases. With cell-based therapies, we can tackle each of these issues. Stem cells (the most basic 'unspecialized' cells of our body) can multiply and form various cells of the body, including heart cells. Similarly, cell products like exosomes are cargo packets they carry the required substances for repair and re-growth of tissues. These biological molecules have 'housekeeping functions, meaning that they ensure that any unwanted product and even bacteria/viruses are removed periodically from the body.

The possibilities of Regenerative Medicine for heart diseases are many blocks in the heart can be dissolved, blood supply can be improved, heart muscles can be strengthened, etc. because these biological molecules are capable of reducing inflammation (swelling) in the body, modify the immune system to function better, enhance the functions of other cells, etc. Since these are part of our own body, providing these molecules in the appropriate quantity at the desired site will enhance healing without side effects. In fact, there is ongoing research on growing healthy heart tissue in labs with these biological molecules to transplant them into the human body. Who knows, someday the whole heart might be grown in a lab! While the future possibilities are endless, the current cell-based therapies can be a definitive addition to enhance the outcomes of existing conventional treatments. Of course, rehabilitation and lifestyle modifications are mandatory to maintain the results.

A holistic approach is important one cannot simply rely on symptom management the core issues have to be targeted and Regenerative Medicine can do just that. The death rate due to heart disease can be reduced and patients will be able to have a better quality of life.

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Regenerative Medicine For Heart Diseases: How It Is Better Than Conventional Treatments | TheHealthSite.co - TheHealthSite

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‘Love hormone’ oxytocin could help reverse damage from heart attacks via cell regeneration – Study Finds

By daniellenierenberg

EAST LANSING, Mich. A chemical released during sex could become a new treatment for heart attack patients, new research reveals. Oxytocin, called the love hormone, helps heal the organ by boosting production of stem cells, researchers at Michigan State University say.

The findings are based on human tissue grown in the lab and experiments on zebrafish, which have a remarkable ability to repair themselves.

Here we show that oxytocin, a neuropeptide also known as the love hormone, is capable of activating heart repair mechanisms in injured hearts in zebrafish and human cell cultures, opening the door to potential new therapies for heart regeneration in humans, says senior author Dr. Aitor Aguirre, an assistant professor at the Department of Biomedical Engineering of Michigan State University, in a media release.

Oxytocin stimulates erections and orgasms. In women, it is believed to help sperm reach the egg. The chemical is produced by the hypothalamus in the brain. It is secreted by the pituitary gland.Abnormal amounts have a connection to sex addiction. Oxytocin is also the foundation of many pleasurable feelings, from exercise to lovemaking.

Now, the research team reports it also causes stem cells from the hearts outer layer, or epicardium, to migrate into the middle, known as the myocardium.There they develop into cardiomyocytes, muscle cells that generate heart contractions. The discovery offers hope of promoting regeneration after damaging events like a heart attack. The cells die off in great numbers after a heart attack. Highly specialized cells dont replenish themselves.

However, previous studies have shown that a subset called EpiPCs (Epicardium-derived Progenitor Cells) can undergo reprogramming, becoming cardiomyocytes or other types of heart cells.Think of the EpiPCs as the stonemasons that repaired cathedrals in Europe in the Middle Ages, Aguirre explains.

Production is inefficient for heart regeneration in humans under natural conditions, but the humble zebrafish may hold the key. They are famous for their extraordinary capacity for regenerating organs including the brain, retina, internal organs, bone, and skin.

They dont suffer heart attacks, but predators are happy to take a bite out of any organ, since zebrafish can regrow their heart when as much as a quarter of it has been lost. This is done by proliferation of cardiomyocytes and EpiPCs. The magic bullet appears to be oxytocin.

In zebrafish, within three days after the heart was exposed to cryoinjury by freezing, expression of oxytocin in the brain soared 20-fold. Scans showed the hormone travelled to the epicardium and bound to the oxytocin receptor. This triggered a molecular cascade, stimulating local cells to expand and develop into EpiPCs.

The new cells headed for the zebrafish myocardium to develop into cardiomyocytes, blood vessels, and other important heart cells, to replace those which had been lost. Crucially, the researchers found oxytocin has a similar effect on cultured human tissue. It turned human Induced Pluripotent Stem Cells (hIPSCs) into EpiPCs.

Numbers doubled due to the hormone. None of 14 other brain hormones tested worked. The effect was much stronger than other molecules tried in mice. On the other hand, genetic engineering that knocked out the oxytocin receptor prevented the regenerative activation of human EpiPCs. The link between oxytocin and the stimulation of EpiPCs was identified in a chemical pathway known to regulate the growth, differentiation and migration of cells.

These results show that it is likely that the stimulation by oxytocin of EpiPC production is evolutionary conserved in humans to a significant extent. Oxytocin is widely used in the clinic for other reasons, so repurposing for patients after heart damage is not a long stretch of the imagination. Even if heart regeneration is only partial, the benefits for patients could be enormous, Aguirre says.

Next, we need to look at oxytocin in humans after cardiac injury. Oxytocin itself is short-lived in the circulation, so its effects in humans might be hindered by that. Drugs specifically designed with a longer half-life or more potency might be useful in this setting. Overall, pre-clinical trials in animals and clinical trials in humans are necessary to move forward.

The study is published in the journal Frontiers in Cell and Developmental Biology.

South West News Service writer Mark Waghorn contributed to this report.

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'Love hormone' oxytocin could help reverse damage from heart attacks via cell regeneration - Study Finds

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Recapitulating Inflammation: How to Use the Colon Intestine-Chip to Study Complex Mechanisms of IBD – Pharmaceutical Executive

By daniellenierenberg

Inflammatory bowel disease (IBD) is increasing around the world. In 1990, around 3.7 million people had the condition; by 2017, that number had increased to 6.8 million. Nearly half of IBD patients dont respond to current treatments, and even for the lucky ones therapeutic efficacy can wane over time. As a result, there is an urgent need to develop a new generation of IBD therapies.

Unfortunately, ineffective drug development models are hampering the search for more effective treatments. Conventional two-dimensional (2D) cell models only capture bits and pieces of IBDs complexity, and many three-dimensional (3D) culture models like organoids fall short because they lack critical biological features, such as vasculature and biomechanical forces.

Animal models have their own drawbacks, as their immune systems fail to replicate many of the mechanisms associated with human immunity.

If you look at the physiology of cardiac muscle or neurons between humans and mice, theyre fairly similar, said Christopher Carman, PhD, director of Immunology at Emulate. Theres more divergence in immunology, and it can be really challenging to extract meaningful insights around immune-system-driven mechanisms. Thats why so many therapeutics fail.

To remedy this, Emulate has developed a Colon Intestine-Chip that combines primary human tissue, vasculature, mechanical forces, and (most importantly) immune cell recruitment to recapitulate the biology that drives IBD.

UNDERSTANDING HOW IBD EVOLVES

IBD begins with an unknown tissue insult, and the body responds by producing inflammatory cytokines and chemokines. In turn, these proteins recruit immune cells to the intestine, inducing further inflammation.

This process generates a cytokine cascade. Two proteins in particular, interferon gamma (IFN) and IL-22, act directly on colon epithelial cells, driving cell death, microvilli loss, and destruction of the tight junctions that guard intestinal permeability.

That is a critical hallmark of this disease, said Carman. As a result, intestinal material, including bacteria and bacterial products, leak into the interstitial space, driving even more inflammation.

MAKING THE COLON INTESTINE-CHIP

The Emulate Colon Intestine-Chip was designed to precisely recapitulate this inflammatory cascade.

This advanced, in vitro intestine model incorporates primary human biopsy tissue cultured into organoids. Critically, the cells retain their stemness, meaning they replicate the stem cell niches that are constantly regenerating in human intestines.

After the organoids are dissociated, they are seeded in the top channel of the Organ-Chip. The bottom channel contains primary human intestine-derived microvascular endothelial cells, which are in close proximity to the epithelial cells, as they would be in vivo. The channels are separated by a porous membrane coated with tissue-relevant extracellular matrix proteins.

From there, mechanical forces on the chipphysiologic flow and cyclic stretchreplicate intestinal peristalsis, which improves cell morphology and functionality while supporting more accurate gene expression.

As a result, epithelial tissues respond to microvasculature cues, and the epithelial cells differentiate into all three major epithelial types at the appropriate ratios.

With this, the Emulate Colon Intestine-Chip is able to model IBD from the initial insult to the cytokine cascade, demonstrating along the way selective immune cell recruitment, cell death, and tight junction loss. This model can be applied to study inflammation-specific immune recruitment from vasculature into epithelial tissue and subsequent downstream impacts.

We have shown that this Organ-Chip strongly reflects what we see in primary human tissue, said Carman. It develops proper tight junctions and a strong functional barrier. On the molecular level, we see transcriptional signatures that are highly reflective of primary human tissue.

This model has demonstrated the efficacy of small molecule inhibitors that target IFN and IL-22 signaling pathways, meaning researchers can use it to validate clinically relevant drug candidates designed to prevent barrier dysfunction.

SELECTIVELY GENERATING INFLAMMATION

One of the Organ-Chips most important abilities is the selective recruitment of immune cells. This selectivity comes from tissue-specific adhesion molecules on both endothelial and immune cells, which must be highly specific to bind.

Around 30% of the bodys circulating immune cells are customized for work in the intestines. They have a molecule called 47 integrin that binds to an endothelial molecule called MAdCAM-1, which is preferentially expressed in the colon endothelium and up-regulated in response to inflammatory cues.

One of the major ways the Colon Intestine-Chip replicates IBD biology is by expressing MAdCAM-1 in response to inflammatory stimuli, giving it tremendous relevance for therapeutic discovery.

The 47 integrin/MAdCAM-1 adhesion molecule axis is an important therapeutic target, said Carman. If we can interfere with that adhesion, we can potentially interrupt the inflammatory cascade. And because this mechanism is selective to the gut, any therapeutic that targets these adhesion molecules would be highly specific to the intestinal system.

One drug, AJM300, is in phase three clinical trials right now and is showing promising safety and efficacy, said Carman. We validated that efficacy in our model. We also used the model to study the corticosteroid dexamethasone, which has been a mainstay in IBD treatment for many years. We recently published the data in an application note.

The Colon Intestine-Chip provides a more complete picture of human IBD pathogenesis, delivering a human-relevant platform to test drug efficacy. However, for Emulate, its just the beginning. Inflammation plays a major role in many conditions, and creating models that effectively replicate those pathways will be essential in validating and advancing therapeutic compounds to support better care.

This IBD model is our first foray into inflammation, said Carman. Were planning on developing many variations on this theme to create better tools for a variety of inflammation-driven indications.

For more information on Emulates IBD model, please download Modeling Inflammation-Specific Immune Cell Recruitment in the Colon Intestine-Chip.

