Curr Cardiol Rev. 2013 Feb; 9(1): 6372.

1Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA

2Stem Cell Institute, University of Minnesota Medical School, Minneapolis, Minnesota, USA

1Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA

1Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA

2Stem Cell Institute, University of Minnesota Medical School, Minneapolis, Minnesota, USA

3Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA

1Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA

2Stem Cell Institute, University of Minnesota Medical School, Minneapolis, Minnesota, USA

3Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA

Received 2012 Jun 11; Revised 2012 Jul 31; Accepted 2012 Aug 27.

Induced pluripotent stem (iPS) cells, are a type of pluripotent stem cell derived from adult somatic cells. They have been reprogrammed through inducing genes and factors to be pluripotent. iPS cells are similar to embryonic stem (ES) cells in many aspects. This review summarizes the recent progresses in iPS cell reprogramming and iPS cell based therapy, and describe patient specific iPS cells as a disease model at length in the light of the literature. This review also analyzes and discusses the problems and considerations of iPS cell therapy in the clinical perspective for the treatment of disease.

Keywords: Cellular therapy, disease model, embryonic stem cells, induced pluripotent stem cells, reprogramm.

Induced pluripotent stem (iPS) cells, are a type of pluripotent stem cell derived from adult somatic cells that have been genetically reprogrammed to an embryonic stem (ES) cell-like state through the forced expression of genes and factors important for maintaining the defining properties of ES cells.

Mouse iPS cells from mouse fibroblasts were first reported in 2006 by the Yamanaka lab at Kyoto University [1]. Human iPS cells were first independently produced by Yamanakas and Thomsons groups from human fibroblasts in late 2007 [2, 3]. iPS cells are similar to ES cells in many aspects, including the expression of ES cell markers, chromatin methylation patterns, embryoid body formation, teratoma formation, viable chimera formation, pluripotency and the ability to contribute to many different tissues in vitro.

The breakthrough discovery of iPS cells allow researchers to obtain pluripotent stem cells without the controversial use of embryos, providing a novel and powerful method to "de-differentiate" cells whose developmental fates had been traditionally assumed to be determined. Furthermore, tissues derived from iPS cells will be a nearly identical match to the cell donor, which is an important factor in research of disease modeling and drug screening. It is expected that iPS cells will help researchers learn how to reprogram cells to repair damaged tissues in the human body.

The purpose of this paper is to summarize the recent progresses in iPS cell development and iPS cell-based therapy, and describe patient specific iPS cells as a disease model, analyze the problems and considerations of iPS therapy in the clinical treatment of disease.

The methods of reprogramming somatic cells into iPS cells are summarized in Table . It was first demonstrated that genomic integration and high expression of four factors, Oct4/Sox2/Klf4/c-Myc or Oct4/Sox2/Nanog/LIN28 by virus, can reprogram fibroblast cells into iPS cells [1-3]. Later, it was shown that iPS cells can be generated from fibroblasts by viral integration of Oct4/Sox2/Klf4 without c-Myc [4]. Although these iPS cells showed reduced tumorigenicity in chimeras and progeny mice, the reprogramming process is much slower, and efficiency is substantially reduced. These studies suggest that the ectopic expression of these three transcription factors (Oct4/Klf4/Sox2) is required for reprogramming of somatic cells in iPS cells.

Various growth factors and chemical compounds have recently been found to improve the induction efficiency of iPS cells. Shi et al., [5] demonstrated that small molecules, able to compensate for Sox2, could successfully reprogram mouse embryonic fibroblasts (MEF) into iPS cells. They combined Oct4/Klf4 transduction with BIX-01294 and BayK8644s and derived MEF into iPS cells. Huangfu et al., [6, 7] reported that 5-azacytidine, DNA methyltransferase inhibitor, and valproic acid, a histone deacetylase inhibitor, improved reprogramming of MEF by more than 100 folds. Valproic acid enables efficient reprogramming of primary human fibroblasts with only Oct4 and Sox2.

Kim et al. showed that mouse neural stem cells, expressing high endogenous levels of Sox2, can be reprogrammed into iPS cells by transduction Oct4 together with either Klf4 or c-Myc [19]. This suggests that endogenous expression of transcription factors, that maintaining stemness, have a role in the reprogramming process of pluripotency. More recently, Tsai et al., [20] demonstrated that mouse iPS cells could be generated from the skin hair follicle papilla (DP) cell with Oct4 alone since the skin hair follicle papilla cells expressed endogenously three of the four reprogramming factors: Sox2, c-Myc, and Klf4. They showed that reprogramming could be achieved after 3 weeks with efficiency similar to other cell types reprogrammed with four factors, comparable to ES cells.

Retroviruses are being extensively used to reprogram somatic cells into iPS cells. They are effective for integrating exogenous genes into the genome of somatic cells to produce both mouse and human iPS cells. However, retroviral vectors may have significant risks that could limit their use in patients. Permanent genetic alterations, due to multiple retroviral insertions, may cause retrovirus-mediated gene therapy as seen in treatment of severe combined immunodeficiency [25]. Second, although retroviral vectors are silenced during reprogramming [26], this silencing may not be permanent, and reactivation of transgenes may occur upon the differentiation of iPS cells. Third, expression of exogenous reprogramming factors could occur. This may trigger the expression of oncogenes that stimulate cancer growth and alter the properties of the cells. Fourth, the c-Myc over-expression may cause tumor development after transplantation of iPS derived cells. Okita et al. [10] reported that the chimeras and progeny derived from iPS cells frequently showed tumor formation. They found that the retroviral expression of c-Myc was reactivated in these tumors. Therefore, it would be desirable to produce iPS cells with minimal, or free of, genomic integration. Several new strategies have been recently developed to address this issue (Table ).

Stadtfeld et al. [16] used an adenoviral vector to transduce mouse fibroblasts and hepatocytes, and generated mouse iPS cells at an efficiency of about 0.0005%. Fusaki et al. [22] used Sendai virus to efficiently generate iPS cells from human skin fibroblasts without genome integration. Okita et al. [27] repeatedly transfected MEF with two plasmids, one carrying the complementary DNAs (cDNAs) of Oct3/4, Sox2, and Klf4 and the other carrying the c-Myc cDNA. This generated iPS cells without evidence of plasmid integration. Using a polycistronic plasmid co-expressing Oct4, Sox2, Klf4, and c-Myc, Gonzalez et al., [28] reprogrammed MEF into iPS cells without genomic integration. Yu et al. [29] demonstrated that oriP/EBNA1 (EpsteinBarr nuclear antigen-1)-based episomal vectors could be used to generate human iPS cells free of exogenous gene integration. The reprogramming efficiency was about 36 colonies/1 million somatic cells. Narsinh et al., [21] derived human iPS cells via transfection of human adipocyte stromal cells with a nonviral minicircle DNA by repeated transfection. This produced hiPS cells colonies from an adipose tissue sample in about 4 weeks.

When iPS cells generated from either plasmid transfection or episomes were carefully analyzed to identify random vector integration, it was possible to have vector fragments integrated somewhere. Thus, reprogramming strategies entirely free of DNA-based vectors are being sought. In April 2009, it was shown that iPS cells could be generated using recombinant cell-penetrating reprogramming proteins [30]. Zhou et al. [30] purified Oct4, Sox2, Klf4 and c-Myc proteins, and incorporated poly-arginine peptide tags. It allows the penetration of the recombinant reprogramming proteins through the plasma membrane of MEF. Three iPS cell clones were successfully generated from 5x 104 MEFs after four rounds of protein supplementation and subsequent culture of 2328 days in the presence of valproic acid.

A similar approach has also been demonstrated to be able to generate human iPS cells from neonatal fibroblasts [31]. Kim et al. over-expressed reprogramming factor proteins in HEK293 cells. Whole cell proteins of the transduced HEK293 were extracted and used to culture fibroblast six times within the first week. After eight weeks, five cell lines had been established at a yield of 0.001%, which is one-tenth of viral reprogramming efficiency. Strikingly, Warren et al., [24] demonstrated that human iPS cells can be derived using synthetic mRNA expressing Oct3/4, Klf4, Sox2 and c-Myc. This method efficiently reprogrammed fibroblast into iPS cells without genome integration.

Strenuous efforts are being made to improve the reprogramming efficiency and to establish iPS cells with either substantially fewer or no genetic alterations. Besides reprogramming vectors and factors, the reprogramming efficiency is also affected by the origin of iPS cells.

A number of somatic cells have been successfully reprogrammed into iPS cells (Table ). Besides mouse and human somatic cells, iPS cells from other species have been successfully generated (Table ).

The origin of iPS cells has an impact on choice of reprogramming factors, reprogramming and differentiation efficiencies. The endogenous expression of transcription factors may facilitate the reprogramming procedure [19]. Mouse neural stem cells express higher endogenous levels of Sox2 and c-Myc than ES cells. Thus, two transcription factors, exogenous Oct4 together with either Klf4 or c-Myc, are sufficient to generate iPS cells from neural stem cells [19]. Ahmed et al. [14] demonstrated that mouse skeletal myoblasts endogenously expressed Sox2, Klf4, and c-Myc and can be easily reprogrammed to iPS cells.

It is possible that iPS cells may demonstrate memory of parental source and therefore have low differentiation efficiency into other tissue cells. Kim et al. [32] showed that iPS cells reprogrammed from peripheral blood cells could efficiently differentiate into the hematopoietic lineage cells. It was found, however, that these cells showed very low differentiation efficiency into neural cells. Similarly, Bar-Nur et al. found that human cell-derived iPS cells have the epigenetic memory and may differentiate more readily into insulin producing cells [33]. iPS cells from different origins show similar gene expression patterns in the undifferentiated state. Therefore, the memory could be epigenetic and are not directly related to the pluripotent status.

The cell source of iPS cells can also affect the safety of the established iPS cells. Miura et al. [54] compared the safety of neural differentiation of mouse iPS cells derived from various tissues including MEFs, tail-tip fibroblasts, hepatocyte and stomach. Tumorigenicity was examined. iPS cells that reprogrammed from tail-tip fibroblasts showed many undifferentiated pluripotent cells after three weeks of in vitro differentiation into the neural sphere. These cells developed teratoma after transplantation into an immune-deficient mouse brain. The possible mechanism of this phenomenon may be attributable to epigenetic memory and/or genomic stability. Pre-evaluated, non-tumorigenic and safe mouse iPS cells have been reported by Tsuji et al. [55]. Safe iPS cells were transplanted into non-obese diabetic/severe combined immunodeficiency mouse brain, and found to produce electrophysiologically functional neurons, astrocytes, and oligodendrocytes in vitro.

The cell source of iPS cells is important for patients as well. It is important to carefully evaluate clinically available sources. Human iPS cells have been successfully generated from adipocyte derived stem cells [35], amniocytes [36], peripheral blood [38], cord blood [39], dental pulp cells [40], oral mucosa [41], and skin fibroblasts (Table ). The properties and safety of these iPS cells should be carefully examined before they can be used for treatment.

Shimada et al. [17] demonstrated that combination of chemical inhibitors including A83-01, CHIR99021, PD0325901, sodium butyrate, and Y-27632 under conditions of physiological hypoxia human iPS cells can be rapidly generated from adipocyte stem cells via retroviral transduction of Oct4, Sox2, Klf4, and L-Myc. Miyoshi et al., [42] generated human iPS cells from cells isolated from oral mucosa via the retroviral gene transfer of Oct4, Sox2, c-Myc, and Klf4. Reprogrammed cells showed ES-like morphology and expressed undifferentiated markers. Yan et al., [40] demonstrated that dental tissue-derived mesenchymal-like stem cells can easily be reprogrammed into iPS cells at relatively higher rates as compared to human fibroblasts. Human peripheral blood cells have also been successfully reprogrammed into iPS cells [38]. Anchan et al. [36] described a system that can efficiently derive iPS cells from human amniocytes, while maintaining the pluripotency of these iPS cells on mitotically inactivated feeder layers prepared from the same amniocytes. Both cellular components of this system are autologous to a single donor. Takenaka et al. [39] derived human iPS cells from cord blood. They demonstrated that repression of p53 expression increased the reprogramming efficiency by 100-fold.

All of the human iPS cells described here are indistinguishable from human ES cells with respect to morphology, expression of cell surface antigens and pluripotency-associated transcription factors, DNA methylation status at pluripotent cell-specific genes and the capacity to differentiate in vitro and in teratomas. The ability to reprogram cells from human somatic cells or blood will allow investigating the mechanisms of the specific human diseases.

The iPS cell technology provides an opportunity to generate cells with characteristics of ES cells, including pluripotency and potentially unlimited self-renewal. Studies have reported a directed differentiation of iPS cells into a variety of functional cell types in vitro, and cell therapy effects of implanted iPS cells have been demonstrated in several animal models of disease.

A few studies have demonstrated the regenerative potential of iPS cells for three cardiac cells: cardiomyocytes, endothelial cells, and smooth muscle cells in vitro and in vivo. Mauritz [56] and Zhang [57] independently demonstrated the ability of mouse and human iPS cells to differentiate into functional cardiomyocytes in vitro through embryonic body formation. Rufaihah [58], et al. derived endothelial cells from human iPS cells, and showed that transplantation of these endothelial cells resulted in increased capillary density in a mouse model of peripheral arterial disease. Nelson et al. [59] demonstrated for the first time the efficacy of iPS cells to treat acute myocardial infarction. They showed that iPS cells derived from MEF could restore post-ischemic contractile performance, ventricular wall thickness, and electrical stability while achieving in situ regeneration of cardiac, smooth muscle, and endothelial tissue. Ahmed et al. [14] demonstrated that beating cardiomyocyte-like cells can be differentiated from iPS cells in vitro. The beating cells expressed early and late cardiac-specific markers. In vivo studies showed extensive survival of iPS and iPS-derived cardiomyocytes in mouse hearts after transplantation in a mouse experimental model of acute myocardial infarction. The iPs derived cardiomyocyte transplantation attenuated infarct size and improved cardiac function without tumorgenesis, while tumors were observed in the direct iPS cell transplantation animals.

Strategies to enhance the purity of iPS derived cardiomyocytes and to exclude the presence of undifferentiated iPS are required. Implantation of pre-differentiation or guided differentiation of iPS would be a safer and more effective approach for transplantation. Selection of cardiomyocytes from iPS cells, based on signal-regulatory protein alpha (SIRPA) or combined with vascular cell adhesion protein-1 (VCAM-1), has been reported. Dubois et al. [60] first demonstrated that SIRPA was a marker specifically expressed on cardiomyocytes derived from human ES cells and human iPS cells. Cell sorting with an antibody against SIRPA could enrich cardiac precursors and cardiomyocytes up to 98% troponin T+ cells from human ESC or iPS cell differentiation cultures. Elliott et al. [61] adopted a cardiac-specific reporter gene system (NKX2-5eGFP/w) and identified that VCAM-1 and SIRPA were cell-surface markers of cardiac lineage during differentiation of human ES cells.