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Recapitulating Inflammation: How to Use the Colon Intestine-Chip to Study Complex Mechanisms of IBD - Pharmaceutical Executive

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CellResearch Corporation (CRC) to present promising new stem cell products for the treatment of chronic diabetic foot ulcers at the world’s premier…

By daniellenierenberg

- CRC data on cord lining media for the treatment of diabetic foot ulcers has been accepted at the DFCon, with Dr Wong Keng Lin Francis, CRC's latest KOL, presenting his findings to world leaders in the field of DFU.- Similarly, the results of Corlicyte's Phase 1 study on the treatment of chronic diabetic foot has also been accepted with the presentation being given by Dr Cecilia Low-Wang, the trials Principal Investigator.- DFCon is a global specialist multi-disciplinary congress that attracts specialists in the field of the diabetic foot and is considered the most influential event in the industry. It is co-founded by Dr David Armstrong, a pre-eminent expert in diabetic foot.- Dr Armstrong, who also serves on CRC's scientific advisory board, will be giving the opening address for CRC's breakfast symposium on their lead products Sollagen and Corlicyte.- CorLiCyte is an umbilical cord lining stem cell therapy, for patients suffering with diabetic foot ulcers (DFU), Sollagen is a brand targeting diabetic's skin.- Global diabetes patient population is set to grow from 537 million in 2021 to 783 million in 20451- DFU is a global health emergency that will affect close to 20% of the diabetic population in their lifetime

LOS ANGELES, Sept. 26, 2022 /PRNewswire/ -- CRC is delighted to announce attendance at DFCon, the global specialist multidisciplinary congress focused on the diabetic foot held in late September 2022 in Los Angeles, USA. The meeting is a gathering of a wide range of both generalists and specialists who diagnose and manage diabetic feet, to discuss best practice in diagnostics and interventions for both treatment and amputation prevention. It was co-founded and is co-chaired by Dr David Armstrong, a pre-eminent expert in diabetic foot who also serves on CRC's scientific advisory board.

Dr David Armstrong will be introducing CRC's headline symposium on Saturday morning where Dr Paul Kemp, the inventor of Apligraf and scientific advisory board member, and esteemed researchers Dr Brian Freed and Dr Wong Keng Lin Francis will present an overview of CRC's technology and data.

Furthermore, CRC have two scientific posters approved for presentation at DFCon on the data generated in Corlicyte and Sollagen:

The first poster "Results of the phase 1 open-label safety study of umbilical cord lining (Corlicyte) to heal chronic diabetic foot ulcers" details the Phase I study in Corlicyte and is authored by Cecilia Low Wang and the team from the University of Colorado who conducted the study.

The second poster by Dr Wong from Sengkang General Hospital/Duke NUS is titled "Early evaluation of Sollagen, a topical exosomal skin conditioner derived from Umbilical cord lining cell media, in treatment of persistent chronic DFU" and details the impressive early data generated with Sollagen in chronic diabetic foot ulcers.

Both posters are a testament to the immense potential of Corlicyte and Sollagen for the treatment of diabetic foot ulcer, a huge issue for patients and health care systems alike.

CRC's presence at such a specialized and well-regarded scientific and medical forum reflects the exciting data the company is generating. It is a strong indication of the academic and clinical network that the company is building to deliver products that can make a dramatic difference to patients with a large unmet medical need.

About CellResearch Corporation (CRC)

CellResearch Corporation was founded in 2002 as a contract research provider focusing on skin cells. In 2004, the company made the discovery that the umbilical cord lining of mammals was an abundant source of both mesenchymal and epithelial stem cells. Today, the company owns this technology through a family of patents and holds the rights to commercialize this technology in most major markets globally. While the closure of diabetic foot ulcers is the company's first allogeneic therapy to make it to the end of Phase 1 USFDA clinical trials, CellResearchCorp has a broad therapeutic pipeline at the pre-clinical stage. Further therapies include solid tumor therapy, inflammatory diseases, cardiac muscle repair, Parkinson's Disease, Age-related Macular Degeneration and Diabetes.

CellResearch Consumer Health, a wholly owned subsidiary of CellResearch Corp, is the commercialization vehicle for CALECIMProfessional and the newly launching Sollagen. It produces an innovative range of skincare and haircare products using cord lining stem cell media to power its products. It is used in clinics/hospitals and as part of an at-home anti-aging skincare regime. It is distributed globally through over 600 aesthetic physicians and online via their own website. It has a key distribution partnership with Menarini Group across Southeast Asia.

CellResearch Corp partner, Cordlife offers parents the opportunity to bank their child's umbilical cord tissue alongside their cord blood. Cordlife has what is believed to be the largest licensed bank of umbilical cord tissue globally. As cell therapies move into the clinic, Cordlife will have the ability to expand stem cells from a banked umbilical cord for autologous and donor-related uses.

http://www.cellresearchcorp.com

https://calecimprofessional.com

Business Development and Investor Relations:

Xavier Simpson

+65 8815 6139

xaviersimpson@cellresearchcorp.com

Cision

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CellResearch Corporation (CRC) to present promising new stem cell products for the treatment of chronic diabetic foot ulcers at the world's premier...

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Adult Stem Cells // Center for Stem Cells and Regenerative Medicine …

By daniellenierenberg

Adult stem cells, also called somatic stem cells, are undifferentiated cells that are found in many different tissues throughout the body of nearly all organisms, including humans. Unlike embryonic stem cells, which can become any cell in the body (called pluripotent), adult stem cells, which have been found in a wide range of tissues including skin, heart, brain, liver, and bone marrow are usually restricted to become any type of cell in the tissue or organ that they reside (called multipotent). These adult stem cells, which exist in the tissue for decades, serve to replace cells that are lost in the tissue as needed, such as the growth of new skin every day in humans.

Scientists discovered adult stem cells in bone marrow more than 50 years ago. These blood-forming stem cells have been used in transplants for patients with leukemia and several other diseases for decades. By the 1990s, researchers confirmed that nerve cells in the brain can also be regenerated from endogenous stem cells. It is thought that adult stem cells in a variety of different tissues could lead to treatments for numerous conditions that range from type 1 diabetes (providing insulin-producing cells) to heart attack (repairing cardiac muscle) to neurological disease (regenerating lost neurons in the brain or spinal cord).

Efforts are underway to stimulate these adult stem cells to regenerate missing cells within damaged tissues. This approach will utilize the existing tissue organization and molecules to stimulate and guide the adult stem cells to correctly regenerate only the necessary cell types. Alternatively, the adult stem cells could be isolated from the tissue and grown outside of the body, in cultures. This would allow the cells to be easily manipulated, although they are often relatively rare and difficult to grow in culture.

Because the isolation of adult stem cells does not result in the destruction of human life, research involving adult stem cells does not raise any of the ethical issues associated with research utilizing human embryonic stem cells. Thus, research involving adult stem cells has the potential for therapies that will heal disease and ease suffering, a major focus of Notre Dames stem cell research. Combined with our efforts with induced pluripotent stem (iPS) cells, the Center for Stem Cells and Regenerative Medicine will advance the Universitys mission to ease suffering and heal disease.

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Adult Stem Cells // Center for Stem Cells and Regenerative Medicine ...

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Bone Marrow market estimated to reach US$13899.60 Million during the forecast period – Digital Journal

By daniellenierenberg

ThisBone Marrow MarketReport provides details on Recent New Developments, Trade Regulations, Import-Export Analysis, Production Analysis, Value Chain Optimization, Market Share, Impact of Domestic and Localized Market Players, Analyzes opportunities in terms of emerging revenue pockets, changing market regulations, strategic market growth analysis, market size, market category growth, niche and application dominance, product endorsements, product launches, geographic expansions , technological innovations in the market.For more information on the bone marrow market, please contact Data Bridge Market Research for a summary of theanalyst, our team will help you make an informed market decision to achieve market growth.

Bone Marrow Market is expected to experience market growth during the forecast period of 2021 to 2028. Data Bridge Market Research analyzes that the market is growing with a CAGR of 5.22% during the forecast period of 2021 to 2028 and it is projected to reach USD 13,899.60 Million by 2028. The increasing number of bone marrow diseases will help accelerate the growth of the bone marrow market.Bone marrow transplant also called hematopoietic stem cell.It is a soft vascular tissue present inside the long bones.It includes two types of stem cells, namely hematopoietic and mesenchymal stem cells.The bone marrow is primarily responsible for hematopoiesis (blood cell formation), lymphocyte production, and fat storage.

Get Report Sample PDF: https://www.databridgemarketresearch.com/request-a-sample/?dbmr=global-bone-marrow-market

The main factors driving the growth of the bone marrow market during the forecast period are the growth in the incidence of non-Hodgkins and Hodgkins lymphoma, thalassemia, and leukemia, as well as common bone marrow diseases worldwide, developments in technology and improvements.in health infrastructure.In addition, advanced signs of bone marrow transplantation for cardiac and neural disorders, increased funding for logistics services, and rising health care spending per capita are some of the other factors expected to further drive growth. growth of the bone marrow market in the coming years.years.However, the high costs of treatment,

Key Players Covered in the Bone Marrow Market Report are AGendia, Agilent Technologies, Inc., Ambrilia Biopharma Inc., Astellas Pharma Inc., diaDexus, Illumina, Inc., QIAGEN, F Hoffmann-La Roche Ltd, Sanofi, Stryker Corporation, PromoCell GmbH, STEMCELL Technologies Inc., Lonza, ReachBio LLC, AllCells, ATCC, Lifeline Cell Technology, Conversant bio, HemaCare, Mesoblast Ltd., Merck KGaA, Discovery Life Sciences, ReeLabs Pvt. Ltd., Gamida Cell, among others national and global players.Market share data is available separately for Global, North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA), and South America.DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

For More Information On Market Analysis, View Research Report Summary At :-https://www.databridgemarketresearch.com/reports/global-bone-marrow-market

Bone MarrowMarket Scope and Market Size

The bone marrow market is segmented based on transplant type, disease indication, and end user.Growth between these segments will help you analyze weak growth segments in industries and provide users with valuable market overview and market insights to help them make strategic decisions to identify leading market applications.

Country-level analysis of thebone marrow market

The bone marrow market is analyzed and information is provided on market size and trends by country, transplant type, disease indication, and end user, as mentioned above.Countries Covered in Bone Marrow Market Report are USA, Canada, and Mexico, North America, Germany, France, UK, Netherlands, Switzerland, Belgium, Russia, Italy, Spain, Turkey, Rest of Europe in Europe, China, Japan, India, South Korea, Singapore, Malaysia, Australia, Thailand, Indonesia, the Philippines, Rest of Asia-Pacific (APAC) in the Asia-Pacific region (APAC), Saudi Arabia, United Arab Emirates , South Africa, Egypt, Israel, Rest of the Middle East and Africa (MEA) under Middle East and Africa (MEA), Brazil,

Europe dominates the bone marrow market due to the proliferation of innovative health centers.Furthermore, the health systems have introduced bone marrow transplantation in their contributions and state-of-the-art public facilities that will further drive the growth of the bone marrow market in the region during the forecast period.North America is expected to witness significant growth in the bone marrow market due to increasing cases of chronic diseases such as blood cancer.In addition, the increase in the geriatric population is one of the factors that is expected to drive the growth of the bone marrow market in the region in the coming years.