Regeneration of functional cells from human stem cells represents the most promising approach for treatment of type 1 diabetes mellitus (T1DM). This may also benefit the patients with type 2 diabetes mellitus (T2DM) who need exogenous insulin. At present, technology for reprogramming human somatic cell into iPS cells brings a remarkable breakthrough in the generation of insulin-producing cells.

Human ES cells can be directed to become fully developed cells and it is expected that iPS cells could also be similarly differentiated. Stem cell based approaches could also be used for modulation of the immune system in T1DM, or to address the problems of obesity and insulin resistance in T2DM.

Tateishi et al., [62] demonstrated that insulin-producing islet-like clusters (ILCs) can be generated from the human iPS cells under feeder-free conditions. The iPS cell derived ILCs not only contain C-peptide positive and glucagon-positive cells but also release C-peptide upon glucose stimulation. Similarly, Zhang et al., [63] reported a highly efficient approach to induce human ES and iPS cells to differentiate into mature insulin-producing cells in a chemical-defined culture system. These cells produce insulin/C-peptide in response to glucose stimuli in a manner comparable to that of adult human islets. Most of these cells co-expressed mature cell-specific markers such as NKX6-1 and PDX1, indicating a similar gene expression pattern to adult islet beta cells in vivo.

Alipo et al. [64] used mouse skin derived iPS cells for differentiation into -like cells that were similar to the endogenous insulin-secreting cells in mice. These -like cells were able to secrete insulin in response to glucose and to correct a hyperglycemic phenotype in mouse models of both T1DM and T2DM after iPS cell transplant. A long-term correction of hyperglycemia could be achieved as determined by hemoglobin A1c levels. These results are encouraging and suggest that induced pluripotency is a viable alternative to directing iPS cell differentiation into insulin secreting cells, which has great potential clinical applications in the treatment of T1DM and T2 DM.

Although significant progress has been made in differentiating pluripotent stem cells to -cells, several hurdles remain to be overcome. It is noted in several studies that the general efficiency of in vitro iPS cell differentiation into functional insulin-producing -like cells is low. Thus, it is highly essential to develop a safe, efficient, and easily scalable differentiation protocol before its clinical application. In addition, it is also important that insulin-producing b-like cells generated from the differentiation of iPS cells have an identical phenotype resembling that of adult human pancreatic cells in vivo.

Currently, the methodology of neural differentiation has been well established in human ES cells and shown that these methods can also be applied to iPS cells. Chambers et al. [65] demonstrated that the synergistic action of Noggin and SB431542 is sufficient to induce rapid and complete neural conversion of human ES and iPS cells under adherent culture conditions. Swistowsk et al. [66] used a completely defined (xenofree) system, that has efficiently differentiated human ES cells into dopaminergic neurons, to differentiate iPS cells. They showed that the process of differentiation into committed neural stem cells (NSCs) and subsequently into dopaminergic neurons was similar to human ES cells. Importantly, iPS cell derived dopaminergic neurons were functional as they survived and improved behavioral deficits in 6-hydroxydopamine-leasioned rats after transplantation. Lee et al. [67] provided detailed protocols for the step-wise differentiation of human iPS and human ES into neuroectodermal and neural crest cells using either the MS5 co-culture system or a defined culture system (Noggin with a small-molecule SB431542), NSB system. The average time required for generating purified human NSC precursors will be 25 weeks. The success of deriving neurons from human iPS cells provides a study model of normal development and impact of genetic disease during neural crest development.

Wernig et al., [68] showed that iPS cells can give rise to neuronal and glial cell types in culture. Upon transplantation into the fetal mouse brain, the cells differentiate into glia and neurons, including glutamatergic, GABAergic, and catecholaminergic subtypes. Furthermore, iPS cells were induced to differentiate into dopamine neurons of midbrain character and were able to improve behavior in a rat model of Parkinson's disease (PD) upon transplantation into the adult brain. This study highlights the therapeutic potential of directly reprogrammed fibroblasts for neural cell replacement in the animal model of Parkinsons disease.

Tsuji et al., [55] used pre-evaluated iPS cells derived for treatment of spinal cord injury. These cells differentiated into all three neural lineages, participated in remyelination and induced the axonal regrowth of host 5HT+ serotonergic fibers, promoting locomotor function recovery without forming teratomas or other tumors. This study suggests that iPS derived neural stem/progenitor cells may be a promising cell source for treatment of spinal cord injury.

Hargus et al., [69] demonstrated proof of principle of survival and functional effects of neurons derived from iPS cells reprogrammed from patients with PD. iPS cells from patients with Parkinsons disease were differentiated into dopaminergic neurons that could be transplanted without signs of neuro-degeneration into the adult rodent striatum. These cells survived and showed arborization, and mediated functional effects in an animal model of Parkinsons disease. This study suggests that disease specific iPS cells can be generated from patients with PD, which be used to study the PD development and in vitro drug screen for treatment of PD.

Reprogramming technology is being applied to derive patient specific iPS cell lines, which carry the identical genetic information as their patient donor cells. This is particularly interesting to understand the underlying disease mechanism and provide a cellular and molecular platform for developing novel treatment strategy.

Human iPS cells derived from somatic cells, containing the genotype responsible for the human disease, hold promise to develop novel patient-specific cell therapies and research models for inherited and acquired diseases. The differentiated cells from reprogrammed patient specific human iPS cells retain disease-related phenotypes to be an in vitro model of pathogenesis (Table ). This provides an innovative way to explore the molecular mechanisms of diseases.

Disease Modeling Using Human iPS Cells

Recent studies have reported the derivation and differentiation of disease-specific human iPS cells, including autosomal recessive disease (spinal muscular atrophy) [70], cardiac disease [71-75], blood disorders [13, 76], diabetes [77], neurodegenerative diseases (amyotrophic lateral sclerosis [78], Huntingtons disease [79]), and autonomic nervous system disorder (Familial Dysautonomia) [80]. Patient-specific cells make patient-specific disease modeling possible wherein the initiation and progression of this poorly understood disease can be studied.

Human iPS cells have been reprogrammed from spinal muscular atrophy, an autosomal recessive disease. Ebert et al., [70] generated iPS cells from skin fibroblast taken from a patient with spinal muscular atrophy. These cells expanded robustly in culture, maintained the disease genotype and generated motor neurons that showed selective deficits compared to those derived from the patients' unaffected relative. This is the first study to show that human iPS cells can be used to model the specific pathology seen in a genetically inherited disease. Thus, it represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies.

Similarly, three other groups reported their findings on the use of iPS cells derived cardiomyocytes (iPSCMs) as disease models for LQTS type-2 (LQTS2). Itzhaki et al., [72] obtained dermal fibroblasts from a patient with LQTS2 harboring the KCNH2 gene mutation and showed that action potential duration was prolonged and repolarization velocity reduced in LQTS2 iPS-CMs compared with normal cardiomyocytes. They showed that Ikr was significantly reduced in iPS-CMs derived from LQTS2. They also tested the potential therapeutic effects of nifedipine and the KATP channel opener pinacidil (which augments the outward potassium current) and demonstrated that they shortened the action potential duration and abolished early after depolarization. Similarly, Lahti et al., [73] demonstrated a more pronounced inverse correlation between the beating rate and repolarization time of LQTS2 disease derived iPS-CMs compared with normal control cells. Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation. Matsa et al., [74] also successfully generated iPS-CMs from a patient with LQTS2 with a known KCNH2 mutation. iPS-CMs with LQTS2 displayed prolonged action potential durations on patch clamp analysis and prolonged corrected field potential durations on microelectrode array mapping. Furthermore, they demonstrated that the KATP channel opener nicorandil and PD-118057, a type 2 IKr channel enhancer attenuate channel closing.

LQTS3 has been recapitulated in mouse iPS cells [75]. Malan et al. [75] generated disease-specific iPS cells from a mouse model of a human LQTS3. Patch-clamp measurements of LQTS 3-specific cardiomyocytes showed the biophysical effects of the mutation on the Na+ current, withfaster recovery from inactivation and larger late currents than observed in normal control cells. Moreover, LQTS3-specific cardiomyocytes had prolonged action potential durations and early after depolarizations at low pacing rates, both of which are classic features of the LQTS3 mutation.

Human iPS cells have been used to recapitulate diseases of blood disorder. Ye et al. [13] demonstrated that human iPS cells derived from periphery blood CD34+ cells of patients with myeloproliferative disorders, have the JAK2-V617F mutation in blood cells. Though the derived iPS cells contained the mutation, they appeared normal in phenotypes, karyotype, and pluripotency. After hematopoietic differentiation, the iPS cell-derived hematopoietic progenitor (CD34+/CD45+) cells showed the increased erythropoiesis and expression of specific genes, recapitulating features of the primary CD34+ cells of the corresponding patient from whom the iPS cells were derived. This study highlights that iPS cells reprogrammed from somatic cells from patients with blood disease provide a prospective hematopoiesis model for investigating myeloproliferative disorders.

Raya et al., [76] reported that somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency after correction of the genetic defect. They demonstrated that corrected Fanconi-anaemia specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal. This study offers proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications.

Maehr et al., [77] demonstrated that human iPS cells can be generated from patients with T1DM by reprogramming their adult fibroblasts. These cells are pluripotent and differentiate into three lineage cells, including insulin-producing cells. These cells provide a platform to assess the interaction between cells and immunocytes in vitro, which mimic the pathological phenotype of T1DM. This will lead to better understanding of the mechanism of T1DM and developing effective cell replacement therapeutic strategy.

Lee et al., [80] reported the derivation of human iPS cells from patient with Familial Dysautonomia, an inherited disorder that affects the development and function of nerves throughout the body. They demonstrated that these iPS cells can differentiate into all three germ layers cells. However gene expression analysis demonstrated tissue-specific mis-splicing of IKBKAP in vitro, while neural crest precursors showed low levels of normal IKBKAP transcript. Transcriptome analysis and cell-based assays revealed marked defects in neurogenic differentiation and migration behavior. All these recaptured familial Dysautonomia pathogenesis, suggesting disease specificity of the with familial Dysautonomia human iPS cells. Furthermore, they validated candidate drugs in reversing and ameliorating neuronal differentiation and migration. This study illustrates the promise of disease specific iPS cells for gaining new insights into human disease pathogenesis and treatment.

Human iPS cells derived reprogrammed from patients with inherited neurodegenerative diseases, amyotrophic lateral sclerosis [78] and Huntingtons disease 79, have also been reported. Dimos et al., [78] showed that they generated iPS cells from a patient with a familial form of amyotrophic lateral sclerosis. These patient-specific iPS cells possess the properties of ES cells and were reprogrammed successfully to differentiate into motor neurons. Zhang et al., [79] derived iPS cells from fibroblasts of patient with Huntingtons disease. They demonstrated that striatal neurons and neuronal precursors derived from these iPS cells contained the same CAG repeat expansion as the mutation in the patient from whom the iPS cell line was established. This suggests that neuronal progenitor cells derived from Huntingtons disease cell model have endogenous CAG repeat expansion that is suitable for mechanistic studies and drug screenings.

Disease specific somatic cells derived from patient-specific human iPS cells will generate a wealth of information and data that can be used for genetically analyzing the disease. The genetic information from disease specific-iPS cells will allow early and more accurate prediction and diagnosis of disease and disease progression. Further, disease specific iPS cells can be used for drug screening, which in turn correct the genetic defects of disease specific iPS cells.

iPS cells appear to have the greatest promise without ethical and immunologic concerns incurred by the use of human ES cells. They are pluripotent and have high replicative capability. Furthermore, human iPS cells have the potential to generate all tissues of the human body and provide researchers with patient and disease specific cells, which can recapitulate the disease in vitro. However, much remains to be done to use these cells for clinical therapy. A better understanding of epigenetic alterations and transcriptional activity associated with the induction of pluripotency and following differentiation is required for efficient generation of therapeutic cells. Long-term safety data must be obtained to use human iPS cell based cell therapy for treatment of disease.

These works were supported by NIH grants HL95077, HL67828, and UO1-100407.

The authors confirm that this article content has no conflicts of interest.

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PMCID: PMC4104807

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1Department of Bioengineering, University of Illinois at Chicago

2Department of Physiology and Biophysics and Department of Bioengineering, University of Illinois at Chicago

1Department of Bioengineering, University of Illinois at Chicago

2Department of Physiology and Biophysics and Department of Bioengineering, University of Illinois at Chicago

Stem cells have the ability to differentiate into specific cell types. The two defining characteristics of a stem cell are perpetual self-renewal and the ability to differentiate into a specialized adult cell type. There are two major classes of stem cells: pluripotent that can become any cell in the adult body, and multipotent that are restricted to becoming a more limited population of cells. Cell sources, characteristics, differentiation and therapeutic applications are discussed. Stem cells have great potential in tissue regeneration and repair but much still needs to be learned about their biology, manipulation and safety before their full therapeutic potential can be achieved.

Stem cells have the ability to build every tissue in the human body, hence have great potential for future therapeutic uses in tissue regeneration and repair. In order for cells to fall under the definition of stem cells, they must display two essential characteristics. First, stem cells must have the ability of unlimited self-renewal to produce progeny exactly the same as the originating cell. This trait is also true of cancer cells that divide in an uncontrolled manner whereas stem cell division is highly regulated. Therefore, it is important to note the additional requirement for stem cells; they must be able to give rise to a specialized cell type that becomes part of the healthy animal.1

The general designation, stem cell encompasses many distinct cell types. Commonly, the modifiers, embryonic, and adult are used to distinguish stem cells by the developmental stage of the animal from which they come, but these terms are becoming insufficient as new research has discovered how to turn fully differentiated adult cells back into embryonic stem cells and, conversely, adult stem cells, more correctly termed somatic stem cells meaning from the body, are found in the fetus, placenta, umbilical cord blood and infants.2 Therefore, this review will sort stem cells into two categories based on their biologic properties - pluripotent stem cells and multipotent stem cells. Their sources, characteristics, differentiation and therapeutic applications are discussed.

Pluripotent stem cells are so named because they have the ability to differentiate into all cell types in the body. In natural development, pluripotent stem cells are only present for a very short period of time in the embryo before differentiating into the more specialized multipotent stem cells that eventually give rise to the specialized tissues of the body (). These more limited multipotent stem cells come in several subtypes: some can become only cells of a particular germ line (endoderm, mesoderm, ectoderm) and others, only cells of a particular tissue. In other words, pluripotent cells can eventually become any cell of the body by differentiating into multipotent stem cells that themselves go through a series of divisions into even more restricted specialized cells.

During natural embryo development, cells undergo proliferation and specialization from the fertilized egg, to the blastocyst, to the gastrula during natural embryo development (left side of panel). Pluripotent, embryonic stem cells are derived from the inner cell mass of the blastoctyst (lightly shaded). Multipotent stem cells (diamond pattern, diagonal lines, and darker shade) are found in the developing gastrula or derived from pluripotent stem cells and are restricted to give rise to only cells of their respective germ layer.