Explore Full TOC At:- https://www.databridgemarketresearch.com/toc/?dbmr=global-bone-marrow-market

The country section of the Bone Marrow market report also provides individual market impact factors and regulatory changes in the country market that affect current and future market trends.Data points such as consumption volumes, production sites and volumes, import and export analysis, price trend analysis, raw material cost, Downstream and Upstream value chain analysis are some of the main indicators used to forecast the scenario. of the market for each country.Additionally, the presence and availability of global brands and the challenges they face due to significant or rare competition from local and national brands,

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Bone Marrow market estimated to reach US$13899.60 Million during the forecast period - Digital Journal

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Kite’s CAR T-cell Therapy Yescarta First in Europe to Receive Positive CHMP Opinion for Use in Second-line Diffuse Large B-cell Lymphoma and…

By daniellenierenberg

Positive Opinion Based on Landmark ZUMA-7 Study in Which 41% of Patients Demonstrated Event-Free Survival at Two Years versus 16% for Standard of Care -

SANTA MONICA, Calif.--(BUSINESS WIRE)--Kite, a Gilead Company (Nasdaq: GILD), today announces that the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for Yescarta (axicabtagene ciloleucel) for adult patients with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy. If approved, Yescarta will be the first Chimeric Antigen Receptor (CAR) T-cell therapy approved for patients in Europe who do not respond to first-line treatment. Although 60% of newly diagnosed LBCL patients will respond to their initial treatment, 40% will relapse or will not respond and need 2nd line treatment.

At Kite, we are committed to bringing the curative potential of cell therapy to the world, and changing the way cancer is treated, said Christi Shaw, CEO, Kite. Todays positive CHMP opinion brings us a step closer to utilizing cell therapy earlier in the treatment journey, potentially transforming the standard of care for the most common and aggressive form of non-Hodgkin lymphoma.

The European Commission will review the CHMP opinion, and a final decision on the marketing authorization is expected in the coming months.

For people with DLBCL and HGBL who do not respond to first-line treatment or have an early relapse, outcomes are often poor and there are limited curative treatment options for these patients, said Marie Jos Kersten, Professor of Hematology at Amsterdam University Medical Centers, Amsterdam. If approved, axicabtagene ciloleucel may offer a new standard of care for patients with relapsed or refractory DLBCL and HGBL. Importantly, in a randomized trial of axicabtagene ciloleucel versus the current standard of care, quality of life also showed greater improvement in the experimental arm.

The positive opinion for Yescarta is based on the primary results of the landmark Phase 3 ZUMA-7 study, the largest and longest trial of a CAR T-cell therapy versus standard of care (SOC) in second-line LBCL. Results demonstrated that at a median follow-up of two years, Yescarta-treated patients had a four-fold greater improvement in the primary endpoint of event-free survival (EFS; hazard ratio 0.40; 95% CI: 0.31-0.51, P<0.001) over the current SOC (8.3 months v 2.0 months). Additionally, Yescarta demonstrated a 2.5 fold increase in patients who were alive at two years without disease progression or need for additional cancer treatment vs SOC (41% v 16%). Improvements in EFS with Yescarta were consistent across key patient subgroups, including elderly patients (HR: 0.28 [95% CI: 0.16-0.46]), primary refractory patients (HR: 0.43 [95% CI: 0.32- 0.57]), high-grade B cell lymphoma including double-hit and triple-hit lymphoma patients (HGBL; HR: 0.28 [95% CI: 0.14-0.59]), and double expressor lymphoma patients (HR: 0.42 [95% CI: 0.27-0.67]).

In a separate, secondary analysis of Patient-Reported Outcomes (PROs) published in Blood patients receiving Yescarta and eligible for the PROs portion of the study (n=165) showed statistically significant improvements in Quality of Life (QoL) at Day 100 compared with those who received SOC (n=131), using a pre-specified analysis for three PRO-domains (EORTC QLQ-C30 Physical Functioning, EORTC QLQ-C30 Global Health Status/QOL, and EQ-5D-5L visual analog scale [VAS]). There was also a trend toward faster recovery to baseline QoL in the Yescarta arm versus SOC.

In the ZUMA-7 trial, Yescarta had a manageable safety profile that was consistent with previous studies. Among the 170 Yescarta-treated patients evaluable for safety, Grade 3 cytokine release syndrome (CRS) and neurologic events were observed in 6% and 21% of patients, respectively. No Grade 5 CRS or neurologic events occurred. In the SOC arm, 83% of patients had high-grade events, mostly cytopenias (low blood counts).

About ZUMA-7

ZUMA-7 is an ongoing, randomized, open-label, global, multicenter (US, Australia, Canada, Europe, Israel) Phase 3 study of 359 patients at 77 centers, evaluating the safety and efficacy of a single-infusion of Yescarta versus current SOC for second-line therapy (platinum-based salvage combination chemotherapy regimen followed by high-dose chemotherapy and autologous stem cell transplant in those who respond to salvage chemotherapy) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy. The primary endpoint is event free survival (EFS) as determined by blinded central review, and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Key secondary endpoints include objective response rate (ORR) and overall survival (OS). Additional secondary endpoints include patient reported outcomes (PROs) and safety.

About Yescarta

Yescarta was first approved in Europe in 2018 and is currently indicated for three types of blood cancer: Diffuse Large B-Cell Lymphoma (DLBCL); Primary Mediastinal Large B-Cell Lymphoma (PMBCL); and Follicular Lymphoma (FL). For the full European Prescribing Information, please visit: https://www.ema.europa.eu/en/medicines/human/EPAR/yescarta

Please see full US Prescribing Information, including BOXED WARNING and Medication Guide.

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and the median duration was 6 days (range: 1-27 days) for patients with iNHL.

Key manifestations of CRS ( 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range:1- 133 days) and the median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities ( 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41), and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained in the management of CRS and neurologic toxicities. Further information is available at http://www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL; Grade 3 infections occurred in 17% of patients, including Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with an unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with an unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

About Kite

Kite, a Gilead Company, is a global biopharmaceutical company based in Santa Monica, California, with manufacturing operations in North America and Europe. Kites singular focus is cell therapy to treat and potentially cure cancer. As the cell therapy leader, Kite has more approved CAR T indications to help more patients than any other company. For more information on Kite, please visit http://www.kitepharma.com. Follow Kite on social media on Twitter (@KitePharma) and LinkedIn.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the ability of Gilead and Kite to initiate, progress or complete clinical trials within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials, including those involving Yescarta; uncertainties relating to regulatory applications and related filing and approval timelines, including the risk that the European Commission may not grant marketing authorization for Yescarta for use in second-line DLBCL and HGBL in a timely manner or at all; the risk that any regulatory approvals, if granted, may be subject to significant limitations on use; the risk that physicians may not see the benefits of prescribing Yescarta for the treatment of LBCL; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gileads Quarterly Report on Form 10-Q for the quarter ended June 30, 2022 as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead and Kite, and Gilead and Kite assume no obligation and disclaim any intent to update any such forward-looking statements.

U.S. Prescribing Information for Yescarta including BOXED WARNING, is available at http://www.kitepharma.com and http://www.gilead.com .

Kite, the Kite logo, Yescarta and GILEAD are trademarks of Gilead Sciences, Inc. or its related companies .

View source version on businesswire.com: https://www.businesswire.com/news/home/20220916005209/en/

Jacquie Ross, Investorsinvestor_relations@gilead.com

Anna Padula, Mediaapadula@kitepharma.com

Source: Gilead Sciences, Inc.

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Kite's CAR T-cell Therapy Yescarta First in Europe to Receive Positive CHMP Opinion for Use in Second-line Diffuse Large B-cell Lymphoma and...

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Global Induced Pluripotent Stem Cells Market (2022 to 2027) – Growth, Trends, Covid-19 Impact and Forecasts – ResearchAndMarkets.com – Business Wire

By daniellenierenberg

DUBLIN--(BUSINESS WIRE)--The "Induced Pluripotent Stem Cells Market - Growth, Trends, Covid-19 Impact, and Forecasts (2022 - 2027)" report has been added to ResearchAndMarkets.com's offering.

The Induced Pluripotent Stem Cells Market is projected to register a CAGR of 8.4% during the forecast period (2022 to 2027).

Companies Mentioned

Key Market Trends

The Drug Development Segment is Expected to Hold a Major Market Share in the Induced Pluripotent Stem Cells Market.

By application, the drug development segment holds the major segment in the induced pluripotent stem cell market. Various research studies focusing on drug development studies with induced pluripotent stem cells have been on the rise in recent years.

For instance, an article titled "Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening" published in the International Journal of Molecular Science in October 2020 discussed the broad use of iPSC derived cardiomyocytes for drug development in terms of adverse drug reactions, mechanisms of cardiotoxicity, and the need for efficient drug screening protocols.

Another article published in the Journal of Cells in December 2021 titled "Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform-A Cardiac Perspective" focused on methods to reprogram somatic cells into human induced pluripotent stem cells and the solutions to overcome the immaturity of the human induced pluripotent stem cells derived cardiomyocytes to mimic the structure and physiological properties of adult human cardiomyocytes to accurately model disease and test drug safety. Thus, this increase in the research of induced pluripotent stem cells for drug development and drug modeling is likely to propel the segment's growth over the study period.

Furthermore, as per an article titled "Advancements in Disease Modeling and Drug Discovery Using iPSC-Derived Hepatocyte-like Cells" published in the Multi-Disciplinary Publishing Institute journal of Cells in March 2022, preserved differentiation and physiological function, amenability to genetic manipulation via tools such as CRISPR/Cas9, and availability for high-throughput screening, make induced pluripotent stem cell systems increasingly attractive for both mechanistic studies of disease and the identification of novel therapeutics.

North America is Expected to Hold a Significant Share in the Market and Expected to do Same in the Forecast Period

The rise in the adoption of highly advanced technologies and systems in drug development, toxicity testing, and disease modeling coupled with the growing acceptance of stem cell therapies in the region are some of the major factors driving the market growth in North America.

The United States Food and Drug Administration in March 2022 discussed the development of strategies to improve cell therapy product characterization. The agency focused on the development of improved methods for testing stem cell products to ensure the safety and efficacy of such treatments when used as therapies.

Likewise, in March 2020, the Food and Drug Administration announced that ImStem drug IMS001, which uses AgeX's pluripotent stem cell technology, would be available for the treatment of multiple sclerosis. Similarly, REPROCELL introduced a customized iPSC generation service in December 2020, as well as a new B2C website to promote the "Personal iPS" service. This service prepares and stores an individual's iPSCs for future injury or disease regeneration treatment.

Thus, the increasing necessity for induced pluripotent stem cells coupled with increasing investment in the health care department is known to propel the growth of the market in this region.

Key Topics Covered:

1 INTRODUCTION

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS

4.1 Market Overview

4.2 Market Drivers

4.2.1 Increase in Research and Development Activities in Stem Cells Therapies

4.2.2 Surge in Adoption of Personalized Medicine

4.3 Market Restraints

4.3.1 Lack of Awareness Regarding Stem Cell Therapies

4.3.2 High Cost of Treatment

4.4 Porter's Five Force Analysis

5 MARKET SEGMENTATION

5.1 By Derived Cell Type

5.2 Application

5.3 End User

5.4 Geography

6 COMPETITIVE LANDSCAPE

6.1 Company Profiles

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

For more information about this report visit https://www.researchandmarkets.com/r/ylzwhr

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Global Induced Pluripotent Stem Cells Market (2022 to 2027) - Growth, Trends, Covid-19 Impact and Forecasts - ResearchAndMarkets.com - Business Wire

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Neural crest – Wikipedia

By daniellenierenberg

Pluripotent embyronic cell group giving rise to diverse cell lineages

Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineageincluding melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia.[1][2]

After gastrulation, neural crest cells are specified at the border of the neural plate and the non-neural ectoderm. During neurulation, the borders of the neural plate, also known as the neural folds, converge at the dorsal midline to form the neural tube.[3] Subsequently, neural crest cells from the roof plate of the neural tube undergo an epithelial to mesenchymal transition, delaminating from the neuroepithelium and migrating through the periphery where they differentiate into varied cell types.[1] The emergence of neural crest was important in vertebrate evolution because many of its structural derivatives are defining features of the vertebrate clade.[4]

Underlying the development of neural crest is a gene regulatory network, described as a set of interacting signals, transcription factors, and downstream effector genes that confer cell characteristics such as multipotency and migratory capabilities.[5] Understanding the molecular mechanisms of neural crest formation is important for our knowledge of human disease because of its contributions to multiple cell lineages. Abnormalities in neural crest development cause neurocristopathies, which include conditions such as frontonasal dysplasia, WaardenburgShah syndrome, and DiGeorge syndrome.[1]

Therefore, defining the mechanisms of neural crest development may reveal key insights into vertebrate evolution and neurocristopathies.

Neural crest was first described in the chick embryo by Wilhelm His Sr. in 1868 as "the cord in between" (Zwischenstrang) because of its origin between the neural plate and non-neural ectoderm.[1] He named the tissue ganglionic crest since its final destination was each lateral side of the neural tube where it differentiated into spinal ganglia.[6] During the first half of the 20th century the majority of research on neural crest was done using amphibian embryos which was reviewed by Hrstadius (1950) in a well known monograph.[7]

Cell labeling techniques advanced the field of neural crest because they allowed researchers to visualize the migration of the tissue throughout the developing embryos. In the 1960s Weston and Chibon utilized radioisotopic labeling of the nucleus with tritiated thymidine in chick and amphibian embryo respectively. However, this method suffers from drawbacks of stability, since every time the labeled cell divides the signal is diluted. Modern cell labeling techniques such as rhodamine-lysinated dextran and the vital dye diI have also been developed to transiently mark neural crest lineages.[6]

The quail-chick marking system, devised by Nicole Le Douarin in 1969, was another instrumental technique used to track neural crest cells.[8][9] Chimeras, generated through transplantation, enabled researchers to distinguish neural crest cells of one species from the surrounding tissue of another species. With this technique, generations of scientists were able to reliably mark and study the ontogeny of neural crest cells.

A molecular cascade of events is involved in establishing the migratory and multipotent characteristics of neural crest cells. This gene regulatory network can be subdivided into the following four sub-networks described below.

First, extracellular signaling molecules, secreted from the adjacent epidermis and underlying mesoderm such as Wnts, BMPs and Fgfs separate the non-neural ectoderm (epidermis) from the neural plate during neural induction.[1][4]

Wnt signaling has been demonstrated in neural crest induction in several species through gain-of-function and loss-of-function experiments. In coherence with this observation, the promoter region of slug (a neural crest specific gene) contains a binding site for transcription factors involved in the activation of Wnt-dependent target genes, suggestive of a direct role of Wnt signaling in neural crest specification.[10]

The current role of BMP in neural crest formation is associated with the induction of the neural plate. BMP antagonists diffusing from the ectoderm generates a gradient of BMP activity. In this manner, the neural crest lineage forms from intermediate levels of BMP signaling required for the development of the neural plate (low BMP) and epidermis (high BMP).[1]

Fgf from the paraxial mesoderm has been suggested as a source of neural crest inductive signal. Researchers have demonstrated that the expression of dominate-negative Fgf receptor in ectoderm explants blocks neural crest induction when recombined with paraxial mesoderm.[11] The understanding of the role of BMP, Wnt, and Fgf pathways on neural crest specifier expression remains incomplete.

Signaling events that establish the neural plate border lead to the expression of a set of transcription factors delineated here as neural plate border specifiers. These molecules include Zic factors, Pax3/7, Dlx5, Msx1/2 which may mediate the influence of Wnts, BMPs, and Fgfs. These genes are expressed broadly at the neural plate border region and precede the expression of bona fide neural crest markers.[4]

Experimental evidence places these transcription factors upstream of neural crest specifiers. For example, in Xenopus Msx1 is necessary and sufficient for the expression of Slug, Snail, and FoxD3.[12] Furthermore, Pax3 is essential for FoxD3 expression in mouse embryos.[13]

Following the expression of neural plate border specifiers is a collection of genes including Slug/Snail, FoxD3, Sox10, Sox9, AP-2 and c-Myc. This suite of genes, designated here as neural crest specifiers, are activated in emergent neural crest cells. At least in Xenopus, every neural crest specifier is necessary and/or sufficient for the expression of all other specifiers, demonstrating the existence of extensive cross-regulation.[4] Moreover, this model organism was instrumental in the elucidation of the role of the Hedgehog signaling pathway in the specification of the neural crest, with the transcription factor Gli2 playing a key role.[14]

Outside of the tightly regulated network of neural crest specifiers are two other transcription factors Twist and Id. Twist, a bHLH transcription factor, is required for mesenchyme differentiation of the pharyngeal arch structures.[15] Id is a direct target of c-Myc and is known to be important for the maintenance of neural crest stem cells.[16]

Finally, neural crest specifiers turn on the expression of effector genes, which confer certain properties such as migration and multipotency. Two neural crest effectors, Rho GTPases and cadherins, function in delamination by regulating cell morphology and adhesive properties. Sox9 and Sox10 regulate neural crest differentiation by activating many cell-type-specific effectors including Mitf, P0, Cx32, Trp and cKit.[4]

The migration of neural crest cells involves a highly coordinated cascade of events that begins with closure of the dorsal neural tube.

After fusion of the neural fold to create the neural tube, cells originally located in the neural plate border become neural crest cells.[17] For migration to begin, neural crest cells must undergo a process called delamination that involves a full or partial epithelial-mesenchymal transition (EMT).[18] Delamination is defined as the separation of tissue into different populations, in this case neural crest cells separating from the surrounding tissue.[19] Conversely, EMT is a series of events coordinating a change from an epithelial to mesenchymal phenotype.[18] For example, delamination in chick embryos is triggered by a BMP/Wnt cascade that induces the expression of EMT promoting transcription factors such as SNAI2 and FoxD3.[19] Although all neural crest cells undergo EMT, the timing of delamination occurs at different stages in different organisms: in Xenopus laevis embryos there is a massive delamination that occurs when the neural plate is not entirely fused, whereas delamination in the chick embryo occurs during fusion of the neural fold.[19]

Prior to delamination, presumptive neural crest cells are initially anchored to neighboring cells by tight junction proteins such as occludin and cell adhesion molecules such as NCAM and N-Cadherin.[20] Dorsally expressed BMPs initiate delamination by inducing the expression of the zinc finger protein transcription factors snail, slug, and twist.[17] These factors play a direct role in inducing the epithelial-mesenchymal transition by reducing expression of occludin and N-Cadherin in addition to promoting modification of NCAMs with polysialic acid residues to decrease adhesiveness.[17][21] Neural crest cells also begin expressing proteases capable of degrading cadherins such as ADAM10[22] and secreting matrix metalloproteinases (MMPs) that degrade the overlying basal lamina of the neural tube to allow neural crest cells to escape.[20] Additionally, neural crest cells begin expressing integrins that associate with extracellular matrix proteins, including collagen, fibronectin, and laminin, during migration.[23] Once the basal lamina becomes permeable the neural crest cells can begin migrating throughout the embryo.

Neural crest cell migration occurs in a rostral to caudal direction without the need of a neuronal scaffold such as along a radial glial cell. For this reason the crest cell migration process is termed free migration. Instead of scaffolding on progenitor cells, neural crest migration is the result of repulsive guidance via EphB/EphrinB and semaphorin/neuropilin signaling, interactions with the extracellular matrix, and contact inhibition with one another.[17] While Ephrin and Eph proteins have the capacity to undergo bi-directional signaling, neural crest cell repulsion employs predominantly forward signaling to initiate a response within the receptor bearing neural crest cell.[23] Burgeoning neural crest cells express EphB, a receptor tyrosine kinase, which binds the EphrinB transmembrane ligand expressed in the caudal half of each somite. When these two domains interact it causes receptor tyrosine phosphorylation, activation of rhoGTPases, and eventual cytoskeletal rearrangements within the crest cells inducing them to repel. This phenomenon allows neural crest cells to funnel through the rostral portion of each somite.[17]

Semaphorin-neuropilin repulsive signaling works synergistically with EphB signaling to guide neural crest cells down the rostral half of somites in mice. In chick embryos, semaphorin acts in the cephalic region to guide neural crest cells through the pharyngeal arches. On top of repulsive repulsive signaling, neural crest cells express 1and 4 integrins which allows for binding and guided interaction with collagen, laminin, and fibronectin of the extracellular matrix as they travel. Additionally, crest cells have intrinsic contact inhibition with one another while freely invading tissues of different origin such as mesoderm.[17] Neural crest cells that migrate through the rostral half of somites differentiate into sensory and sympathetic neurons of the peripheral nervous system. The other main route neural crest cells take is dorsolaterally between the epidermis and the dermamyotome. Cells migrating through this path differentiate into pigment cells of the dermis. Further neural crest cell differentiation and specification into their final cell type is biased by their spatiotemporal subjection to morphogenic cues such as BMP, Wnt, FGF, Hox, and Notch.[20]

Neurocristopathies result from the abnormal specification, migration, differentiation or death of neural crest cells throughout embryonic development.[24][25] This group of diseases comprises a wide spectrum of congenital malformations affecting many newborns. Additionally, they arise because of genetic defects affecting the formation of neural crest and because of the action of Teratogens [26]

Waardenburg's syndrome is a neurocristopathy that results from defective neural crest cell migration. The condition's main characteristics include piebaldism and congenital deafness. In the case of piebaldism, the colorless skin areas are caused by a total absence of neural crest-derived pigment-producing melanocytes.[27] There are four different types of Waardenburg's syndrome, each with distinct genetic and physiological features. Types I and II are distinguished based on whether or not family members of the affected individual have dystopia canthorum.[28] Type III gives rise to upper limb abnormalities. Lastly, type IV is also known as Waardenburg-Shah syndrome, and afflicted individuals display both Waardenburg's syndrome and Hirschsprung's disease.[29] Types I and III are inherited in an autosomal dominant fashion,[27] while II and IV exhibit an autosomal recessive pattern of inheritance. Overall, Waardenburg's syndrome is rare, with an incidence of ~ 2/100,000 people in the United States. All races and sexes are equally affected.[27] There is no current cure or treatment for Waardenburg's syndrome.