Based on the two defining characteristics of stem cells (unlimited self-renewal and ability to differentiate), they can be described as having four outcomes or fates3 (). A common fate for multipotent stem cells is to remain quiescent without dividing or differentiating, thus maintaining its place in the stem cell pool. An example of this is stem cells in the bone marrow that await activating signals from the body. A second fate of stem cells is symmetric self-renewal in which two daughter stem cells, exactly like the parent cell, arise from cell division. This does not result in differentiated progeny but does increase the pool of stem cells from which specialized cells can develop in subsequent divisions. The third fate, asymmetric self-renewal, occurs when a stem cell divides into two daughter cells, one a copy of the parent, the other a more specialized cell, named a somatic or progenitor cell. Asymmetric self-renewal results in the generation of differentiated progeny needed for natural tissue development/regeneration while also maintaining the stem cell pool for the future. The fourth fate is that in which a stem cell divides to produce two daughters both different from the parent cell. This results in greater proliferation of differentiated progeny with a net loss in the stem cell pool.

Four potential outcomes of stem cells. A) Quiescence in which a stem cell does not divide but maintains the stem cell pool. B) Symmetric self-renewal where a stem cell divides into two daughter stem cells increasing the stem cell pool. C) Asymmetric self-renewal in which a stem cell divides into one differentiated daughter cell and one stem cell, maintaining the stem cell pool. D) Symmetric division without self-renewal where there is a loss in the stem cell pool but results in two differentiated daughter cells. (SC- Stem cell, DP-Differentiated progeny)

The factors that determine the fate of stem cells is the focus of intense research. Knowledge of the details could be clinically useful. For example, clinicians and scientists might direct a stem cell population to expand several fold through symmetrical self-renewal before differentiation into multipotent or more specialized progenitor cells. This would ensure a large, homogeneous population of cells at a useful differentiation stage that could be delivered to patients for successful tissue regeneration.

Pluripotent stem cells being used in research today mainly come from embryos, hence the name, embryonic stem cells. Pre-implantation embryos a few days old contain only 10-15% pluripotent cells in the inner cell mass (). Those pluripotent cells can be isolated, then cultured on a layer of feeder cells which provide unknown cues for many rounds of proliferation while sustaining their pluripotency.

Recently, two different groups of scientists induced adult cells back into the pluripotent state by molecular manipulation to yield induced pluripotent stem cells (iPS) that share some of the same characteristics as embryonic stem cells such as proliferation, morphology and gene expression (in the form of distinct surface markers and proteins being expressed).4-8 Both groups used retroviruses to carry genes for transcription factors into the adult cells. These genes are transcribed and translated into proteins that regulate the expression of other genes designed to reprogram the adult nucleus back into its embryonic state. Both introduced the embryonic transcription factors known as Sox2 and Oct4. One group also added Klf4 and c-Myc4, and the other group added Lin28 and Nanog.6 Other combinations of factors would probably also work, but, unfortunately, neither the retroviral carrier method nor the use of the oncogenic transcription factor c-Myc are likely to be approved for human therapy. Consequently, a purely chemical approach to deliver genes into the cells, and safer transcription factors are being tried. Results of these experiments look promising.9

Multipotent stem cells may be a viable option for clinical use. These cells have the plasticity to become all the progenitor cells for a particular germ layer or can be restricted to become only one or two specialized cell types of a particular tissue. The multipotent stem cells with the highest differentiating potential are found in the developing embryo during gastrulation (day 14-15 in humans, day 6.5-7 in mice). These cells give rise to all cells of their particular germ layer, thus, they still have flexibility in their differentiation capacity. They are not pluripotent stem cells because they have lost the ability to become cells of all three germ layers (). On the low end of the plasticity spectrum are the unipotent cells that can become only one specialized cell type such as skin stem cells or muscle stem cells. These stem cells are typically found within their organ and although their differentiation capacity is restricted, these limited progenitor cells play a vital role in maintaining tissue integrity by replenishing aging or injured cells. There are many other sub-types of multipotent stem cells occupying a range of differentiation capacities. For example, multipotent cells derived from the mesoderm of the gastrula undergo a differentiation step limiting them to muscle and connective tissue; however, further differentiation results in increased specialization towards only connective tissue and so on until the cells can give rise to only cartilage or only bone.

Multipotent stem cells found in bone marrow are best known, because these have been used therapeutically since the 1960s10 (their potential will be discussed in greater detail in a later section). Recent research has found new sources for multipotent stem cells of greater plasticity such as the placenta and umbilical cord blood.11 Further, the heart, until recently considered void of stem cells, is now known to contain stem cells with the potential to become cardiac myocytes.12 Similarly, neuro-progenitor cells have been found within the brain.13

The cardiac stem cells are present in such small numbers, that they are difficult to study and their function has not been fully determined. The second review in this series will discuss their potential in greater detail.

Since Federal funding for human embryonic stem cells is restricted in the United States, many scientists use the mouse model instead. Besides their ability to self-renew indefinitely and differentiate into cell types of all three germ layers, murine and human pluripotent stem cells have much in common. It should not be surprising that so many pluripotency traits are conserved between species given the shared genomic sequences and intra-cellular structure in mammals. Both mouse and human cells proliferate indefinitely in culture, have a high nucleus to cytoplasm ratio, need the support of growth factors derived from other live cells, and display similar surface antigens, transcription factors and enzymatic activity (i.e. high alkaline phosphatase activity).14 However, differences between mouse and human pluripotent cells, while subtle, are very important. Although the transcription factors mentioned above to induce pluripotency from adult cells (Oct3/4 and Sox2) are shared, the extracellular signals needed to regulate them differ. Mouse embryonic stem cells need the leukemia inhibitory factor and bone morphogenic proteins while human require the signaling proteins Noggin and Wnt for sustained pluripotency.15 Surface markers used to identify pluripotent cells also differ slightly between the two species as seen in the variants of the adhesion molecule SSEA (SSEA-1 in mouse, SSEA-3 & 4 in humans).16 Thus, while pluripotency research in mouse cells is valuable, a direct correlation to the human therapy is not likely.

Last, but certainly not least, a big difference between mouse and human stem cells are the moral and ethical dilemmas that accompany the research. Some people consider working with human embryonic stem cells to be ethically problematic while very few people have reservations on working with the mouse models. However, given the biological differences between human and mouse cells, most scientists believe that data relevant for human therapy will be missed by working only on rodents.

Cell surface markers are typically also used to identify multipotent stem cells. For example, mesenchymal stem cells can be purified from the whole bone marrow aspirate by eliminating cells that express markers of committed cell types, a step referred to as lineage negative enrichment, and then further separating the cells that express the sca-1 and c-Kit surface markers signifying mesenchymal stem cells. Both the lineage negative enrichment step and the sca-1/c-Kit isolation can be achieved by using flow cytometry and is discussed in further detail in the following review. The c-Kit surface marker also is used to distinguish the recently discovered cardiac stem cells from the rest of the myocardium. A great deal of recent work in cardiovascular research has centered on trying to find which markers indicate early multipotent cells that will give rise to pre-cardiac myocytes. Cells with the specific mesodermal marker, Kdr, give rise to the progenitor cells of the cardiovascular system including contracting cardiac myocytes, endothelial cells and vascular smooth muscle cells and are therefore considered to be the earliest cells with specification towards the cardiovascular lineage.17 Cells at this early stage still proliferate readily and yet are destined to become cells of the cardiovascular system and so may be of great value therapeutically.

Scientists are still struggling to reliably direct differentiation of stem cells into specific cell types. They have used a virtual alphabet soup of incubation factors toward that end (including trying a variety of growth factors, chemicals and complex substrates on which the cells are grown), with, so far, only moderate success. As an example of this complexity, one such approach to achieve differentiation towards cardiac myocytes is to use the chemical activin A and the growth factor BMP-4. When these two factors are administered to pluripotent stem cells in a strictly controlled manner, both in concentration and temporally, increased efficiency is seen in differentiation towards cardiac myocytes, but still, only 30% of cells can be expected to become cardiac.18

Multipotent cells have also been used as the starting point for cell therapy, again with cocktails of growth factors and/or chemicals to induce differentiation toward a specific, desired lineage. Some recipes are simple, such as the use of retinoic acid to induce mesenchymal stem cells into neuronal cells,19 or transforming growth factor- to make bone marrow-derived stem cells express cardiac myocyte markers.20 Others are complicated or ill-defined such as addition of the unknown factors secreted by cells in culture. Physical as well as chemical cues cause differentiation of stem cells. Simply altering the stiffness of the substrate on which cells are cultured can direct stem cells to neuronal, myogenic or osteogenic lineages.21 Cells evolve in physical and chemical environments so a combination of both will probably be necessary for optimal differentiation of stem cells. The importance of physical cues in the cells environment will be discussed in greater detail in the final review of this series. Ideally, for stem cells to be used therapeutically, efficient, uniform protocols must be established so that cells are a well-controlled and well-defined entity.

Pluripotent stem cells have not yet been used therapeutically in humans because many of the early animal studies resulted in the undesirable formation of unusual solid tumors, called teratomas. Teratomas are made of a mix of cell types from all the early germ layers. Later successful animal studies used pluripotent cells modified to a more mature phenotype which limits this proliferative capacity. Cells derived from pluripotent cells have been used to successfully treat animals. For example, animals with diabetes have been treated by the creation of insulin-producing cells responsive to glucose levels. Also, animals with acute spinal cord injury or visual impairment have been treated by creation of new myelinated neurons or retinal epithelial cells, respectively. Commercial companies are currently in negotiations with the FDA regarding the possibility of advancing to human trials. Other animal studies have been conducted to treat several maladies such as Parkinsons disease, muscular dystrophy and heart failure.18,22,23

Scientists hope that stem cell therapy can improve cardiac function by integration of newly formed beating cardiac myocytes into the myocardium to produce greater force. Patches of cardiac myocytes derived from human embryonic stem cells can form viable human myocardium after transplantation into animals,24 with some showing evidence of electrical integration.25,26 Damaged rodent hearts showed slightly improved cardiac function after injection of cardiac myocytes derived from human embryonic stem cells.21 The mechanisms for the gain in function are not fully understood but it may be only partially due to direct integration of new beating heart cells. It is more likely due to paracrine effects that benefit other existing heart cells (see next review).

Multipotent stem cells harvested from bone marrow have been used since the 1960s to treat leukemia, myeloma and lymphoma. Since cells there give rise to lymphocytes, megakaryocytes and erythrocytes, the value of these cells is easily understood in treating blood cancers. Recently, some progress has been reported in the use of cells derived from bone marrow to treat other diseases. For example, the ability to form whole joints in mouse models27 has been achieved starting with mesenchymal stem cells that give rise to bone and cartilage. In the near future multipotent stem cells are likely to benefit many other diseases and clinical conditions. Bone marrow-derived stem cells are in clinical trials to remedy heart ailments. This is discussed in detail in the next review of this series.

Pluripotent and multipotent stem cells have their respective advantages and disadvantages. The capacity of pluripotent cells to become any cell type is an obvious therapeutic advantage over their multipotent kin. Theoretically, they could be used to treat diseased or aging tissues in which multipotent stem cells are insufficient. Also, pluripotent stem cells proliferate more rapidly so can yield higher numbers of useful cells. However, use of donor pluripotent stem cells would require immune suppressive drugs for the duration of the graft28 while use of autologous multipotent stem cells (stem cells from ones self) would not. This ability to use ones own cells is a great advantage of multipotent stem cells. The immune system recognizes specific surface proteins on cells/objects that tell them whether the cell is from the host and is healthy. Autologous, multipotent stem cells have the patients specific surface proteins that allow it to be accepted by the hosts immune system and avoid an immunological reaction. Pluripotent stem cells, on the other hand, are not from the host and therefore, lack the proper signals required to stave off rejection from the immune system. Research is ongoing trying to limit the immune response caused by pluripotent cells and is one possible advantage that iPS cells may have.

The promises of cures for human ailments by stem cells have been much touted but many obstacles must still be overcome. First, more human pluripotent and multipotent cell research is needed since stem cell biology differs in mice and men. Second, the common feature of unlimited cell division shared by cancer cells and pluripotent stem cells must be better understood in order to avoid cancer formation. Third, the ability to acquire large numbers of the right cells at the right stage of differentiation must be mastered. Fourth, specific protocols must be developed to enhance production, survival and integration of transplanted cells. Finally, clinical trials must be completed to assure safety and efficacy of the stem cell therapy. When it comes to stem cells, knowing they exist is a long way from using them therapeutically.

Supported by NIH (HL 62426 and T32 HL 007692)

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Introduction to Stem Cell Therapy

Cardiac Stem Cells Comments Off on Introduction to Stem Cell Therapy | October 16th, 2021

Mesenchymal Stem Cells (MSC), also termed Mesenchymal Stromal Cells, are multipotent cells that can differentiate into a variety of cell types and have the capacity for self renewal. MSC have been shown to differentiate in vitro or in vivo into adipocytes, chondrocytes, osteoblasts, myocytes, neurons, hepatocytes, and pancreatic islet cells. Optimized PromoCell media are available to support both the growth of MSC and their differentiation into several different lineages. Recent experiments suggest that differentiation capabilities into diverse cell types vary between MSC of different origin.

PromoCell hMSC are harvested from normal human adipose tissue,bone marrow, andumbilical cord matrix (Whartons jelly) of individual donors.

The cells are tested for their ability to differentiate in vitro into adipocytes, chondrocytes, and osteoblasts. OurhMSC show a verified marker expression profile that complies with ISCT* recommendations, providing well characterized cells.

*ISCT (International Society for Cellular Therapy) Cytotherapy (2006) Vol. 8, No. 4, 315-317

NEW: Our hMSC are now also available from HLA-typed donors.

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Cardiac Stem Cells Comments Off on Human Mesenchymal Stem Cells (hMSC) – PromoCell | October 16th, 2021

Abstract

Traumatic spinal cord injury (SCI) is a life changing neurological condition with substantial socioeconomic implications for patients and their care-givers. Recent advances in medical management of SCI has significantly improved diagnosis, stabilization, survival rate and well-being of SCI patients. However, there has been small progress on treatment options for improving the neurological outcomes of SCI patients. This incremental success mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiological changes that occur in the injured spinal cord. Therefore, in the past few decades, considerable efforts have been made by SCI researchers to elucidate the pathophysiology of SCI and unravel the underlying cellular and molecular mechanisms of tissue degeneration and repair in the injured spinal cord. To this end, a number of preclinical animal and injury models have been developed to more closely recapitulate the primary and secondary injury processes of SCI. In this review, we will provide a comprehensive overview of the recent advances in our understanding of the pathophysiology of SCI. We will also discuss the neurological outcomes of human SCI and the available experimental model systems that have been employed to identify SCI mechanisms and develop therapeutic strategies for this condition.