Also implicated in defects related to neural crest cell development and migration is Hirschsprung's disease (HD or HSCR), characterized by a lack of innervation in regions of the intestine. This lack of innervation can lead to further physiological abnormalities like an enlarged colon (megacolon), obstruction of the bowels, or even slowed growth. In healthy development, neural crest cells migrate into the gut and form the enteric ganglia. Genes playing a role in the healthy migration of these neural crest cells to the gut include RET, GDNF, GFR, EDN3, and EDNRB. RET, a receptor tyrosine kinase (RTK), forms a complex with GDNF and GFR. EDN3 and EDNRB are then implicated in the same signaling network. When this signaling is disrupted in mice, aganglionosis, or the lack of these enteric ganglia occurs.[30]

Prenatal alcohol exposure (PAE) is among the most common causes of developmental defects.[31] Depending on the extent of the exposure and the severity of the resulting abnormalities, patients are diagnosed within a continuum of disorders broadly labeled Fetal Alcohol Spectrum Disorder (FASD). Severe FASD can impair neural crest migration, as evidenced by characteristic craniofacial abnormalities including short palpebral fissures, an elongated upper lip, and a smoothened philtrum. However, due to the promiscuous nature of ethanol binding, the mechanisms by which these abnormalities arise is still unclear. Cell culture explants of neural crest cells as well as in vivo developing zebrafish embryos exposed to ethanol show a decreased number of migratory cells and decreased distances travelled by migrating neural crest cells. The mechanisms behind these changes are not well understood, but evidence suggests PAE can increase apoptosis due to increased cytosolic calcium levels caused by IP3-mediated release of calcium from intracellular stores. It has also been proposed that the decreased viability of ethanol-exposed neural crest cells is caused by increased oxidative stress. Despite these, and other advances much remains to be discovered about how ethanol affects neural crest development. For example, it appears that ethanol differentially affects certain neural crest cells over others; that is, while craniofacial abnormalities are common in PAE, neural crest-derived pigment cells appear to be minimally affected.[32]

DiGeorge syndrome is associated with deletions or translocations of a small segment in the human chromosome 22. This deletion may disrupt rostral neural crest cell migration or development. Some defects observed are linked to the pharyngeal pouch system, which receives contribution from rostral migratory crest cells. The symptoms of DiGeorge syndrome include congenital heart defects, facial defects, and some neurological and learning disabilities. Patients with 22q11 deletions have also been reported to have higher incidence of schizophrenia and bipolar disorder.[33]

Treacher Collins Syndrome (TCS) results from the compromised development of the first and second pharyngeal arches during the early embryonic stage, which ultimately leads to mid and lower face abnormalities. TCS is caused by the missense mutation of the TCOF1 gene, which causes neural crest cells to undergo apoptosis during embryogenesis. Although mutations of the TCOF1 gene are among the best characterized in their role in TCS, mutations in POLR1C and POLR1D genes have also been linked to the pathogenesis of TCS.[34]

Neural crest cells originating from different positions along the anterior-posterior axis develop into various tissues. These regions of neural crest can be divided into four main functional domains, which include the cranial neural crest, trunk neural crest, vagal and sacral neural crest, and cardiac neural crest.

Cranial neural crest migrates dorsolaterally to form the craniofacial mesenchyme that differentiates into various cranial ganglia and craniofacial cartilages and bones.[21] These cells enter the pharyngeal pouches and arches where they contribute to the thymus, bones of the middle ear and jaw and the odontoblasts of the tooth primordia.[35]

Trunk neural crest gives rise two populations of cells.[36] One group of cells fated to become melanocytes migrates dorsolaterally into the ectoderm towards the ventral midline. A second group of cells migrates ventrolaterally through the anterior portion of each sclerotome. The cells that stay in the sclerotome form the dorsal root ganglia, whereas those that continue more ventrally form the sympathetic ganglia, adrenal medulla, and the nerves surrounding the aorta.[35]

The vagal and sacral neural crest cells develop into the ganglia of the enteric nervous system and the parasympathetic ganglia.[35]

Cardiac neural crest develops into melanocytes, cartilage, connective tissue and neurons of some pharyngeal arches. Also, this domain gives rise to regions of the heart such as the musculo-connective tissue of the large arteries, and part of the septum, which divides the pulmonary circulation from the aorta.[35]The semilunar valves of the heart are associated with neural crest cells according to new research.[37]

Several structures that distinguish the vertebrates from other chordates are formed from the derivatives of neural crest cells. In their "New head" theory, Gans and Northcut argue that the presence of neural crest was the basis for vertebrate specific features, such as sensory ganglia and cranial skeleton. Furthermore, the appearance of these features was pivotal in vertebrate evolution because it enabled a predatory lifestyle.[38][39]

However, considering the neural crest a vertebrate innovation does not mean that it arose de novo. Instead, new structures often arise through modification of existing developmental regulatory programs. For example, regulatory programs may be changed by the co-option of new upstream regulators or by the employment of new downstream gene targets, thus placing existing networks in a novel context.[40][41] This idea is supported by in situ hybridization data that shows the conservation of the neural plate border specifiers in protochordates, which suggest that part of the neural crest precursor network was present in a common ancestor to the chordates.[5] In some non-vertebrate chordates such as tunicates a lineage of cells (melanocytes) has been identified, which are similar to neural crest cells in vertebrates. This implies that a rudimentary neural crest existed in a common ancestor of vertebrates and tunicates.[42]

Ectomesenchyme (also known as mesectoderm):[43] odontoblasts, dental papillae, the chondrocranium (nasal capsule, Meckel's cartilage, scleral ossicles, quadrate, articular, hyoid and columella), tracheal and laryngeal cartilage, the dermatocranium (membranous bones), dorsal fins and the turtle plastron (lower vertebrates), pericytes and smooth muscle of branchial arteries and veins, tendons of ocular and masticatory muscles, connective tissue of head and neck glands (pituitary, salivary, lachrymal, thymus, thyroid) dermis and adipose tissue of calvaria, ventral neck and face

Endocrine cells:chromaffin cells of the adrenal medulla, glomus cells type I/II.

Peripheral nervous system:Sensory neurons and glia of the dorsal root ganglia, cephalic ganglia (VII and in part, V, IX, and X), Rohon-Beard cells, some Merkel cells in the whisker,[44][45] Satellite glial cells of all autonomic and sensory ganglia, Schwann cells of all peripheral nerves.

Enteric cells:Enterochromaffin cells.[46]

Melanocytes and iris muscle and pigment cells, and even associated with some tumors (such as melanotic neuroectodermal tumor of infancy).

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Neural crest - Wikipedia

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Rise In Number Of CROS In Various Regions Such As Europe Is Expected To Fuel The Growth Of Induced Pluripotent Stem Cell Market At An Impressive CAGR…

By daniellenierenberg

Rise In Research And Development Projects In Various Regions Such As East Asia, South Asia Are Expected To Offer An Opportunity Of US $ 0.5 Bn In 2022-2026 Period.

Fact.MR A Market Research and Competitive Intelligence Provider: The global induced pluripotent stem cell (iPSC) market was valued at US $ 1.8 Bn in 2022, and is expected to witness a value of US $ 2.3 Bn by the end of 2026.

Moreover, historically, demand for induced pluripotent stem cells had witnessed a CAGR of 6.6%.

Rise in spending on research and development activities in various sectors such as healthcare industry is expected to drive the adoption of human Ips cell lines in various applications such as personalized medicine and precision.

Moreover, increasing scope of application of human iPSC cell lines in precision medicine and emphasis on therapeutic applications of stem cells are expected to be driving factors of iPSC market during the forecast period.

Surge in government spending and high awareness about stem cell research across various organizations are predicted to impact demand for induced pluripotent stem cells. Rising prevalence of chronic diseases and high adoption of stem cells in their treatment is expected to boost the market growth potential.

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Besides this, various cells such as neural stem cells, embryonic stem cells umbilical cord stem cells, etc. are anticipated to witness high demand in the U.S. due to surge in popularity of stem cell therapies.

Key Takeaways:

Growth Drivers:

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Key Restraints:

Competitive Landscape:

Many key players in the market are increasing their investments in R&D to provide offerings in stem cell therapies, which are gaining traction for the treatment of various chronic diseases.

For instance:

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Rise In Number Of CROS In Various Regions Such As Europe Is Expected To Fuel The Growth Of Induced Pluripotent Stem Cell Market At An Impressive CAGR...

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New research digs into the genetic drivers of heart failure, with an eye to precision treatments – STAT

By daniellenierenberg

When coronary arteries are blocked, starving the heart of blood, there are good medications and treatments to deploy, from statins to stents. Not so for heart failure, the leading factor involved in heart disease, the top cause of death worldwide.

Its whats on death certificates, said cardiologist Christine Seidman.

Seidman has long been interested in heart muscle disorders and their genetic drivers. She studies heart failure and other conditions that affect the myocardium the muscular tissue of the heart not the blood vessels where atherosclerosis and heart attacks come from, although their consequences are also felt in the myocardium, including heart failure.

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With her colleagues at Brigham and Womens Hospital and Harvard Medical School, she and a long list of international collaborators have been exploring the genetic underpinnings of heart failure. Based on experiments deploying a new technique called single-nucleus RNA sequencing on samples from heart patients, on Thursday they reported in Science their discovery of how genotypes change the way the heart functions.

Their work raises the possibility that some of the molecular pathways that lead to heart failure could be precisely targeted, in contrast to treating heart failure as a disease with only one final outcome.

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Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting, she said. To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

Seidman talked with STAT about the research, including how snRNAseq solves the smoothie problem, and what it might mean for patients. The conversation has been edited for clarity and brevity.

What happens in heart failure?

The heart becomes misshapen in one of two ways. It either becomes hypertrophied, where the walls of heart muscle become thickened and the volume within the heart is diminished, in what we call hypertrophic cardiomyopathy. Or it becomes dilated, when the volume in the heart is expanded and the walls become stretched. I think of it as an overinflated balloon, and that is called dilated cardiomyopathy.

Hypertrophy and dilatation are known to cause the heart over time to have profoundly diminished functional capacity. And clinically, we call that heart failure, much more commonly arising from dilated cardiomyopathy.

What does it feel like to patients?

When we see patients clinically, theyre short of breath, they have fluid retention. When we look at their hearts, we see that the pump function is diminished. That has led to a hypothesis of heart failure as sort of the end stage of many different disorders, but eventually the heart walks down a final common pathway. Then you need a transplant or a left ventricular assist device, or youre going to die prematurely.

What can be done?

Heart failure is a truly devastating condition, and it can arise early in life, in middle age, and in older people. There is no treatment for it, no cure for it, except cardiac transplantation, of course, which provides a whole host of other problems.

How did you approach this problem?

One of the questions we wanted to answer is, are there signals that we can discern that say there are different pathways and there are molecules that are functioning in those pathways that ultimately converge for failure, but through different strategies of your heart?

We treat every patient with heart failure with diuretics. We give them a series of different medications to reduce the pressure against which the heart has to contract. Im clinically a cardiologist, but molecularly Im a geneticist, so it doesnt make sense. If your house is falling down because the bricks are sticking together or if its falling down because the roof leaks and the water is pooling, you do things differently.

Tell me how you used single-cell RNA sequencing to learn more.

Looking at RNA molecules gives us a snapshot of how much a gene is active or inactive at a particular time point. Until recently, we couldnt do that in the heart because the approach had been to take heart tissue, grind it all up, and look at the RNAs that are up or down. But that gives you what we call a smoothie: Its all the different component cells those strawberries, blueberries, bananas mixed together.

But theres a technology now called single-cell RNA sequencing. And that says, what are the RNAs that are up or down in the cardiomyocytes as compared to the smooth muscle cells, as compared to the fibroblasts, all of which are in the cells? You get a much more precise look at whats changing in a different cell type. And thats the approach that we use, because cardiomyocytes [the cells in the heart that make it contract] are very large. Theyre at least three times bigger than other cells. We cant capture the single cell it literally does not fit through the microfluidic device. And so we sequenced the nuclei, which is where the RNA emanates from.

What did you find?

There were some similarities, but what was remarkable was the degree of differences that we saw in cardiomyocytes, in endothelial cells, in fibroblasts. Theres a signature thats telling us I walked down this pathway as compared to a different one that caused the heart to fail, but through activation or lack of activation of different signals along the way.

And that to me is the excitement, because if we can say that, we can then go back and say, OK, what happens if we were to have tweaked the pathway in this genotype and a different pathway in a different genotype? Thats really what precision therapy could be about, and thats where we aim to get to.

Whats the next step?

It may be that several genotypes will have more similarities as compared to other genotypes. But understanding that, I think, will allow us to test in experimental models, largely in mice, but increasingly in cellular models of disease, in iPS [induced pluripotent stem] cells that we can now begin to use molecular technologies to silence a pathway and see what that does to the cardiomyocytes, or silence the fibroblast molecule and see what that does in that particular genotype.

To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

What might this mean for patients?

If we knew that an intervention would make a difference thats where the experiments are we would intervene when we saw manifestations of disease. So the reason I can tell you with confidence that certain genes cause dilated cardiomyopathy is theres a long time between the onset of that expansion of the ventricle until you develop heart failure. So theres years for us to be able to stop it in its tracks or potentially revert the pathology, if we can do that.

What else can you say?

I would be foolish not to mention the genetic cause of dilated cardiomyopathy. Ultimately, if you know the genetic cause of dilated cardiomyopathy, this is where gene therapy may be the ultimate cure. Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting.

My colleagues have estimated that approximately 1 in 250 to 1 in 500 people may have an important genetic driver of heart muscle disease, cardiomyopathy. Thats a huge number, but not all of them will progress to heart failure, thank goodness. Around the world, there are 23 million people with heart failure. Its what ends up on most peoples death certificate. It is the most common cause of death.

Its a huge, huge burden. And there really is no cure for it except transplantation. We dont have a reparative capacity, so were going to have to know a cause and be able to intervene precisely for that cause.

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New research digs into the genetic drivers of heart failure, with an eye to precision treatments - STAT

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Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education – India Education Diary

By daniellenierenberg

Research led by Muhammad Riaz, PhD, Jinkyu Park, PhD, and Lorenzo Sewanan, MD, PhD, from the Qyang and Campbell laboratories at Yale, provides a mechanism to identify abnormalities linked with a hereditary cardiac condition, hypertrophic cardiomyopathy (HCM), in which walls of the left ventricle become abnormally thick and often stiff. The findings appear in the journal Circulation.

Patients with familial HCM have an increased risk of sudden death, heart failure, and arrhythmias. HCM is the most common inherited cardiac disease, affecting one in 500 people. The disease is thought to be caused by mutations that regulate cardiac muscle contraction, compromising the hearts ability to pump blood. However, the mechanisms behind the disease are poorly understood.

For this multi-model study, the researchers used stem cell approaches to understand the mechanisms that drive inherited HCM. The technology, induced pluripotent stem cells (iPSCs), can accelerate insights into the genetic causes of disease and the development of new treatments using the patients own cells.

This is a humbling experience that a patients disease phenotypes teach researchers fundamental basic knowledge that sets the stage for innovative new therapies. Furthermore, our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues, said Yibing Qyang, PhD, associate professor of medicine (cardiology) and of pathology.

We wanted to understand the disease mechanism and find a new therapeutic strategy, Park said.

Probing the heart disorders mechanismThe concept originated with an 18-month-old patient who suffered from familial HCM. Through a collaboration with Daniel Jacoby, MD, adjunct associate professor of cardiovascular medicine and an expert on HCM, who provided medical care for this patient, Park and the team used stem cell technologies to address a fundamental question, the disease mechanisms behind HCM. They collected 10 cc of the patients blood and introduced stem cell factors into the blood cells to generate self-renewable iPSCs. By applying cardiac knowledge, they coaxed iPSCs into patients own cardiomyocytes (heart cells) for cardiac disease studies. We discovered a general mechanism which explains the disease progression, said Park.

Next, they engineered heart tissues that resembled the early-onset disease scenario of the young patient. The disease was a severe presentation at the age of 18 months, which suggested that the disease started at the fetal/neonatal stage.

The next phase of the study was to recreate a 3-D model that was used to mimic the progression of the disease, including mechanical properties such as contraction and force production of that muscle, to understand how much force is compromised if the mutation is present. This was performed in collaboration with Stuart Campbell, PhD, and Sewanan from Yales Department of Biomedical Engineering. Coupled with computational modeling for muscle contraction, the authors developed robust systems that allowed them to examine the biomechanical properties of the tissue at three-dimensional levels.

Finally, using advanced gene editing technologies, the research team modified these mutations. They discovered that after the mutations were corrected, the disease was reversed. These insights about sarcomeric protein mutations could lead to novel therapeutics for HCM and other diseases. The interaction between mutations could also suggest that the same biomechanical mechanism exists in other conditions such as ischemic heart disease.

Our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues.

Yibing Qyang, PhDWe can apply these findings to cardiac conditions associated with hypertension, diabetes, or aging, said Riaz.

Applying the findings to heart diseaseOne of the fundamental challenges was that we needed to generate iPSCs from the patients family, Riaz added. Using this technology, Park was able to recreate primary cells from the cells of a patient with HCM, a process which takes over a month. Riaz and Park used stem cells to identify the vital role of pathological tissue remodeling, which is caused by sarcomeric hypertrophic cardiomyopathy mutations.

We are hopeful that our findings will be replicated in the scientific community, said Riaz. This is an example of bed to bench research, where scientists extract materials from clinics and conduct the experiment in the laboratory and then discover new methods to treat patients.

The authors also noted that RNA sequencing could be used as a guide to characterize the disease at a molecular level. Scientists may be able to identify more targeted drugs by examining the biomechanical properties of the tissue. We can now screen multiple drugs to see whether any of those drugs are able to rescue the phenotype, they said.

Riaz, now an associate research scientist in the Qyang lab, began as a cancer researcher. He earned a PhD from the Erasmus University Medical Center, based in Rotterdam, Netherlands. He later studied genetic disorders in skeletal muscle disease before joining the lab in 2017.

Park, also from the Qyang lab, graduated from Seoul National University, South Korea in 2013. He completed postdoctoral research at the University of Missouri where he focused on vascular biology and emerging areas in stem cell technology.

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Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort – Cureus

By daniellenierenberg

Immediate cord clamping (ICC), within a few seconds after birth, became routine in the latter half of the 20th century, as part of a tranche of medical birth-related interventions that collectively, undoubtedly improved maternal and neonatal survival and outcomes [1]. The trend to ICC (within 15-20 seconds after birth) was partly driven by some early studies suggesting that the most benefit in terms of blood volume is achieved within this time frame [2], and that deferred cord clamping (DCC) increased rates of polycythemia and jaundice [1]. It may also have been partly driven by increased rates of operative deliveries and consequent pressure to minimize surgical times, as well as the increased availability and effectiveness of neonatal resuscitation. Furthermore, ICC was proposed as a means to reduce the risk of maternal exposure to fetal blood group antigens at a time (before RhD immunoprophylaxis) when hemolytic disease of the fetus and newborn was far more common than it is now.

Formal evidence that ICC was beneficial was never sought, and recent research summarized in systematic reviews [3-6] has suggested that it may be harmful when compared with DCC for various intervals from 30 seconds until when the cord stops pulsating (defined in some studies as physiological cord clamping). ICC before the onset of breathing exposes the newborn baby to a period of significantly restricted cardiac function, whereas DCC until after the onset of breathing (which often does not occur until late in the first minute after birth) may mean that the expanding pulmonary circulation is able to fill with blood from the placenta, rather than by reverse flow across the ductus arteriosus [7]. This may improve left ventricular preload and stabilize pressures and flows in major vessels [7].

In addition, when cord clamping is deferred, babies may receive a transfusion of blood from the umbilical cord and placenta. A recent systematic review demonstrated that DCC in preterm babies improves peak hematocrit in the first week by 2.7% (95% confidence intervals (CI) 1.88-3.52) and reduced the proportion of babies receiving any subsequent blood transfusion (RD: -0.07, 95%CI -0.11 to -0.04) [6]. Some studies have found a weight increase in the first two minutes after birth when the cord is not clamped, supporting the hypothesis of placental transfusion [8]. Yet, recent evidence shows that placental transfusion may not always occur (Conference abstract: Vijayaselvi R, Abraham A, Kumar M, Kuruvilla A, Mathews J, Duley L. Measuring Umbilical Flow and Placental Transfusion for Preterm Births: Weighing Babies at 33-36 Weeks Gestation with Cord Intact. 1st Congress of Joint European Neonatal Societies; 2015).

The relative roles of cardiovascular stabilization at birth versus placental transfusion in improving outcomes have not been established. Understanding the contributions of these two mechanisms has significant implications for research and practice: for example, if the size of placental transfusion is more important, then prescribing a top-up transfusion soon after birth for babies with lower than average hemoglobin (who are known to be at higher risk of various adverse outcomes) [9] may be justified, especially for the babies for whom DCC has been precluded by maternal or fetal conditions. These include significant maternal bleeding, and monochorionic twins, where deferred cord clamping in the first twin could lead to one twin losing blood to the other. However, if it is the effects on improving cardiovascular stability in the first minutes (with consequential benefits for cardiorespiratory function and reducing severity of illness during the subsequent neonatal intensive care unit (NICU) stay), regardless of the magnitude of transfusion, then early top-up transfusion is unlikely to be helpful.

Observational studies suggest that exposure to blood transfusion itself is harmful to preterm babies, increasing the risk of adverse outcomes [10]. However, this suggestion has not been supported by the small number (to date) of randomized controlled trials of blood (red cell) transfusion thresholds [11-14]. It is unlikely to be the means by which DCC reduced deaths in the largest trial to date of deferred cord clamping in preterm babies, the Australian Placental Transfusion Study (APTS), and in the most recent systematic review on this, because neither showed a difference in rates of other adverse outcomes [6,15].

Another possibility is that it is the umbilical cord blood stem cells received by the baby are the main reason for the observed benefits to both survival and reduced requirement for later blood transfusion [16]. Umbilical cord blood has been demonstrated to be such a good contributor to hematopoiesis that it is a recognized stem cell resource for pediatric and adult hematopoietic stem cell transplant [17]. In addition, umbilical cord blood is a potential regenerative and immunomodulatory agent for a variety of clinical conditions [18], so in this case, the extent of placental transfusion would be critical to the improvement of outcomes, and transfusion with adult red cells would not suffice. There are no established methods to quantify the contribution of umbilical cord stem cells to placental transfusion. However, a larger volume of placental transfusion results in the baby receiving more nucleated cells [19], including more umbilical cord stem cells.

Discerning whether these effects (initial enhanced cardiovascular stability leading to early and sustained reduction in severity of illness or volume of placental transfusion) appear to be the main driver of improved outcomes is likely to contribute to practice change, as well as to informing the design of future research studies into methods to improve outcomes of high-risk newborn babies and reduce their transfusion dependence.

The causal mechanisms of reduced transfusion requirements found in DCC relative to ICC are yet to be resolved. The aim of the study is to address the question; In preterm infants (P) does DCC (I) compared to ICC (C) reduce dependence on red cell transfusion via enhanced cardiovascular stability (mediator 1, M1) or via an increased volume of placental transfusion (M2).