Keywords: spinal cord injury, secondary injury mechanisms, clinical classifications and demography, animal models, glial and immune response, glial scar, chondroitin sulfate proteoglycans (CSPGs), cell death

Spinal cord injury (SCI) is a debilitating neurological condition with tremendous socioeconomic impact on affected individuals and the health care system. According to the National Spinal Cord Injury Statistical Center, there are 12,500 new cases of SCI each year in North America (1). Etiologically, more than 90% of SCI cases are traumatic and caused by incidences such as traffic accidents, violence, sports or falls (2). There is a reported male-to-female ratio of 2:1 for SCI, which happens more frequently in adults compared to children (2). Demographically, men are mostly affected during their early and late adulthood (3rd and 8th decades of life) (2), while women are at higher risk during their adolescence (1519 years) and 7th decade of their lives (2). The age distribution is bimodal, with a first peak involving young adults and a second peak involving adults over the age of 60 (3). Adults older than 60 years of age whom suffer SCI have considerably worse outcomes than younger patients, and their injuries usually result from falls and age-related bony changes (1).

The clinical outcomes of SCI depend on the severity and location of the lesion and may include partial or complete loss of sensory and/or motor function below the level of injury. Lower thoracic lesions can cause paraplegia while lesions at cervical level are associated with quadriplegia (4). SCI typically affects the cervical level of the spinal cord (50%) with the single most common level affected being C5 (1). Other injuries include the thoracic level (35%) and lumbar region (11%). With recent advancements in medical procedures and patient care, SCI patients often survive these traumatic injuries and live for decades after the initial injury (5). Reports on the clinical outcomes of patients who suffered SCI between 1955 and 2006 in Australia demonstrated that survival rates for those suffering from tetraplegia and paraplegia is 91.2 and 95.9%, respectively (5). The 40-year survival rate of these individuals was 47 and 62% for persons with tetraplegia and paraplegia, respectively (5). The life expectancy of SCI patients highly depends on the level of injury and preserved functions. For instance, patients with ASIA Impairment Scale (AIS) grade D who require a wheelchair for daily activities have an estimated 75% of a normal life expectancy, while patients who do not require wheelchair and catheterization can have a higher life expectancy up to 90% of a normal individual (6). Today, the estimated life-time cost of a SCI patient is $2.35 million per patient (1). Therefore, it is critical to unravel the cellular and molecular mechanisms of SCI and develop new effective treatments for this devastating condition. Over the past decades, a wealth of research has been conducted in preclinical and clinical SCI with the hope to find new therapeutic targets for traumatic SCI.

SCI commonly results from a sudden, traumatic impact on the spine that fractures or dislocates vertebrae. The initial mechanical forces delivered to the spinal cord at the time of injury is known as primary injury where displaced bone fragments, disc materials, and/or ligaments bruise or tear into the spinal cord tissue (79). Notably, most injuries do not completely sever the spinal cord (10). Four main characteristic mechanisms of primary injury have been identified that include: (1) Impact plus persistent compression; (2) Impact alone with transient compression; (3) Distraction; (4) Laceration/transection (8, 11). The most common form of primary injury is impact plus persistent compression, which typically occurs through burst fractures with bone fragments compressing the spinal cord or through fracture-dislocation injuries (8, 12, 13). Impact alone with transient compression is observed less frequently but most commonly in hyperextension injuries (8). Distraction injuries occur when two adjacent vertebrae are pulled apart causing the spinal column to stretch and tear in the axial plane (8, 12). Lastly, laceration and transection injuries can occur through missile injuries, severe dislocations, or sharp bone fragment dislocations and can vary greatly from minor injuries to complete transection (8). There are also distinct differences between the outcomes of SCI in military and civilian cases. Compared to civilian SCI, blast injury is the common cause of SCI in battlefield that usually involves multiple segments of the spinal cord (14). Blast SCI also results in higher severity scores and is associated with longer hospital stays (15). A study on American military personnel, who sustained SCI in a combat zone from 2001 to 2009, showed increased severity and poorer neurological recovery compared to civilian SCI (15). Moreover, lower lumbar burst fractures and lumbosacral dissociation happen more frequently in combat injuries (1). Regardless of the form of primary injury, these forces directly damage ascending and descending pathways in the spinal cord and disrupt blood vessels and cell membranes (11, 16) causing spinal shock, systemic hypotension, vasospasm, ischemia, ionic imbalance, and neurotransmitter accumulation (17). To date, the most effective clinical treatment to limit tissue damage following primary injury is the early surgical decompression (< 24 h post-injury) of the injured spinal cord (18, 19). Overall, the extent of the primary injury determines the severity and outcome of SCI (20, 21).

Functional classification of SCI has been developed to establish reproducible scoring systems by which the severity of SCI could be measured, compared, and correlated with the clinical outcomes (20). Generally, SCI can be classified as either complete or incomplete. In complete SCI, neurological assessments show no spared motor or sensory function below the level of injury (4). In the past decades, several scoring systems have been employed for clinical classification of neurological deficits following SCI. The first classification system, Frankel Grade, was developed by Frankel and colleagues in 1969 (22). They assessed the severity and prognosis of SCI using numerical sensory and motor scales (22). This was a 5-grade system in which Grade A was the most severe SCI with complete loss of sensory and motor function below the level of injury. Grade B represented complete motor loss with preserved sensory function and sacral sparing. Patients in Grade C and D had different degrees of motor function preservation and Grade E represented normal sensory and motor function. The Frankel Grade was widely utilized after its publication due to its ease of use. However, lack of clear distinction between Grades C and D and inaccurate categorization of motor improvements in patients over time, led to its replacement by other scoring systems (20).

Other classification methods followed Frankel's system. In 1987, Bracken et al. at Yale University School of Medicine classified motor and sensory functions separately in a 5 and 7-scale systems, respectively (23). However, this scoring system failed to account for sacral function (20). Moreover, integration of motor and sensory classifications was impossible in this system and it was abandoned due to complexity and impracticality in clinical settings (20). Several other scoring systems were developed in 1970' and 1980's by different groups such as Lucas and Ducker at the Maryland Institute for Emergency Medical Services in late 1970's (24), Klose and colleagues at the University of Miami Neuro-spinal Index (UMNI) in early 1980s (25) and Chehrazi and colleagues (Yale Scale) in 1981 (26). These scoring systems also became obsolete due to their disadvantage in evaluation of sacral functions, difficulty of use or discrepancies between their motor and sensory scoring sub-systems (20).

The ASIA scoring system is currently the most widely accepted and employed clinical scoring system for SCI. ASIA was developed in 1984 by the American Spinal Cord Injury Association and has been updated over time to improve its reliability (). In this system, sensory function is scored from 02 and motor function from 0 to 5 (20). The ASIA impairment score (AIS) ranges from complete loss of sensation and movement (AIS = A) to normal neurological function (AIS = E). The first step in ASIA system is to identify the neurological level of injury (NLI). In this assessment, except upper cervical vertebrae that closely overlay the underlying spinal cord segments, the anatomical relationship between the spinal cord segments and their corresponding vertebra is not reciprocally aligned along the adult spinal cord (20). At thoracic and lumbar levels, each vertebra overlays a spinal cord segment one or two levels below and as the result, a T11 vertebral burst fracture results in neurological deficit at and below L1 spinal cord segment. Hence, the neurological level of injury (NLI) is defined as the most caudal neurological level at which all sensory and motor functions are normal (20). Upon identifying the NLI, if the injury is complete (AIS = A), zone of partial preservation (ZPP) is determined (20). ZPP is defined as all the segments below the NLI that have some preserved sensory or motor function. A precise record of ZPP enables the examiners to distinguish spontaneous from treatment-induced functional recovery, thus, essential for evaluating the therapeutic efficacy of treatments (20). Complete loss of motor and preservation of some sensory functions below the neurological level of the injury is categorized as AIS B (20). If motor function is also partially spared below the level of the injury, AIS score can be C or D (20). The AIS is scored D when the majority of the muscle groups below the level of the injury exhibit strength level of 3 or higher (for more details see ). ASIA classification combines the assessments of motor, sensory and sacral functions, thus addressing the shortcomings of previous scoring systems (20). The validity and reproducibility of ASIA system combined with its accuracy in prediction of patients' outcome have made it the most accepted and reliable clinical scoring system utilized for neurological classification of SCI (20).

ASIA scoring for the neurological classification of the SCI. A sample scoring sheet used for ASIA scoring in clinical setting is provided (adopted from: http://asia-spinalinjury.org).

In clinical management of SCI, neurological outcomes are generally determined at 72 h after injury using ASIA scoring system (20, 27). This time-point has shown to provide a more precise assessment of neurological impairments after SCI (28). One important predictor of functional recovery is to determine whether the injury was incomplete or complete. As time passes, SCI patients experience some spontaneous recovery of motor and sensory functions. Most of the functional recovery occurs during the first 3 months and in most cases reaches a plateau by 9 months after injury (20). However, additional recovery may occur up to 1218 months post-injury (20). Long term outcomes of SCI are closely related to the level of the injury, the severity of the primary injury and progression of secondary injury, which will be discussed in this review.

Depending on the level of SCI, patients experience paraplegia or tetraplegia. Paraplegia is defined as the impairment of sensory or motor function in lower extremities (27, 28). Patients with incomplete paraplegia generally have a good prognosis in regaining locomotor ability (~76% of patients) within a year (27). Complete paraplegic patients, however, experience limited recovery of lower limb function if their NLI is above T9 (29). An NLI below T9 is associated with 38% chance of regaining some lower extremity function (29). In patients with complete paraplegia, the chance of recovery to an incomplete status is only 4% with only half of these patients regaining bladder and bowel control (29). Tetraplegia is defined as partial or total loss of sensory or motor function in all four limbs. Patients with incomplete tetraplegia will gain better recovery than complete tetra- and paraplegia (30). Unlike complete SCI, recovery from incomplete tetraplegia usually happens at multiple levels below the NLI (20). Patients generally reach a plateau of recovery within 912 months after injury (20). Regaining some motor function within the first month after the injury is associated with a better neurological outcome (20). Moreover, appearance of muscle flicker (a series of local involuntary muscle contractions) in the lower extremities is highly associated with recovery of function (31). Patients with complete tetraplegia, often (6690%) regain function at one level below the injury (28, 30). Importantly, initial muscle strength is an important predictor of functional recovery in these patients (20). Complete tetraplegic patients with cervical SCI can regain antigravity muscle function in 27% of the cases when their initial muscle strength is 0 on a 5-point scale (32). However, the rate of regaining antigravity muscle strength at one caudal level below the injury increases to 97% when the patients have initial muscle strength of 12 on a 5-point scale (33).

An association between sensory and motor recovery has been demonstrated in SCI where spontaneous sensory recovery usually follows the pattern of motor recovery (20, 34). Maintenance of pinprick sensation at the zone of partial preservation or in sacral segments has been shown as a reliable predictor of motor recovery (35). One proposed reason for this association is that pinprick fibers in lateral spinothalamic tract travel in proximity of motor fibers in the lateral corticospinal tract, and thus, preservation of sensory fibers can be an indicator of the integrity of motor fiber (20). Diagnosis of an incomplete injury is of great importance and failure to detect sensory preservation at sacral segments results in an inaccurate assessment of prognosis (20).

In the past few decades, various animal models have been developed to allow understanding the complex biomedical mechanisms of SCI and to develop therapeutic strategies for this condition. An ideal animal model should have several characteristics including its relevance to the pathophysiology of human SCI, reproducibility, availability, and its potential to generate various severities of injury (36).

Small rodents are the most frequently employed animals in SCI studies due to their availability, ease of use and cost-effectiveness compared to primates and larger non-primate models of SCI (36, 37). Among rodents, rats more closely mimic pathophysiological, electrophysiological, functional, and morphological features of non-primate and human SCI (38). In rat (39), cat (40), monkey (41), and human SCI (17), a cystic cavity forms in the center of the spinal cord, which is a surrounded by a rim of anatomically preserved white matter. A study by Metz and colleagues compared the functional and anatomical outcomes of rat contusive injuries and human chronic SCI (42). High resolution MRI assessments identified that SCI-induced neuroanatomical changes such as spinal cord atrophy and size of the lesion were significantly correlated with the electrophysiological and functional outcomes in both rat and human contusive injuries (42). Histological assessments in rats also showed a close correlation between the spared white matter and functional preservation following injury (42). These studies provide evidence that rat models of contusive SCI could serve as an adequate model to develop and evaluate the structural and functional benefits of therapeutic strategies for SCI (42).

Mice show different histopathology than human SCI in which the lesion site is filled with dense fibrous connective-like tissue (4346). Mouse SCI studies show the presence of fibroblast-like cells expressing fibronectin, collagen, CD11b, CD34, CD13, and CD45 within the lesion core of chronic SCI, while it is absent in the injured spinal cord of rats (47). Another key difference between rat and mice SCI is the time-point of inflammatory cell infiltration. While microglia/macrophage infiltration is relatively consistent between rat and mouse models of SCI (47), there is a temporal difference in infiltration of neutrophils and T cells between the two species (47, 48). In SCI rats, infiltration of neutrophils, the first responders, peaks at 6 h post injury, followed by a significant decline at 2448 h after SCI (48). Similarly, in mouse SCI, neutrophil infiltration occurs within 6 h following injury; however, their numbers continue to rise and do not peak until 314 days post injury (49). T cell infiltration also varies between rat and mouse SCI models (50). In rats, T cell infiltration occurs between 3 and 7 days post injury and declines by 50% in the following 2 weeks (47), whereas in mice, T cell infiltration is not detected until 14 days post injury and their number doubles between 2 and 6 weeks post injury (47). Regardless of their pathophysiological relevance, mice have been used extensively in SCI studies primarily due to the availability of transgenic and mutant mouse models that have allowed uncovering molecular and cellular mechanisms of SCI (38).

In recent years, there has been emerging interest in employment of non-human primates and other larger animals such as pig, dog and cat as intermediate pre-clinical models (5153) to allow more effective translation of promising treatments from rodent models to human clinical trials (50). Although rodents have served as invaluable models for studying SCI mechanisms and therapeutic development, larger mammals, in particular non-human primates, share a closer size, neuroanatomy, and physiology to humans. Importantly, their larger size provides a more relevant platform for drug development, bioengineering inventions, and electrophysiological and rehabilitation studies. Nonetheless, both small and large animal models of SCI have limitations in their ability to predict the outcome in human SCI. One important factor is high degree of variability in the nature of SCI incidence, severity and location of the injury in human SCI, while in laboratory animal models, these variabilities are less (36). Values acquired by clinical scoring systems such as ASIA or Frankel scoring systems lack the consistency of the data acquired from laboratory settings, which makes the translation of therapeutic interventions from experimental to clinical settings challenging (36). A significant effect from an experimental treatment in consistent laboratory settings may not be reproducible in clinical settings due to high variability and heterogeneity in human populations and their injuries (36). To date, several pharmacological and cellular preclinical discoveries have led to human clinical trials based on their efficacy in improving the outcomes of SCI in small animal models. However, the majority of these trials failed to reproduce the same efficacy in human SCI. Thus, in pre-clinical studies, animal models, and study designs should be carefully chosen to reflect the reality of clinical setting as closely as possible (36). Larger animals provide the opportunity to refine promising therapeutic strategies prior to testing in human SCI; however, their higher cost, need for specialized facilities and small subject (sample) size have limited their use in SCI research (50). Thus, rodents are currently the most commonly employed models for preclinical discoveries and therapeutic development, while the use of larger animals is normally pursued for late stage therapies that have shown efficacy and promise in small animal models. provides a summary of available SCI models.