The study is a nested retrospective study, called the Transfusions in the APTS Newborns Study (TITANS) (study registration: ACTRN12620000195954), of the cohort of babies who were enrolled and randomly assigned to ICC or DCC in the Australian and New Zealand (NZ) sites for APTS (study registration: ACTRN12610000633088). This design has been developed to take advantage of the comprehensive dataset already collected for APTS, and because there is currently no suitable prospective study that could address the same research questions in such a large group of participants.

Babies had been considered eligible for APTS if obstetricians or maternal-fetal medicine specialists anticipated that delivery would occur before 30 weeks of gestation. Exclusion criteria included fetal hemolytic disease, hydrops fetalis, twin-twin transfusion, genetic syndromes, and potentially lethal malformations. Further details are available in the original APTS publication [15]. In the present TITANS analysis, we will also exclude any baby with a diagnosis of hemolytic anemia or aplastic/hypoplastic anemia.

There were 1401 babies enrolled for APTS from the 13 Australian and 5 NZ hospital sites [15]. APTS data was provided to the TITANS team on 31 July, 2020. It is planned to collect additional data from Australian and NZ APTS sites using a customised, secure web-based database application (REDCap) [20], which is maintained by the University of Sydney, Sydney, Australia. Data will be obtained from source documents (patient hospital records and laboratory reports) using the electronic data collection application from each study site. The individual participant data collected will correspond to the minimum data required to answer the research questions. Baby identification (ID) and other babies details from APTS will be used to re-identify participants and link them to hospital records. Identified data will be collected, in order to allow linkage between the data newly collected from patient records and hospital laboratories and the existing APTS dataset. The data will be checked with respect to range, internal consistency, consistency with published reports and missing items. After data cleaning and analysis, data will be stored in re-identifiable form, with each participants data being identified with the same study numbering system as used for the APTS study.

We will combine the data already extracted, stored and cleaned from APTS with the additional data obtained from study sites for each participating baby, to determine which factors are most influential in reducing transfusion requirements. The specific objectives are, after adjustment for prior risk factors (listed below), to determine:

1.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by placental transfusion (measured by hematocrit (Hct)) as seen in Figure 1 (a, c) following the causal path X M1 Y, where X is the intervention, ICC or DCC, Y is the outcome, mediator M1 is placental transfusion, and M2 is initial severity of illness stability

2.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by initial severity of illness (respiratory support, sampling line yes/no and total duration number, blood pressure, cumulative blood sample volume) as seen in Figure 1 (b, c) following the causal path X M2 Y

3.Whether the effect of cord clamping intervention on the outcome (blood transfusions) is driven by multiple mediators (placental transfusion and initial severity of illness) as seen in Figure 1 (c)

4.Whether cording clamping intervention (ICC or DCC) has a direct effect on the outcome after accounting for the mediators as seen in all panels of Figure 1: X Y.

The protocol was approved by the Northern Sydney Local Health District Human Research Ethics Committee in November 2019 (Version 3.0, Reference 2019/ETH12819), the Mater Misericordiae Ltd Human Research Ethics Committee (Version 1.0, Reference HREC/MML/56247), the Mercy Health Human Research Ethics Committee (Version 2.0, Reference 2020-078), and the Southern Health and Disability Ethics Committee (Version 1.0, Reference 19/STH/195). The ethics committees have granted a waiver of consent. The study is conducted in accordance with the National Health and Medical Research Council Statement on Ethical Conduct in Research Involving Humans.

Intervention

The intervention consisted of either immediate or delayed cord clamping (as assigned in APTS). Immediate clamping was defined as clamping the cord within 10 seconds of delivery. Delayed clamping was defined as clamping the cord at least 60 seconds after delivery, with the infant held as low as possible, below the introitus or placenta, and with no palpation of the cord. Variations in the protocol were allowed if they would aid the mother, baby, or both. If the baby was non-vigorous (heart rate <100 beats per minute, low muscle tone, or lack of breathing, or crying), clinicians were allowed to break protocol using their discretion. Cord milking was not part of the protocol for either intervention. Further details may be sourced from the original APTS publication [15].

Outcomes

The primary outcome is the proportion of babies receiving red cell transfusion (for restoration of hemoglobin or blood volume). The secondary outcomes are number of transfusions per baby, cumulative transfusion volume (mL/kg) per baby, and primary reasons for each transfusion.

Putative Mediators

M1: Indicators of placental transfusion to be assessed will be hematocrit (on admission, highest on the first day, highest in the first week collected before any postnatal transfusion).

M2: Indicators of initial severity of illness to be assessed will be cumulative blood sample volume collected throughout hospital stay (number of blood tests multiplied by hospitals usual sample volume for each type of test), sampling line (umbilical arterial line or peripheral arterial line) - yes/no and total duration, mechanical ventilation or inspired O2, and blood pressure.

Sensitivity Analyses (For the Primary Outcome Analysis Only)

Sensitivity analyses will adjust for the following variables: gender, birth <27 weeks vs. 27 weeks, method of delivery (vaginal versus cesarean), intraventricular hemorrhage (IVH) (yes/no and grade III/IV yes/no), surgery for patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and sodium in the first 24 hours of life. We will also test model assumptions relating to sequential ignorability and post-randomization confounding (discussed further in the data analysis plan).

Potential Confounders (Covariates)

The following covariates may be used for adjustment in the analysis: gestational age at randomization before birth and any oral iron supplement pre-transfusion.

Timing of Assessments

Putative mediating variables will only be analyzed if they have been measured before the outcome and will be excluded if there is not adequate time and date information available. If the multiple mediator model is applied, careful consideration of timing information will be evaluated. If there is insufficient empirical information to conclude the causal ordering of mediators (M1 causes M2), we will adjust our analytic approach (as discussed in the analysis plan) and discuss any limitations.

Data Analysis Plan

The analysis will include all babies who were initially randomized in the APTS trial for whom we were able to obtain the relevant data and be based on intention-to-treat. All statistical analyses will be conducted in R version 4.1.3 (2022-03-10; R Foundation for Statistical Computing, Vienna, Austria). Descriptive characteristics for continuous data will be presented as means or medians, as appropriate, and categorical data will be presented as frequencies and percentages.

A model-based inference approach will be applied to estimate the average causal mediation effect (ACME), average direct effect (ADE), and the average total effect as recommended [23-25]. This approach will be applied with the R mediation package [26]. We will initially fit two models, one model with mediation as the dependent variable and intervention as the independent variable (mediator model), and a second model with the outcome as the dependent variable, and both mediation and intervention as independent variables (outcome model). To account for the clustering of multiples, estimates will be calculated with generalized estimating equations with a compound symmetric correlation structure to account for within subject correlations. Depending on the outcome (binary, count, skew) these will be modelled with the appropriate family and link functions.

A counterfactual framework will be applied to the mediator and outcome models to simulate the values of the mediator and outcome to estimate the potential values of the mediator. This process is used to estimate the ACME, ADE, and average total effects; 95%CI will be estimated with 1000 bootstrap simulations.

We will apply single mediator models on both placental transfusion variables and initial severity of illness variables if mediators are statistically independent, as seen in Table 1. Independence will be tested using linear regression and any appropriate link functions. If both mediators are not statistically independent, we will investigate the possibility of multiple mediator models, which require an expanded framework for analysis [21]. Here we assume that initial severity of illness is causally related to placental transfusion. For this process, we will use the method developed by Imai and Yamamoto [21] to estimate the ACME and ADE. Following this, 95%CI will be estimated with 1000 bootstrap simulations. If theoretical and empirical timing data and sensitivity analyses suggest that M1 and M2 have non-causal correlation and may be affected by an unmeasured latent mediator, we will adjust our approach to estimate interventional direct and path-specific indirect effects [27,28].

Sensitivity analyses have been limited to a set of biologically plausible and clinically meaningful groups that will be explored by including them for adjustment with covariates, and with the introduction of interaction terms if appropriate. Missing data will be described, reasons for missing data will be explored, and the impact of missing data on conclusions about the treatment effect on the primary outcome will also be explored where possible (e.g., using sensitivity analyses and multiple imputation techniques).

Methodological Assumptions

The causal mediation approach assumes sequential ignorability: that the treatment effect on the outcome is not confounding and that the mediator effect on the outcome is not confounded. As treatment was randomly allocated to neonates, we will assume that the treatment-mediator relationship is not confounded. However, the mediator itself has not been randomized. Thus, unknown confounders may be driving a spurious effect in the mediator-outcome relationship. We will employ additional sensitivity analyses to estimate whether any mediation effects are sensitive to the violation of the assumption of sequential ignorability. To test the possibility of unmeasured confounders we will examine the correlation between residuals in the mediator model and the outcome model. If there is no correlation this would suggest there is no unmeasured confounding, if there is correlation between the residuals, an unmeasured mediator may be affecting both the measured mediator and the outcome. We will apply the method developed by Imai et al. andTingley et al. [23,26] that uses sensitivity analyses to evaluate if the ACME estimate is sensitive to unmeasured confounding.

Post-randomization confounders are dependent on the treatment allocated, affect both mediator and outcome, and can corrupt the mediation estimate. In the context of the present trial, it is possible that non-adherence to the intervention is a post-randomization confounder. We are analyzing our data based on intention to treat principles; however, a sensitivity analysis based on the actual time of cord clamping to assess the influence of non-adherence with the treatment protocol on our estimates may be performed.

Blood transfusions of neonates have been associated with a number of serious adverse outcomes [29]. Nevertheless, there are few evidence-based methods to reduce transfusion exposure [30]. The APTS study found that DCC was associated with a statistically significant reduced need for red cell transfusions by about 10% compared to ICC [15]. However, the mechanism remains unclear.

The study will, at a minimum, provide further information that should increase clinicians understanding of the pathways by which DCC (or other methods to accomplish placental transfusion) results in beneficial patient outcomes. Since one of the main barriers to implementation is lack of understanding about the mechanisms by which such a simple practice change should have such dramatic effects, this should improve adherence to recommendations to defer cord clamping for most babies, thereby reducing mortality and transfusion incidence.

By elaborating on the mechanisms, it may also provide good evidence for how other routine neonatal intensive care practices and interventions affect likelihood of needing to transfuse. Better understanding of these effects may lead to other testable hypotheses or improvements in other aspects of practice, further reducing transfusion exposure and improving other outcomes.

Potential limitations of the study include the dependence on some routinely collected clinical data, which were not collected at the time by the original study according to predefined research definitions. However, we have no reason to think that potential problems of data quality would have been influenced by study group allocation and so do not anticipate that this will be a source of bias.

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Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort - Cureus

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Buffalo center fuels research that can save your life from heart disease and stroke – Buffalo News

By daniellenierenberg

Dr. Jennifer Lang splits most of her work life treating patients at Gates Vascular Institute and conducting research in her lab several floors up in the same building.

UB medical physics students Simon Wu and Emily Vanderbelt work with flow-through 3D-printed aneurysm models using X-rays in the Canon Stroke & Vascular Research Center, part of the University at BuffaloClinical and Translational Research Center on the Buffalo Niagara Medical Campus.

The arrangement suits her well as she continues promising research to learn if a stem cell-derived treatment can repair damaged heart tissue.

Lang, a cardiologist, and her University at Buffalo team, face a dilemma: The immune system revs into high gear when the heart suffers a serious setback, limiting the power of stem cells to heal.

The daunting task seems more surmountable these days because she works in a building filled with researchers of all stripes.

I do collaborations with groups that I otherwise wouldn't have. Its led to some really new, interesting results, said Lang, assistant professor in the UB Jacobs School of Medicine and Biomedical Sciences who practices with UBMD Internal Medicine and at the Buffalo VA Medical Center.

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This day, a surgical team worked seamlessly to monitor her vital signs and feather a medical device through a catheter into the left side of her damaged heart. The procedure slowed her heartrate so her organs could take a couple of days to re-collect themselves and give her a fighting chance to recover.

UB-fueled research unfolds on floors five through eight of the building at 875 Ellicott St., alongside Buffalo General Medical Center.

Ten years ago, the university invested $118 million into its Clinical and Translational Research Center, and about $25 million for equipment came from industry partners who wanted to join forces with physicians, engineers and others in the science fields.

The center became the first major pieceof the UB medical school to move onto the downtown Buffalo Niagara Medical Campus, followed in late 2017 by the $375 million Jacobs School teaching and research complex, around the corner at Main and High streets.

Both foster translational medicine, which combines disciplines, resources and techniques to move benchtop research to the patient bedside, eventually strengthening community health.

Langs work symbolizes the approach.

The Buffalo native can see her high school alma mater, City Honors, from her workplace. She went to Cornell University as an undergraduate and returned to Buffalo to go to medical school. Buoyed by fellow UB students, faculty and mentors, she chose to stay in the city for her internal medicine residency and cardiology fellowship.

Lang did her classroom work and research on the UB South Campus and most of her clinical work 8 miles away, on the downtown Medical Campus.

Stairs and elevators are the only things that separate her from most of her collaborators and patients today.

I moved into this building when it opened 10 years ago, she said. At the time, I was completing my cardiology fellowship. There was a physical divide, so I was thrilled with the new arrangement. Things can happen in parallel now.

Dr. Timothy Murphy, left, director of theUB Clinical and Translational Research Center in Buffalo, works with research technician Charmaine Kirkham in their lab, which focuses on potential treatments forchronic obstructive pulmonary disease (COPD).

That was the plan, said Dr. Timothy Murphy, director of the UB Clinical and Translational Research Center.

Clinical research and health care have become more and more seamlessly integrated, he said. The building contributed to that.

Murphy, another regional native, was among those who shared and helped carry out the vision of Gates Vascular Institute founder Dr. L. Nelson Nick Hopkins III, who chaired the UB Department of Neurosurgery from 1989 to 2013 and wanted to create a more innovative vascular center.

Murphy moved his lab in 2006 from the VA Medical Center near South Campus to the UB Center for Bioinformatics and Life Sciences on the Medical Campus, so he could be involved in the design of the UB research center, on floors above Gates Vascular, as well as at the Jacobs School particularly its labs.

They always talked about physicians and researchers bumping into each other, talking to each other, and having graduate students and postdocs and technicians talk to each other, Murphy said. Having done it now for all these years, I see it really does work.

He and his research team continue a 20-year study on the bacterial infection that causes COPD in hopes it will help lead to vaccines that prevent the infection and new treatments to clear the bacteria from the lower airway.

As senior associate dean forclinical and translational researchat the Jacobs School, he is also the point person for coordinating UB-related clinical trials and encouraging collisions between health care researchers on the Medical Campus and around the world.

There were 70 such trials on the Medical Campus in 2015, when the building where he works was in its infancy. Today, there are more than 200.

"Things can happen in parallel now," says Dr. Jennifer Lang, a cardiologist, researcher and University at Buffalo assistant professor who splits her research and clinical time in the same building on the Buffalo Niagara Medical Campus.

Labs focused on obstetric and gynecological advances and keys to healthy aging occupy space near his seventh-floor lab.

The Clinical and Translational Research Center was established in 2012. UB added a biobank in 2019 to store medical specimens for ongoing clinical studies.

Its collaborative framework helped UB land a $15 million Clinical and Translational Science Awardin 2015 from the National Institutes of Health (NIH) to encourage research efforts across university departments and specialties to boost innovation, speed development of medical treatments, and reduce health disparities in poor, rural and minority communities.

The five-year grant was renewed in 2020 with nearly $22 million more, encouraging Buffalo-based researchers to work with others who got awards, including researchers with Harvard, Johns Hopkins, Stanford and Yale universities.

A printer creates a 3D model, slice by slice, at the Canon Stroke & Vascular Research Center in the University at Buffalo Clinical and Translational Research Center. Lab researchers experiment with different mixtures of six polymers to make the most malleable and useful models for medical research.

Throughout the building, the goal is to improve medical devices and treatments that make an impact in the clinics and catheter suites in the Gates Vascular Institute on the floors below the research center and provide data and education that informs others, including patients.

The eighth-floor Canon Stroke & Vascular Research Center, which tops the UB research center, is a case in point.

Ciprian Chip Ionita, its director, came to UB from Romania in 1999 and worked his first dozen years on the South Campus.

We were the first ones to move in, said Ionita, assistant professor of biomedical engineering and member of the medical school's Department of Neurosurgery.

The lab was designed to help innovate and improve medical devices and neurovascular procedures.

Part of its work involves using MRIs, CT scans and other radiological images of Gates Vascular patients to create 3D-printed models of the circulatory system and heart.

3D printing created this replica of part of a patient's spinal column at the Canon Stroke & Vascular Research Center. Researchers there push the boundaries until their findings are refined to the point where they can be applied to model-making on two highly calibrated 3D printers in the Jacobs Institute downstairs from the lab that meet FDA standards. We fail up here about 90% of the time, says Ciprian Chip Ionita, lab director. They fail maybe 1%, so were testing everything that's possible.

Medical school and other lab researchers use the models produced here to better understand how anatomy and disease of former and current patients led to poor health and, in some cases, poor surgical outcomes.

Gates Vascular surgeons also can use 3D models that replicate the anatomy of patients awaiting surgery to practice feathering catheters and medical devices through bends, nooks and crannies of the blood vessels, and deploy medical devices in spines and the circulatory system as they maneuver past muscles, bones, blockages and other obstructions that might come into play.

During practice interventions, we analyze everything, Ionita said, because we can go into these models with sensors to measure blood flow, blood pressure and more.

You can create a model that says, Here's somebody who has a carotid artery that's 50% (blocked) and he's 50 years old, Ionita said. Or we can say, 'Here is a young person in their 20s, and is fully compliant, no stenosis or whatever.' And those mechanical properties are translated by the printer.

Even cadaver donors cant do that.

The goal is to lower the rate of complications and be successful in one shot during a procedure, said Ionita, who supervises up to 10 graduate biomedical engineering students, and roughly 20 undergraduate, graduate and medical school students.

Those who pay close attention to 3D models and other medical research based on data from patients treated in the building include Dr. Elad Levy, co-director of the Gates Vascular Stroke Center; Dr. Adnan Siddiqui, director of neurological and stroke services at Kaleida Health; and Dr. Vijay Iyer, medical director of cardiology and the Structural Heart Program at Kaleida. All three have ties to UB.

Even here, Ionita said, physician-scientists and other researchers see the damage that smoking, high blood pressure and living in ZIP codes where poverty is rampant can create complications that lead to worse health and surgical outcomes.

Eric Wozniak, a senior research and development technician in the Idea to Reality lab at the Jacobs Institute, uses a microscope as he works to improve catheter technology.

Doctors and staff improve treatment protocols and surgical prowess with help from those who work on the top half of the building for UB and the Jacobs Institute. The latter is named for Dr. Lawrence D. Jacobs, a Buffalo neurosurgeon whose research led to the first treatments for multiple sclerosis.

Four years after Jacobs died in 2001, his brother Jeremy, chair of the Delaware North Cos. and the UB Council, approached the university about creating a lasting memorial for the respected physician. He later signed on to the concept of creating a multidisciplinary vascular center, starting with a $10 million donation for the institute that bears the family name.

The institute includes an atrium, caf and glass-walled spaces that overlook procedure rooms on the floor below. It has 50 employees, including more than 30 biomedical and electrical engineers, who seek company-sponsored research funding, help collect data and make prototypes for clinical trials, and work with researchers to publish their work in medical journals.

In 2016, the institute was designated a 3D Printing Center of Excellence in Health Care by Israeli-based Stratasys Ltd., a leading 3D printing-maker. In early 2018, it created a proof-of-concept Idea to Reality Center, known as i2R, to further improve medical devices and surgical techniques in the vascular space.

This is our secret sauce lab, said Siddiqui, Jacobs Institute CEO. There's nothing we do downstairs that we could not do better.

This is a device designed and built in the Idea 2 Reality lab at the Jacobs Institute in Buffalo. The lab improves medical devices and technology used in vascular procedures and treatments.

Dr. Carlos Pena, who ran the FDA Neurologic Devices Division for 15 years, joined the institute staff last year to improve the chances technology conceived and designed with help from the institute gets to market.

Every company wants to talk to him, Siddiqui said. He tells them what testing needs to be done. Some of that gets done in-house. A lot of it goes to the university or, when they have a clinical trial, that gets done downstairs so the entire ecosystem is functioning, I think better than Nick Hopkins ever imagined.

Lang, the cardiologist, doesnt miss her former workday commutes. She loves the design and location of the building that sets the standard for vascular care.

Most of her days mix benchtop research in her lab and patient visits and procedures on the floors below. When there is time, she can visit her husband, Fraser Sim, neuroscience director and associate professor at the medical school.

Because we're in such close proximity to the Jacobs School now, we're also really able to engage the medical students earlier in their careers and encourage more research, Lang said. And because we're so close to the hospital, we're able to involve medical residents and fellows in our research projects much more than ever before.

University at Buffalo medical school postdoctoral research associateToubaTarvirdizadeh focuses on cardiac research in the lab of Dr. Jennifer Lang at the UB Clinical and Translational Research Center in Buffalo.

She has spent a decade trying to find better ways for a stem cell derivative that can withstand an immune response and rejuvenate heart tissue without major complications, a result that could help patients recover from a heart attack and lessen the strain of heart failure.

Four years ago, Lang and her doctoral student researcher, Kyle Mentkowski, discovered a way that lowered the immune response in mice that received the derivative.

Mentkowski, now a post-doctorate researcher at Harvard-affiliated Massachusetts General Hospital, was talking with another group of student researchers in the building when they thought it might be a good idea to bring Dr. Jessica Reynolds, an immunologist and UB medical school associate professor, into the research.

The collaboration created robust, reproducible results in mice models, Lang said, and the start of testing in human immune cells she and her colleagues hope can benefit patients within the next decade.

Collaborators now regularly get together to chat at the Jacobs Institute.

The NIH seems very interested in this as a potential clinical therapy, Lang said, but the field as a whole is still in the beginning stages of understanding where we need to go next.

Dr. Aaron Hoffman, left, University at Buffalo medical school associate professor of surgery, and Dr. Kenneth Snyder, UB associate professor of neurosurgery, chat during a break in the Jacobs Institute atrium.

UB researchers have shared some of their findings with researchers making similar inroads elsewhere, she said, and the work spawned other collaborations with Reynolds, her research team and scientists in the UB Department of Biomedical Engineering.

This type of unplanned interaction is not a unique occurrence in this building, Lang said. Our story is just one of many.

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