Animal models are also classified based on the type of SCI. The following sections will provide an overview on the available SCI models that are developed based on injury mechanisms, their specifications and relevance to human SCI ().

A complete transection model of SCI is relatively easy to reproduce (51). However, this model is less relevant to human SCI as a complete transection of the spinal cord rarely happens (51). While they do not represent clinical reality of SCI, transection models are specifically suitable for studying axonal regeneration or developing biomaterial scaffolds to bridge the gap between proximal and distal stamps of the severed spinal cord (51). Due to complete disconnection from higher motor centers, this model is also suitable for studying the role of propriospinal motor and sensory circuits in recovery of locomotion following SCI (51, 80). Partial transection models including hemi-section, unilateral transection and dorsal column lesions are other variants of transection models (51). Partial transection models are valuable for investigation of nerve grafting, plasticity and where a comparison between injured and non-injured pathways is needed in the same animal (51). However, these models lead to a less severe injury and higher magnitude of spontaneous recovery rendering them less suitable for development and evaluation of new therapies (51).

Contusion is caused by a transient physical impact to the spinal cord and is clinically-relevant. There are currently three types of devices that can produce contusion injury in animal models: weight-drop apparatus, electromagnetic impactor, and a recently introduced air gun device (51). The impactor model was first introduced by Gruner at New York University (NYU) in 1992 (81). The original NYU impactor included a metal rod of specific weight (10 g) that could be dropped on the exposed spinal cord from a specific height to induce SCI (51). This model allowed induction of a defined severity of SCI by adjusting the height, which the rod fell on the spinal cord (81). Parameters such as time, velocity at impact and biomechanical response of the tissue can be recorded for analysis and verification (51). The NYU impactor was later renamed to Multicenter Animal Spinal Cord Injury Study (MASCIS) impactor, and conditions surrounding the study and use of the MASCIS impactor were standardized (51). Since its introduction, the MASCIS impactor has been updated twice. The most recent version, MACIS III, was introduced in 2012 and included both electromagnetic control and digital recording of the impact parameters (51). However, inability to control duration of impact and weight bounce, that could cause multiple impacts, have been known limitations of MASCIS impactors (51).

The Infinite Horizon (IH) impactor is another type of impactor that utilizes a stepping motor to generate force-controlled impact in contrast to free fall in the MASICS impactor (51). This feature allows for better control over the force of impact and prevents weight bounce as the computer-controlled metal impounder can be immediately retracted upon transmitting a desired force to the spinal cord (51). IH impactor can be set to different force levels to provide mild, moderate and severe SCI in rats (ex. 100, 150, and 200 kdyn) (51). A limitation with IH impactors is unreliability of their clamps in holding the spinal column firmly during the impact that can cause inconsistent parenchymal injury and neurological deficits (51).

Ohio State University (OSU) impactor is a computer controlled electromagnetic impactor that was originally invented in 1987 and refined in 1992 to improve reliability (58). As the OSU impactor is electromagnetically controlled, multiple strikes are avoided (51). Subsequently, a modified version of the OSU impactor was developed in 2000 for use in mice (43). However, the OSU impactor is limited by its inability to determine the precise initial contact point with the spinal cord due to displacement of CSF upon loading the device (51). To date, MASCIS, IH and OSU impactor devices have been employed extensively and successfully to induce SCI. These impactor devices are available for small and large animals such as mice, rats, marmosets, cats, and pigs (51, 82).

Compressive models of SCI have been also employed for several decades (61). While contusion injury is achieved by applying a force for a very brief period (milliseconds), the compression injury consists of an initial contusion for milliseconds followed by a prolonged compression through force application for a longer duration (seconds to minutes) (51). Thus, compression injury can be categorized as contusive-compressive models (51). Various models of compressive SCI are available.

Clip compression is the most commonly used compression model of SCI in rat and mice (51, 61, 62, 83). It was first introduced by Rivlin and Tator in 1978 (61). In this model, following laminectomy, a modified aneurism clip with a calibrated closing force is applied to the spinal cord for a specific duration of time (usually 1 min) to induce a contusive-compressive injury (51). The severity of injury can be calibrated and modified by adjusting the force of the clip and the duration of compression (51). For example, applying a 50 g clip for 1 min typically produces a severe SCI, while a 35 g clip creates a moderate to severe injury with the same duration (83). Aneurysm clips were originally designed for use in rat SCI, however, in recent years smaller and larger clips have been developed to accommodate its use in mice (62) and pig models (52). The clip compression model has several advantages compared to contusion models. This method is less expensive and easier to perform (51). Importantly, in contrast to the impactor injury that contusion is only applied dorsally to the spinal cord, the clip compression model provides contusion and compression simultaneously both dorsally and ventrally. Hence, clip compression model more closely mimics the most common form of human SCI, which is primarily caused by dislocation and burst compression fractures (83). Despite its advantages, clip compression model can create variabilities such as the velocity of closing and actual delivered force that cannot be measured precisely at the time of application (51).

Calibrated forceps compression has been also employed to induce SCI in rodents. This simple and inexpensive compressive model was first utilized in 1991 for induction of SCI in guinea pigs (64). In this method, a calibrated forceps with a spacer is used to compress the spinal cord bilaterally (51). This model lacks the initial impact and contusive injury, which is associated with most cases of human traumatic SCI. Accordingly, this model is not a clinically relevant model for reproducing human SCI pathology and therapeutic development (51).

Balloon Compression model has been also utilized extensively in primates and larger animals such as dogs and cats (8486). In this model, a catheter with an inflatable balloon is inserted in the epidural or subdural space. The inflation of the balloon with air or saline for a specific duration of time provides the force for induction of SCI (51). Generally, all compression models (clip, forceps, and balloon) have the same limitation as the velocity and amount of force are unmeasurable (51).

In conclusion, while existing animal models do not recapitulate all clinical aspects of human SCI, the compression and contusion models are considered to be the most relevant and commonly employed methods for understanding the secondary injury mechanisms and therapeutic development for SCI.

Secondary injury begins within minutes following the initial primary injury and continues for weeks or months causing progressive damage of spinal cord tissue surrounding the lesion site (7). The concept of secondary SCI was first introduced by Allen in 1911 (87). While studying SCI in dogs, he observed that removal of the post traumatic hematomyelia improved neurological outcome. He hypothesized that presence of some biochemical factors in the necrotic hemorrhagic lesion causes further damage to the spinal cord (87). The term of secondary injury is still being used in the field and is referred to a series of cellular, molecular and biochemical phenomena that continue to self-destruct spinal cord tissue and impede neurological recovery following SCI () (20).

Summary of secondary injury processes following traumatic spinal cord injury. Diagram shows the key pathophysiological events that occur after primary injury and lead to progressive tissue degeneration. Vascular disruption and ischemia occur immediately after primary injury that initiate glial activation, neuroinflammation, and oxidative stress. These acute changes results in cell death, axonal injury, matrix remodeling, and formation of a glial scar.

Secondary injury can be temporally divided into acute, sub-acute, and chronic phases. The acute phase begins immediately following SCI and includes vascular damage, ionic imbalance, neurotransmitter accumulation (excitotoxicity), free radical formation, calcium influx, lipid peroxidation, inflammation, edema, and necrotic cell death (7, 20, 88). As the injury progresses, the sub-acute phase of injury begins which involves apoptosis, demyelination of surviving axons, Wallerian degeneration, axonal dieback, matrix remodeling, and evolution of a glial scar around the injury site (). Further changes occur in the chronic phase of injury including the formation of a cystic cavity, progressive axonal die-back, and maturation of the glial scar (7, 8992). Here, we will review the key components of acute secondary injury that contribute to the pathophysiology of SCI (, ).

Pathophysiology of traumatic spinal cord injury. This schematic diagram illustrates the composition of normal and injured spinal cord. Of note, while these events are shown in one figure, some of the pathophysiological events may not temporally overlap and can occur at various phases of SCI, which are described here. Immediately after primary injury, activation of resident astrocytes and microglia and subsequent infiltration of blood-borne immune cells results in a robust neuroinflammatory response. This acute neuroinflammatory response plays a key role in orchestrating the secondary injury mechanisms in the sub-acute and chronic phases that lead to cell death and tissue degeneration, as well as formation of the glial scar, axonal degeneration and demyelination. During the acute phase, monocyte-derived macrophages occupy the epicenter of the injury to scavenge tissue debris. T and B lymphocytes also infiltrate the spinal cord during sub-acute phase and produce pro-inflammatory cytokines, chemokines, autoantibodies reactive oxygen and nitrogen species that contribute to tissue degeneration. On the other hand, M2-like macrophages and regulatory T and B cells produce growth factors and pro-regenerative cytokines such as IL-10 that foster tissue repair and wound healing. Loss of oligodendrocytes in acute and sub-acute stages of SCI leads to axonal demyelination followed by spontaneous remyelination in sub-acute and chronic phases. During the acute and sub-acute phases of SCI; astrocytes, OPCs and pericytes, which normally reside in the spinal cord parenchyma, proliferate and migrate to the site of injury and contribute to the formation of the glial scar. The glial scar and its associated matrix surround the injury epicenter and create a cellular and biochemical zone with both beneficial and detrimental roles in the repair process. Acutely, the astrocytic glial scar limits the spread of neuroinflammation from the lesion site to the healthy tissue. However, establishment of a mature longstanding glial scar and upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) are shown to inhibit axonal regeneration/sprouting and cell differentiation in subacute and chronic phases.

Disruption of spinal cord vascular supply and hypo-perfusion is one of the early consequences of primary injury (93). Hypovolemia and hemodynamic shock in SCI patients due to excessive bleeding and neurogenic shock result in compromised spinal cord perfusion and ischemia (93). Larger vessels such as anterior spinal artery usually remain intact (94, 95), while rupture of smaller intramedullary vessels and capillaries that are susceptible to traumatic damage leads to extravasation of leukocytes and red blood cells (93). Increased tissue pressure in edematous injured spinal cord and hemorrhage-induced vasospasm in intact vessels further disrupts blood flow to the spinal cord (93, 95). In rat and monkey models of SCI, there is a progressive reduction in blood flow at the lesion epicenter within the first few hours after injury which remains low for up to 24 h (96). The gray matter is more prone to ischemic damage compared to the white matter as it has a 5-fold higher density of capillary beds and contains neurons with high metabolic demand (95, 97, 98). After injury, white matter blood flow typically returns to normal levels within 15 min post injury, whereas there are multiple hemorrhages in the gray matter and as a result, re-perfusion usually does not occur for the first 24 h (9, 99, 100). Vascular insult, hemorrhage and ischemia ultimately lead to cell death and tissue destruction through multiple mechanisms, including oxygen deprivation, loss of adenosine triphosphate (ATP), excitotoxicity, ionic imbalance, free radical formation, and necrotic cell death. Cellular necrosis and release of cytoplasmic content increase the extracellular level of glutamate causing glutamate excitotoxicity (93, 101). Moreover, re-establishment of blood flow in ischemic tissue leads to further damage through generating free radicals and eliciting an inflammatory response (93, 102) that will be discussed in this review.

Within few minutes after primary SCI, the combination of direct cellular damage and ischemia/hypoxia triggers a significant rise of extracellular glutamate, the main excitatory neurotransmitter in the CNS (7). Glutamate binds to ionotropic (NMDA, AMPA, and Kainate receptors) as well as metabotropic receptors resulting in calcium influx inside the cells (103105) (93). The effect of glutamate is not restricted to neurons as its receptors are vastly expressed on the surface of all glia and endothelial cells (103106). Astrocytes can also release excess glutamate extracellularly upon elevation of their intracellular Ca2+ levels. Reduced ability of activated astrocytes for glutamate re-uptake from the interstitial space due to lipid peroxidation results in further accumulation of glutamate in the SCI milieu (93). Using microdialysis, elevated levels of glutamate have been detected in the white matter in the acute stage of injury (107). Based on a study by Panter and colleagues, glutamate increase is detected during the first 2030 min post SCI and returns to the basal levels after 60 min (108).

Under normal condition, concentration of free Ca2+ can considerably vary in different parts of the cell (109). In the cytosol, Ca2+ ranges from 50100 nM while it approaches 0.51.0 mM in the lumen of endoplasmic reticulum (110112). A long-lasting abnormal increase in Ca2+ concentration in cytosol, mitochondria or endoplasmic reticulum has detrimental consequences for the cell (109113). Mitochondria play a central role in calcium dependent neuronal death (113). In neurons, during glutamate induced excitotoxicity, NMDA receptor over-activity leads to mitochondrial calcium overload, which can cause apoptotic or necrotic cell death (113). Shortly after SCI, Ca2+ enters mitochondria through the mitochondrial calcium uniporter (MCU) (114). While the amount of mitochondrial calcium is limited during the resting state of a neuron, they can store a high amount of Ca2+ following stimulation (113). Calcium overload also activates a host of protein kinases and phospholipases that results in calpain mediated protein degradation and oxidative damage due to mitochondrial failure (93). In the injured white matter, astrocytes, oligodendrocytes and myelin are also damaged by the increased release of glutamate and Ca2+-dependent excitotoxicity (115). Within the first few hours after injury, oligodendrocytes show signs of caspase-3 activation and other apoptotic features, and their density declines (116). Interestingly, while glutamate excitotoxicity is triggered by ionic imbalance in the white matter, in the gray matter, it is largely associated with the activity of neuronal NMDA receptors (117, 118). Altogether, activation of NMDA receptors and consequent Ca2+ overload appears to induce intrinsic apoptotic pathways in neurons and oligodendrocytes and causes cell death in the first week of SCI in the rat (119, 120). Administration of NMDA receptor antagonist (MK-801) shortly following SCI has been associated with improved functional recovery and reduced edema (121).

Mitochondrial calcium overload also impedes mitochondrial respiration and results in ATP depletion disabling Na+/K+ ATPase and increasing intracellular Na+ (119, 122124). This reverses the function of the Na+ dependent glutamate transporter that normally utilizes Na+ gradient to transfer glutamate into the cells (119, 125, 126). Moreover, the excess intracellular Na+ reverses the activity of Na+/Ca2+ exchanger allowing more Ca+ influx (127). Cellular depolarization activates voltage gated Na+ channels that results in entry of Cl and water into the cells along with Na+ causing swelling and edema (128). Increased Na+ concentration over-activates Na+/H+ exchanger causing a rise in intracellular H+ (101, 129). Resultant intracellular acidosis increases membrane permeability to Ca2+ that exacerbates the injury-induced ionic imbalance (101, 129). Axons are more susceptible to the damage caused by ionic imbalance due to their high concentration of voltage gated Na+ channels in the nodes of Ranvier (7). Accumulating evidence shows that administration of Na+ channel blockers such as Riluzole attenuates tissue damage and improves functional recovery in SCI underlining sodium as a key player in secondary injury mechanisms (130133).

SCI results in production of free radicals and nitric oxide (NO) (114). Mitochondrial Ca2+ overload activates NADPH oxidase (NOX) and induces generation of superoxide by electron transport chain (ETC) (114). Reactive oxygen and nitrogen species (ROS and RNS) produced by the activity of NOX and ETC activates cytosolic poly (ADP ribose) polymerase (PARP). PARP consumes and depletes NAD+ causing failure of glycolysis, ATP depletion and cell death (114). Moreover, PAR polymers produced by PARP activity, induce the release of apoptosis inducing factor (AIF) from mitochondria and induce cell death (114). On the other hand, acidosis caused by SCI results in the release of intracellular iron from ferritin and transferrin (93). Spontaneous oxidation of Fe2+ to Fe3+ gives rise to more superoxide radicals (93). Subsequently, the Fenton reaction between Fe3+ and hydrogen peroxide produces highly reactive hydroxyl radicals (134). The resultant ROS and RNS react with numerous targets including lipids in the cell membrane with the most deleterious effects (93, 135). Because free radicals are short-lived and difficult to assess, measurements of their activity and final products, such as Malondialdehyde (MDA), are more reliable following SCI. Current evidence indicates that MDA levels are elevated as early as 1 h and up to 1 week after SCI (136, 137).

Oxidation of lipids and proteins is one of the key mechanisms of secondary injury following SCI (93). Lipid peroxidation starts when ROSs interact with polyunsaturated fatty acids in the cell membrane and generate reactive lipids that will then form lipid peroxyl radicals upon interacting with free superoxide radicals (138, 139). Each lipid peroxyl radical can react with a neighboring fatty acid, turn it into an active lipid and start a chain reaction that continues until no more unsaturated lipids are available or terminates when the reactive lipid quenches with another radical (93). The final products of this termination step of the lipid peroxidation is 4-hydroxynonenal (HNE) and 2-propenal, which are highly toxic to the cells (138140). Lipid peroxidation is also an underlying cause of ionic imbalance through destabilizing cellular membranes such as cytoplasmic membrane and endoplasmic reticulum (93). Moreover, lipid peroxidation leads to Na+/K+ ATPase dysfunction that exacerbates the intracellular Na+ overload (141). In addition to ROS associated lipid peroxidation, amino acids are subject to significant RNS associated oxidative damage following SCI (93). RNSs (containing ONOO) can nitrate the tyrosine residues of amino acids to form 3-nitrotyrosine (3-NT), a marker for peroxynitrite (ONOO) mediated protein damage (139). Lipid and protein oxidation following SCI has a number of detrimental consequences at cellular level including mitochondrial respiratory and metabolic failure as well as DNA alteration that ultimately lead to cell death (141).

Cell death is a major event in the secondary injury mechanisms that affects neurons and glia after SCI (142145). Cell death can happen through various mechanisms in response to various injury-induced mediators. Necrosis and apoptosis were originally identified as two major cell death mechanisms following SCI (146148). However, recent research has uncovered additional forms of cell death. In 2012, the Nomenclature Committee on Cell Death (NCCD) NCCD defined 12 different forms of cell death such as necroptosis, pyroptosis, and netosis (149). Among the identified modes of cell death, to date, necrosis, necroptosis, apoptosis, and autophagy have been studied more extensively in the context of SCI and will be discussed in this review.

Following SCI, neurons and glial cells die through necrosis as the result of mechanical damage at the time of primary injury that also continues to the acute and subacute stages of injury (7, 150). Necrosis occurs due to a multitude of factors including accumulation of toxic blood components (151), glutamate excitotoxicity and ionic imbalance (152), ATP depletion (153), pro-inflammatory cytokine release by neutrophils and lymphocytes (154, 155), and free radical formation (142, 156158). It was originally thought that necrosis is caused by a severe impact on a cell that results in rapid cell swelling and lysis. However, follow up evidence showed that in the case of seizure, ischemia and hypoglycemia, necrotic neurons show signs of shrunken, pyknotic, and condensed nuclei, with swollen, irreversibly damaged mitochondria and plasma membrane that are surrounded by astrocytic processes (159). Moreover, necrosis was conventionally viewed as instantaneous energy-independent non-programmed cell death (142, 156). However, recent research has identified another form of necrosis, termed as necroptosis, that is executed by regulated mechanisms.

Programmed necrosis or necroptosis has been described more recently as a highly regulated, caspase-independent cell death with similar morphological characteristics as necrosis (160). Necroptosis is a receptor-mediated process. It is induced downstream of the TNF receptor 1 (TNFR1) and is dependent on the activity of the receptor interacting protein kinase 1 (RIPK1) and RIPK3. Recent studies has uncovered a key role for RIPK1 as the mediator of necroptosis and a regulator of the innate immune response involved in both inflammation and cell death (161). Evidence from SCI studies show that lysosomal damage can potentiate necroptosis by promoting RIPK1 and RIPK3 accumulation (161). Interestingly, inhibition of necroptosis by necrostatin-1, a RIPK1 inhibitor, improves functional outcomes after SCI (150). These initial findings suggest that modulation of necroptosis pathways seems to be a promising target for neuroprotective strategies after SCI.

Apoptosis is the most studied mechanism of cell death after SCI. Apoptosis represents a programmed, energy dependent mode of cell death that begins within hours of primary injury (7). This process takes place in cells that survive the primary injury but endure enough insult to activate their apoptotic pathways (142). In apoptosis, the cell shrinks and is eventually phagocytosed without induction of an inflammatory response (156). Apoptosis typically occurs in a delayed manner in areas more distant to the injury site and most abundantly affects oligodendrocytes. In rat SCI, apoptosis happens as early as 4 h after the injury and reaches a peak at 7 day (156). At the site of injury majority of oligodendrocytes are lost within 7 days after SCI (162). However, apoptosis can be observed at a diminished rate for weeks after SCI (162, 163). Microglia and astrocytes also undergo apoptosis (156, 164). Interestingly, apoptotic cell death occurs in the chronically injured spinal cord in rat, monkey and human models of SCI, which is thought to be due to loss of trophic support from degenerating axons (146, 165).

Apoptosis is induced through extrinsic and intrinsic pathways based on the triggering mechanism (166). The extrinsic pathway is triggered by activation of death receptors such as FAS and TNFR1, which eventually activates caspase 8 (167). The intrinsic pathway, however, is regulated through a balance between intracellular pro- and anti-apoptotic proteins and is triggered by the release of cytochrome C from mitochondria and activating caspase 9 (167). In SCI lesion, apoptosis primarily happens due to injury induced Ca2+ influx, which activates caspases and calpain; enzymes involved in breakdown of cellular proteins (7). Moreover, it is believed that the death of neurons and oligodendrocytes in remote areas from the lesion epicenter can be mediated through cytokines such as TNF-, free radical damage and excitotoxicity since calcium from damaged cells within the lesion barely reaches these remote areas (8, 168). Fas mediated cell death has been suggested as a key mechanism of apoptosis following SCI (144, 169172). Post-mortem studies on acute and chronic human SCI and animal models revealed that Fas mediated apoptosis plays a role in oligodendrocyte apoptosis and inflammatory response at acute and subacute stages of SCI (173). Fas deficient mice exhibit a significant reduction in apoptosis and inflammatory response evidenced by reduced macrophage infiltration and inflammatory cytokine expression following SCI (173). Interestingly, Fas deficient mice show a significantly improved functional recovery after SCI (173) suggesting the promise of anti-apoptotic strategies for SCI.

SCI also results in a dysregulated autophagy (174). Normally, autophagy plays an important role in maintaining the homeostasis of cells by aiding in the turnover of proteins and organelles. In autophagy, cells degrade harmful, defective or unnecessary cytoplasmic proteins and organelles through a lysosomal dependent mechanism (175, 176). The process of autophagy starts with the formation of an autophagosome around the proteins and organelles that are tagged for autophagy (176). Next, fusion of the phagosome with a lysosome form an autolysosome that begins a recycling process (176). In response to cell injury and endoplasmic reticulum (ER) stress, autophagy is activated and limits cellular loss (177, 178). Current evidence suggests a neuroprotective role for autophagy after SCI (175, 179). Dysregulation of autophagy contributes to neuronal loss (174, 180). Accumulation of autophagosomes in ventral horn motor neurons have been detected acutely following SCI (181). Neurons with dysregulated autophagy exhibit higher expression of caspase 12 and become more prone to apoptosis (174). Moreover, blocking autophagy has been associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease (182184). Autophagy promotes cell survival through elimination of toxic proteins and damaged mitochondria (185, 186). Interestingly, autophagy is crucial in cytoskeletal remodeling and stabilizes neuronal microtubules by degrading SCG10, a protein involved in microtubule disassembly (179). Pharmacological induction of autophagy in a hemi-section model of SCI in mice has been associated with improved neurite outgrowth and axon regeneration, following SCI (179). Altogether, although further studies are needed, autophagy is currently viewed as a beneficial mechanism in SCI.

Neuroinflammation is a key component of the secondary injury mechanisms with local and systemic consequences. Inflammation was originally thought to be detrimental for the outcome of SCI (187). However, now it is well-recognized that inflammation can be both beneficial and detrimental following SCI, depending on the time point and activation state of immune cells (188). There are multiple cell types involved in the inflammatory response following injury including neutrophils, resident microglia, and astrocytes, dendritic cells (DCs), blood-born macrophages, B- and T-lymphocytes (189) (). The first phase of inflammation (02 days post injury) involves the recruitment of resident microglia and astrocytes and blood-born neutrophils to the injury site (190). The second phase of inflammation begins approximately 3 days post injury and involves the recruitment of blood-born macrophages, B- and T-lymphocytes to the injury site (189, 191193). T lymphocytes become activated in response to antigen presentation by macrophages, microglia and other antigen presenting cells (APCs) (194). CD4+ helper T cells produce cytokines that stimulate B cell antibody production and activate phagocytes (195) (). In SCI, B cells produce autoantibodies against injured spinal cord tissue, which exacerbate neuroinflammation and cause tissue destruction (196). While inflammation is more pronounced in the acute phase of injury, it continues in subacute and chronic phase and may persist for the remainder of a patients' life (193). Interestingly, composition and phenotype of inflammatory cells change based on the injury phase and the signals present in the injury microenvironment. It is established that microglia/macrophages, T cells, B cells are capable of adopting a pro-inflammatory or an anti-inflammatory pro-regenerative phenotype in the injured spinal cord (191, 197199). The role of each immune cell population in the pathophysiology of SCI will be discussed in detail in upcoming sections.

Immune response in spinal cord injury. Under normal circumstances, there is a balance between pro-inflammatory effects of CD4+ effector T cells (Teff) and anti-inflammatory effects of regulatory T and B cells (Treg and Breg). Treg and Breg suppress the activation of antigen specific CD4+ Teff cells through production of IL-10 and TGF-. Injury disrupts this balance and promote a pro-inflammatory environment. Activated microglia/macrophages release pro-inflammatory cytokines and chemokines and present antigens to CD4+ T cells causing activation of antigen specific effector T cells. Teff cells stimulate antigen specific B cells to undergo clonal expansion and produce autoantibodies against spinal cord tissue antigens. These autoantibodies cause neurodegeneration through FcR mediated phagocytosis or complement mediated cytotoxicity. M1 macrophages/microglia release pro-inflammatory cytokines and reactive oxygen species (ROS) that are detrimental to neurons and oligodendrocytes. Breg cells possess the ability to promote Treg development and restrict Teff cell differentiation. Breg cells could also induce apoptosis in Teff cells through Fas mediate mechanisms.

Astrocytes are not considered an immune cell per se; however, they play pivotal roles in the neuroinflammatory processes in CNS injury and disease. Their histo-anatomical localization in the CNS has placed them in a strategic position for participating in physiological and pathophysiological processes in the CNS (200). In normal CNS, astrocytes play major roles in maintaining CNS homeostasis. They contribute to the structure and function of blood-brain-barrier (BBB), provide nutrients and growth factors to neurons (200), and remove excess fluid, ions, and neurotransmitters such as glutamate from synaptic spaces and extracellular microenvironment (200). Astrocytes also play key roles in the pathologic CNS by regulating BBB permeability and reconstruction as well as immune cell activity and trafficking (201). Astrocytes contribute to both innate and adaptive immune responses following SCI by differential activation of their intracellular signaling pathways in response to environmental signals (201).

Astrocytes react acutely to CNS injury by increasing cytokine and chemokine production (202). They mediate chemokine production and recruitment of neutrophils through an IL-1R1-Myd88 pathway (202). Activation of the nuclear factor kappa b (NF-B) pathway, one of the key downstream targets of interleukin (IL)1R-Myd88 axis, increases expression of intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), which are necessary for adhesion and extravasation of leukocytes in inflammatory conditions such as SCI (201, 202). Within minutes of injury, production of IL-1 is significantly elevated in astrocytes and microglia (203). Moreover, chemokines such as monocyte chemoattractant protein (MCP)-1, chemokine C-C motif ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL1), and CXCL2 are produced by astrocytes, and enhance the recruitment of neutrophils and pro-inflammatory macrophages following injury (201, 202). Astrocytes also promote pro-inflammatory M1-like phenotype in microglia/macrophages in the injured spinal cord through their production of TNF-, IL-12, and IFN- (204206). Interestingly, astrocytes also produce anti-inflammatory cytokines, such as TGF- and IL-10, which can promote a pro-regenerative M2-like phenotype in microglia/macrophages (201, 207, 208).

Immunomodulatory role of astrocytes is defined by activity of various signaling pathways through a wide variety of surface receptors (200). For example, gp130, a member of IL-6 cytokine family, activates SHP2/Ras/Erk signaling cascade in astrocytes and limits neuroinflammation in autoimmune rodent models (209). TGF- signaling in astrocytes has been implicated in modulation of neuroinflammation through inhibition of NF-B activity and nuclear translocation (201, 210). STAT3 is another key signaling pathway in astrocytes with beneficial properties in neuroinflammation. Increase in STAT3 phosphorylation enhances astrocytic scar formation and restricts the expansion of inflammatory cells in mouse SCI, which is associated with improved functional recovery (211). Detrimental signaling pathways in astrocytes are known to be activated by cytokines, sphingolipids and neurotrophins (200). As an example, IL-17 is a key pro-inflammatory cytokine produced by effector T cells that can bind to IL-17R on the astrocyte surface (200). Activation of IL-17R results in the activation of NF-B, which enhances expression of pro-inflammatory mediators, activation of oxidative pathways and exacerbation of neuroinflammation (200, 212). This evidence shows the significance of astrocytes in the inflammatory processes following SCI and other neuroinflammatory diseases of the CNS.

Neutrophils infiltrate the spinal cord from the bloodstream within the first few hours after injury (213). Their population increases acutely in the injured spinal cord tissue and reaches a peak within 24 h post-injury (214). The presence of neutrophils is mostly limited to the acute phase of SCI as they are rarely found sub-acutely in the injured spinal cord (214). The role of neutrophils in SCI pathophysiology is controversial. Evidence shows that neutrophils contribute to phagocytosis and clearance of tissue debris (48). They release inflammatory cytokines, proteases and free radicals that degrade ECM, activate astrocytes and microglia and initiate neuroinflammation (48). Although neutrophils have been conventionally associated with tissue damage (48, 215), their elimination compromises the healing process and impedes functional recovery (216).

To elucidate the role of neutrophils in SCI, Stirling and colleagues used a specific antibody to reduce circulating LyG6/Gr1+ neutrophils in a mouse model of thoracic contusive SCI (216). This approach significantly reduced neutrophil infiltration in the injured spinal cord by 90% at 24 and 48 h after SCI (216). Surprisingly, neutrophil depletion aggravated the neurological and structural outcomes in the injured animals suggesting a beneficial role for neutrophils in the acute phase of injury (216). It is shown that simulated neutrophils release IL-1 receptor antagonist that can exert neuroprotective effects following SCI (217). Moreover, ablation of neutrophils results in altered expression of cytokines and chemokines and downregulation of growth factors such as fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs) and bone morphogenetic proteins (BMPs) in the injured spinal cord that seemingly disrupt the normal healing process (216). Altogether, neutrophils play important roles in regulating neuroinflammation at the early stage of SCI that shapes the immune response and repair processes at later stages. While neutrophils were originally viewed as being detrimental in SCI, emerging evidence shows their critical role in the repair process. Further investigations are required to elucidate the role of neutrophils in SCI pathophysiology.

Following neutrophil invasion, microglia/macrophages populate the injured spinal cord within 23 days post-SCI. Macrophage population is derived from invading blood-borne monocytes or originate from the CNS resident macrophages that reside in the perivascular regions within meninges and subarachnoid space (218, 219). The population of microglia/macrophages reaches its peak at 710 days post-injury in mouse SCI, followed by a decline in the subacute and chronic phases (20, 220). While macrophages and microglia share many functions and immunological markers, they have different origins. Microglia are resident immune cells of the CNS that originate from yolk sac during the embryonic period (221). Macrophages are derived from blood monocytes, which originate from myeloid progeny in the bone marrow (222, 223). Upon injury, acute disruption of brain-spinal cord barrier (BSB) enables monocytes, to infiltrate the spinal cord tissue and transform into macrophages (222). Macrophages populate the injury epicenter, while resident microglia are mainly located in the perilesional area (222). Once activated, macrophages, and microglia are morphologically and immunohistologically indistinguishable (224). Macrophages and microglia play a beneficial role in CNS regeneration. They promote the repair process by expression of growth promoting factors such as nerve growth factor (NGF), neurotrophin-3 (NT-3) and thrombospondin (225, 226). Macrophages and microglia are important for wound healing process following SCI due to their ability for phagocytosis and scavenging damaged cells and myelin debris following SCI (222, 227).

Based on microenvironmental signals, macrophages/microglia can be polarized to either pro-inflammatory (M1-like) or anti-inflammatory pro-regenerative (M2-like) phenotype, and accordingly contribute to injury or repair processes following SCI (191, 224, 228230). Whether both microglia and macrophages possess the ability to polarize or it is mainly the property of monocyte derived macrophages is still a matter of debate and needs further elucidation (231233). Some evidence show that Proinflammatory M1-like microglia/macrophages can be induced by exposure to Th1 specific cytokine, interferon (IFN)- (224, 230). Moreover, the SCI microenvironment appears to drive M1 polarization of activated macrophages (231). SCI studies have revealed that increased level of the proinflammatory cytokine, TNF-, and intracellular accumulation of iron drives an M1-like proinflammatory phenotype in macrophages after injury (231). Importantly, following SCI, activated M1-like microglia/macrophages highly express MHCII and present antigens to T cells and contribute to the activation and regulation of innate and adaptive immune response () (224, 228). Studies on acute and subacute SCI and experimental autoimmune encephalomyelitis (EAE) models have shown that M1-like macrophages are associated with higher expression of chondroitin sulfate proteoglycans (CSPGs) and increased EAE severity and tissue damage (234237). In vitro, addition of activated M1-like macrophages to dorsal root ganglion (DRG) neuron cultures leads to axonal retraction and failure of regeneration as the expression of CSPGs is much higher in M1-like compared to M2-like macrophages (237, 238). M1-like macrophages also produce other repulsive factors such as repulsive guidance molecule A (RGMA) that is shown to induce axonal retraction following SCI (239, 240). Interestingly, recent evidence shows that IFN- and TNF polarized M1 microglia show reduced capacity for phagocytosis (241), a process that is critical for tissue repair after SCI.

Pro-regenerative M2-like microglia/macrophages, are polarized by Th2 cytokines, IL-4 and IL-13 and exhibit a high level of IL-10, TGF-, and arginase-1 with reduced NF-B pathway activity (224). IL-10 is a potent immunoregulatory cytokine with positive roles in repair and regeneration following CNS injury (242244). IL-10 knock-out mice show higher production of pro-inflammatory and oxidative stress mediators after SCI (245). Lack of IL-10 is also correlated with upregulated levels of pro-apoptotic factors such as Bax and reduced expression of anti-apoptotic factors such as Bcl-2 (245). SCI mice that lacked IL-10 exhibited poorer recovery of function compared to wild-type mice (245). Our recent studies show that IL-10 polarized M2 microglia show enhanced capacity for phagocytosis (241). We have also found that M2 polarized microglia enhance the ability of neural precursor cells for oligodendrocyte differentiation through IL-10 mediated mechanisms (241). In addition to immune modulation, M2-like microglia/macrophages promote axonal regeneration (224). However, similar to the detrimental effects of prolonged M1 macrophage response, excessive M2-like activity promotes fibrotic scar formation through the release of factors such as TGF-, PDGF, VEGF, IGF-1, and Galectin-3 (224, 246248). Hence, a balance between proinflammatory M1 and pro-regenerative M2 macrophage/microglia response is beneficial for the repair of SCI (249).

T and B lymphocytes play pivotal role in the adaptive immune response after SCI (194). Lymphocytes infiltrate the injured spinal cord acutely during the first week of injury and remain chronically in mouse and rat SCI (47, 193, 194, 196). In contrast to the innate immune response that can be activated directly by foreign antigens, the adaptive immune response requires a complex signaling process in T cells elicited by antigen presenting cells (250). Similar to other immune cells, T and B lymphocytes adopt different phenotypes and contribute to both injury and repair processes in response to microenvironmental signals (194, 251). SCI elicits a CNS-specific autoimmune response in T and B cells, which remains active chronically (196). Autoreactive T cells can exert direct toxic effects on neurons and glial cells (194, 252). Moreover, T cells can indirectly affect neural cell function and survival through pro-inflammatory cytokine and chemokine production (e.g. IL-1, TNF-, IL-12, CCL2, CCL5, and CXCL10) (194, 252). Genetic elimination of T cells (in athymic nude rats) or pharmacological inhibition of T cells (using cyclosporine A and tacrolimus) leads to improved tissue preservation and functional recovery after SCI (194, 253) signifying the impact of T cells in SCI pathophysiology and repair.

Under normal circumstances, systemic autoreactive effector CD4+ helper T cells (Teff) are suppressed by CD4+FoxP3+ regulatory T cells (Treg) () (194, 254). This inhibition is regulated through various mechanisms such as release of anti-inflammatory cytokines IL-10 and TGF- by the Treg cells () (194). Moreover, it is known that Treg mediated inhibition of antigen presentation by dendritic cells (DCs) prevent Teff cell activation (194). Following SCI, this Treg -Teff regulation is disrupted. Increased activity of autoreactive Teff cells contributes to tissue damage through production of pro-inflammatory cytokines and chemokines, promoting M1-like macrophage phenotype and induction of Fas mediated neuronal and oligodendroglial apoptosis () (173). Moreover, autoreactive Teff cells promote activation and differentiation of antigen specific B cells to autoantibody producing plasma cells that contribute to tissue damage after SCI (255). In SCI and MS patients, myelin specific proteins such as myelin basic protein (MBP) significantly increase the population of circulating T cells (256, 257). Moreover, serological assessment of SCI patients has shown high levels of CNS reactive IgM and IgG isotypes confirming SCI-induced autoimmune activity of T and B cells () (196, 258, 259). In animal models of SCI, serum IgM level increases acutely followed by an elevation in the levels of IgG1 and IgG2a at later time-points (196). In addition to autoantibody production, autoreactive B cells contribute to CNS injury through pro-inflammatory cytokines that stimulate and maintain the activation states of Teff cells (194, 260). B cell knockout mice (BCKO) that have no mature B cell but with normal T cells, show a reduction in lesion volume, lower antibody levels in the cerebrospinal fluid and improved recovery of function following SCI compared to wild-type counterparts (255). Of note, antibody mediated injury is regulated through complement activation as well as macrophages/microglia that express immunoglobulin receptors (193, 255).

The effect of SCI on systemic B cell response is controversial. Evidence shows that SCI can suppress B cell activation and antibody production (261). Studies in murine SCI have shown that B cell function seems to be influenced by the level of injury (262). While injury to upper thoracic spinal cord (T3) suppresses the antibody production, a mid-thoracic (T9) injury has no effect on B cell antibody production (262). An increase in the level of corticosterone in serum together with elevation of splenic norepinephrine found to be responsible for the suppression of B cell function acutely following SCI (261). Elevated corticosterone and norepinephrine leads to upregulation of lymphocyte beta-2 adrenergic receptors eliciting lymphocyte apoptosis (194). This suggests a critical role for sympathetic innervation of peripheral lymphoid tissues in regulating B cell response following CNS injury (261). Despite their negative roles, B cells also contribute to spinal cord repair following injury through their immunomodulatory Breg phenotype () (263). Breg cells control antigen-specific T cell autoimmune response through IL-10 production (264).

Detrimental effects of SCI-induced autoimmunity are not limited to the spinal cord. Autoreactive immune cells contribute to the exacerbation of post-SCI sequelae such as cardiovascular, renal and reproductive dysfunctions (194). For example, presence of an autoantibody against platelet prostacyclin receptor has been associated with a higher incidence of coronary artery disease in SCI patients (265). Collectively, evidence shows the critical role of adaptive immune system in SCI pathophysiology and repair. Thus, treatments that harness the pro-regenerative properties of the adaptive immune system can be utilized to reduce immune mediated tissue damage, improve neural tissue preservation and facilitate repair following SCI.

Traumatic SCI triggers the formation of a glial scar tissue around the injury epicenter (266, 267). The glial scar is a multifactorial phenomenon that is contributed f several populations in the injured spinal cord including activated astrocytes, NG2+ oligodendrocyte precursor cells (OPCs), microglia, fibroblasts, and pericytes (268271). The heterogeneous scar forming cells and associated ECM provides a cellular and biochemical zone within and around the lesion () (272). Resident and infiltrating inflammatory cells contribute to the process of glial activation and scar formation by producing cytokines (e.g., IL-1 and IL-6) chemokines and enzymes that activate glial cells or disrupt BSB (267). Activated microglia/macrophages produce proteolytic enzymes such as matrix metalloproteinases (MMPs) that increase vascular permeability and further disruption of the BSB (273). Inhibition of MMPs improves neural preservation and functional recovery in animal models of SCI (273275). In addition to glial and immune cells, fibroblasts, pericytes and ependymal cells also contribute to the structure of the glial scar (267). In penetrating injuries where meninges are compromised, meningeal fibroblasts infiltrate the lesion epicenter (276). Fibroblasts contribute to the production of fibronectin, collagen, and laminin in the ECM of the inured spinal cord (267) and are a source of axon-repulsing molecules such as semaphorins that influence axonal regeneration following SCI (277). Fibroblasts have also been found in contusive injuries where meninges are intact (268, 270). Studies using genetic fate mapping in these injuries have unraveled that perivascular pericytes and fibroblasts migrate to the injury site and form a fibrotic core in the scar which matures within 2 weeks post-injury (268, 270). SCI also triggers proliferation and migration of the stem/progenitor cell pool of the spinal cord parenchyma and ependyma. These cells can give rise to new scar forming astrocytes and OPCs (278280). In a mature glial scar, activated microglia/macrophages occupy the innermost portion closer to the injury epicenter surrounded by NG2+ OPCs () (267), while reactive astrocytes reside in the injury penumbra and form a cellular barrier (267). Of note, in human SCI, the glial scar begins to form within the first hours after the SCI and remains chronically in the spinal cord tissue (281). The glial scar has been found within the injured human spinal cord up to 42 years after the injury (267).

Activated astrocytes play a leading role in the formation of the glial scar (267). Following injury, astrocytes increase their expression of intermediate filaments, GFAP, nestin and vimentin, and become hypertrophied (282, 283). Reactive astrocytes proliferate and mobilize to the site of injury and form a mesh like structure of intermingled filamentous processes around the injury epicenter (284, 285). The astrocytic glial scar has been shown to serve as a protective barrier that prevents the spread of infiltrating immune cells into the adjacent segments (267, 284, 286). Attenuating astrocyte reactivity and scar formation by blockade of STAT3 activation results in poorer outcomes in SCI (211, 286). Reactive astrogliosis is also essential for reconstruction of the BBB, and blocking this process leads to exacerbated leukocyte infiltration, cell death, myelin damage, and reduced functional recovery (211, 285, 286). Despite the protective role of the astrocytic glial scar in acute SCI, its evolution and persistence in the sub-acute and chronic stages of injury has been considered as a potent inhibitor for spinal cord repair and regeneration (267, 287). A number of inhibitory molecules have been associated with activated astrocytes and their secreted products such as proteoglycans and Tenascin-C (288). Thus, manipulation of the astrocytic scar has been pursued as a promising treatment strategy for SCI (267, 289).

Chondroitin sulfate proteoglycans (CSPGs) are well-known for their contribution to the inhibitory role of the glial scar in axonal regeneration (290295), sprouting (296299), conduction (300302), and remyelination (241, 303307). In normal condition, basal levels of CSPGs are expressed in the CNS that play critical roles in neuronal guidance and synapse stabilization (90, 308). Following injury, CSPGs (neurocan, versican, brevican, and phosphacan) are robustly upregulated and reach their peak of expression at 2 weeks post-SCI and remain upregulated chronically (309, 310). Mechanistically, disruption of BSB and hemorrhage following traumatic SCI triggers upregulation of CSPGs in the glial scar by exposing the scar forming cells to factors in plasma such as fibrinogen (311). Studies in cortical injury have shown that fibrinogen induces CSPG expression in astrocytes through TGF/Smad2 signaling pathway (311). The authors show that intracellular Smad2 translocation is essential for Smad2 signal transduction process and its inhibition reduces scar formation (312). In contrast, another study has identified that TGF induces CSPGs production in astrocytes through a SMAD independent pathway (313). This study showed a significant upregulation of CSPGs in SMAD2 and SMAD4 knockdown astrocytes. Interestingly, CSPG upregulation was found to be mediated by the activation of the phosphoinositide 3-kinase (PI3K)/Akt and mTOR axis (313). Further studies are required to confirm these findings.

Extensive research in the past few decades has demonstrated the inhibitory effect of CSPGs on axon regeneration (314, 315). The first successful attempt on improving axon outgrowth and/or sprouting by enzymatic degradation of CSPGs using chondroitinase ABC (ChABC) in a rat SCI model was published in 2002 by Bradbury and colleagues (291). This study showed significant improvement in recovery of locomotor and proprioceptive functions following intrathecal delivery of ChABC in a rat model of dorsal column injury (291). This observation was followed by several other studies demonstrating the promise of CSPGs degradation in improvement of axon regeneration and sprouting of the serotonergic (295, 297, 299, 303), sensory (293, 298, 316), corticospinal (291, 297, 303, 317), and rubrospinal fibers (318) in animal models of CNS injury. Additionally, ChABC treatment is shown to be neuroprotective by preventing CSPG induced axonal dieback and degeneration (303, 319, 320). Studies by our group also showed that degradation of CSPGs using ChABC attenuates axonal dieback in corticospinal fibers in chronic SCI model in the rat (303). ChABC also blocks macrophage-mediated axonal degeneration in neural cultures and after SCI (238).

The inhibitory effects of astrocytic glial scar on axonal regeneration has been recently challenged after SCI (321). Using various transgenic mouse models, a study by Sofroniew's and colleagues has shown that spontaneous axon regrowth failed to happen following the ablation or prevention of astrocytic scar in acute and chronic SCI. They demonstrated that when the intrinsic ability of dorsal root ganglion (DRG) neurons for growth was enhanced by pre-conditioning injury as well as local delivery of a combination of axon growth promoting factors into the SCI lesion, the axons grew to the wall of the glial scar and CSPGs within the lesion. However, when astrocyte scarring was attenuated, the pre-conditioned/growth factor stimulated DRG neurons showed a reduced ability for axon growth (321). From these observations, the authors suggested a positive role for the astrocytic scar in axonal regeneration following SCI (321). Overall, this study points to the importance of reactive and scar forming astrocytes and their pivotal role in the repair process following SCI (322). This is indeed in agreement with previous studies by the same group that showed a beneficial role for activated astrocytes in functional recovery after SCI by limiting the speared of infiltrated inflammatory cells and tissue damage in SCI (285). It is also noteworthy that the glial scar is contributed by various cell populations and not exclusively by astrocytes (269, 271). Therefore, the outcomes of this study need to be interpreted in the context of astrocytes and astrocytic scar. Moreover, the reduced capacity of the injured spinal cord for regeneration is not solely driven by the glial scar as other factors including inflammation and damaged myelin play important inhibitory role in axon regeneration (323, 324). Taken together, further investigation is needed to delineate the mechanisms of the glial scar including the contribution of astrocyte-derived factors on axon regeneration in SCI.

While CSPGs were originally identified as an inhibitor of axon growth and plasticity within the glial scar, emerging evidence has also identified them as an important regulator of endogenous cell response. Emerging evidence has identified CSPGs as an inhibitor of oligodendrocytes (241, 272, 306). Replacement of oligodendrocytes is an important repair process in SCI and other demyelinating conditions such as MS (90). SCI and MS triggers activation of endogenous OPCs and their mobilization to the site of injury (143, 162, 306, 325). In vitro and in vivo evidence shows that CSPGs limit the recruitment of NPCs and OPCs to the lesion and inhibit oligodendrocyte survival, differentiation and maturation (145, 272, 305, 306, 326). Our group and others have shown that targeting CSPGs by ChABC administration or xyloside, or through inhibition of their signaling receptors enhances the capacity of NPCs and OPCs for proliferation, oligodendrocyte differentiation and remyelination following SCI and MS-like lesions (145, 303, 304, 306).

Mechanistically, the inhibitory effects of CSPGs on axon growth and endogenous cell differentiation is mainly governed by signaling through receptor protein tyrosine phosphatase sigma (RPTP) and leukocyte common antigen-related phosphatase receptor (LAR) (327). RPTP is the main receptor mediating the inhibition of axon growth by CSPGs (327, 328). Improved neuronal regeneration has been demonstrated in RPTP/ mice model of SCI and peripheral nerve injury (328, 329). Blockade of RPTP and LAR by intracellular sigma peptide (ISP) and intracellular LAR peptide (ILP), facilitates axon regeneration following SCI (327, 330). Inhibition of RPTP results in significant improvement in locomotion and bladder function associated with serotonergic re-innervation below the level of injury in rat SCI (327). Our group has also shown that CSPGs induce caspase-3 mediated apoptosis in NPCs and OPCs in vitro and in oligodendrocytes in the injured spinal cord that is mediated by both RPTP and LAR (241). Inhibition of LAR and RPTP sufficiently attenuates CSPG-mediated inhibition of oligodendrocyte maturation and myelination in vitro and attenuated oligodendrocyte cell death after SCI (241).

CSPGs have been implicated in regulating immune response in CNS injury and disease. Interestingly, our recent studies indicated that CSPGs signaling appears to restrict endogenous repair by promoting a pro-inflammatory immune response in SCI (241, 331). Inhibition of LAR and RPTP enhanced an anti-inflammatory environment after SCI by promoting the populations of pro-regenerative M2-like microglia/macrophages and regulatory T cells (241) that are known to promote repair process (224). These findings are also in agreement with recent studies in animal models of MS that unraveled a pro-inflammatory role for CSPGs in autoimmune demyelinating conditions (332). In MS and EAE, studies by Stephenson and colleagues have shown that CSPGs are abundant within the leucocyte-containing perivascular cuff, the entry point of inflammatory cells to the CNS tissue (332). Presence of CSPGs in these perivascular cuffs promotes trafficking of immune cells to induce a pro-inflammatory response in MS condition. In contrast to these new findings, early studies in SCI described that preventing CSPG formation with xyloside treatment at the time of injury results in poor functional outcome, while manipulation of CSPGs at 2 days after SCI was beneficial for functional recovery (333). These differential outcomes were associated with the modulatory role of CSPGs in regulating the response of macrophages/microglia. Disruption in CSPG formation immediately after injury promoted an M1 pro-inflammatory phenotype in macrophages/microglia, whereas delayed manipulation of CSPGs resulted in a pro-regenerative M2 phenotype (333). In EAE, by products of CSPG degradation also improve the outcomes by attenuating T cell infiltration and their expression of pro-inflammatory cytokines IFN- and TNF (334).

These emerging findings suggest an important immunomodulatory role for CSPGs in CNS injury and disease; further investigations are needed to elucidate CSPG mechanisms in regulating neuroinflammation. Altogether, current evidence has identified a multifaceted inhibitory role for CSPGs in regulating endogenous repair mechanisms after SCI, suggesting that targeting CSPGs may present a promising treatment strategy for SCI.

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Traumatic Spinal Cord Injury: An Overview of ...

Spinal Cord Stem Cells Comments Off on Traumatic Spinal Cord Injury: An Overview of … | October 16th, 2021

Abstract

Stem cells or mother or queen of all cells are pleuropotent and have the remarkable potential to develop into many different cell types in the body. Serving as a sort of repair system for the body, they can theoretically divide without limit to replenish other cells as long as the person or animal is alive. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. Stem cells differ from other kinds of cells in the body. All stem cells regardless of their source have three general properties:

They are unspecialized; one of the fundamental properties of a stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions.

They can give rise to specialized cell types. These unspecialized stem cells can give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.

They are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood cells, or nerve cells which do not normally replicate themselves - stem cells may replicate many times. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. Today, donated organs and tissues are often used to replace those that are diseased or destroyed. Unfortunately, the number of people needing a transplant far exceeds the number of organs available for transplantation. Pleuropotent stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions, and disabilities including Parkinsons and Alzheimers diseases, spinal cord injury, stroke, Cerebral palsy, Battens disease, Amyotrophic lateral sclerosis, restoration of vision and other neuro degenerative diseases as well.

Stem cells may be the persons own cells (a procedure called autologous transplantation) or those of a donor (a procedure called allogenic transplantation). When the persons own stem cells are used, they are collected before chemotherapy or radiation therapy because these treatments can damage stem cells. They are injected back into the body after the treatment.

The sources of stem cells are varied such as pre-implantation embryos, children, adults, aborted fetuses, embryos, umbilical cord, menstrual blood, amniotic fluid and placenta

New research shows that transplanted stem cells migrate to the damaged areas and assume the function of neurons, holding out the promise of therapies for Alzheimers disease, Parkinsons, spinal cord injury, stroke, Cerebral palsy, Battens disease and other neurodegenerative diseases.

The therapeutic use of stem cells, already promising radical new treatments for cancer, immune-related diseases, and other medical conditions, may someday be extended to repairing and replenishing the brain. In a study published in the February 19, 2002, Proceedings of the National Academy of Sciences, researchers exposed the spinal cord of a rat to injury, paralyzing the animals hind limbs and lower body. Stem cells grown in exponential numbers in the laboratory were then injected into the site of the injury. It was seen that week after the injury, motor function improved dramatically,

The following diseases have been treated by various stem cell practitioners with generally positive results and the spectrum has ever since been increasing.

Cerebral palsy is a disorder caused by damage to the brain during pregnancy, delivery or shortly after birth. It is often accompanied by seizures, hearing loss, difficulty speaking, blindness, lack of co-ordination and/or mental retardation. Studies in animals with experimentally induced strokes or traumatic injuries have indicated that benefit is possible by stem cell therapy. The potential to do these transplants via injection into the vasculature rather than directly into the brain increases the likelihood of timely human studies. As a result, variables appropriate to human experiments with intravascular injection of cells, such as cell type, timing of the transplant and effect on function, need to be systematically performed in animal models Studies in animals with experimentally induced strokes or traumatic injuries have indicated that benefit is possible with injury, with the hope of rapidly translating these experiments to human trials.(1)

Cerebral palsy produces chronic motor disability in children. The causes are quite varied and range from abnormalities of brain development to birth-related injuries to postnatal brain injuries. Due to the increased survival of very premature infants, the incidence of cerebral palsy may be increasing. While premature infants and term infants who have suffered neonatal hypoxic-ischemic (HI) injury represent only a minority of the total cerebral palsy population, this group demonstrates easily identifiable clinical findings, and much of their injury is to oligodendrocytes and the white matter (2)

Alzheimers is a complex, fatal disease involving progressive cell degeneration, beginning with the loss of brain cells that control thought, memory and language. The disease, which currently has no cure, was first described by German physician Dr. Alzheimer, who discovered amyloid plaques and neurofibrillary tangles in the brain of a woman who died of an unusual mental illness. A compound similar to the components of DNA may improve the chances that stem cells transplanted from a patients bone marrow to the brain will take over the functions of damaged cells and help treat Alzheimers disease and other neurological illnesses. A research team led by University of Central Florida professor Kiminobu Sugaya found that treating bone marrow cells in laboratory cultures with bromodeoxyuridine, a compound that becomes part of DNA, made adult human stem cells more likely to develop as brain cells after they were implanted in adult rat brains.

It has long been recognized that Alzheimers disease (AD) patients present an irreversible decline of cognitive functions as consequence of cell deterioration in a structure called nucleus basalis of Meynert The reduction of the number of cholinergic cells causes interference in several aspects of behavioral performance including arousal, attention, learning and emotion. It is also common knowledge that AD is an untreatable degenerative disease with very few temporary and palliative drug therapies. Neural stem cell (NSC) grafts present a potential and innovative strategy for the treatment of many disorders of the central nervous system including AD, with the possibility of providing a more permanent remedy than present drug treatments. After grafting, these cells have the capacity to migrate to lesioned regions of the brain and differentiate into the necessary type of cells that are lacking in the diseased brain, supplying it with the cell population needed to promote recovery. (3)

Malignant multiple sclerosis (MS) is a rare but clinically important subtype of MS characterized by the rapid development of significant disability in the early stages of the disease process. These patients are refractory to conventional immunomodulatory agents and the mainstay of their treatment is plasmapheresis or immunosuppression with mitoxantrone, cyclophosphamide, cladribine or, lately, bone marrow transplantation. A report on the case of a 17-year old patient with malignant MS who was treated with high-dose chemotherapy plus anti-thymocyte globulin followed by autologous stem cell transplantation. This intervention resulted in an impressive and long-lasting clinical and radiological response (4).

In other experiment treatment of 24 patients (14 women, 10 men) with relapsing-remitting Multiple Sclerosis, in the course of 28 years was done For treatment, used were embryonic stem cell suspensions (ESCS) containing stem cells of mesenchymal and ectodermal origin obtained from active growth zones of 48 weeks old embryonic cadavers organs. Suspensions were administered in the amount of 13 ml, cell count being 0,1-100x105/ml. In the course of treatment, applied were 24 different suspensions, mode of administration being intracavitary, intravenous, and subcutaneous. After treatment, syndrome of early post-transplant improvement was observed in 70% of patients, its main manifestations being decreased weakness, improved appetite and mood, decreased depression. In the course of first post-treatment months, positive dynamics was observed in the following aspects: Nystagmus, convergence disturbances, spasticity, and coordination. In such symptoms as dysarthria, dysphagia, and ataxia, positive changes occurred at much slower rate. In general, the treatment resulted in improved range and quality of motions in the extremities, normalized muscle tone, decreased fatigue and general weakness, and improved quality of life. Forth, 87% of patients reported no exacerbations, no aggravation of neurological symptoms, and no further progression of disability. MRI performed in 12 years after the initial treatment, showed considerable subsidence of focal lesions, mean by 31%, subsidence of gadolinium enhanced lesions by 48%; T2-weighted images showed marked decrease of the focis relative density.

Doctors firstly isolated adult stem cells from the patients brain, they were then cultured in vitro and encouraged to turn into dopamine-producing neurons. As soon as tests showed that the cells were producing dopamine they were then re-injected into the mans brain. After the transplant, the mans condition was seen to improve and he experienced a reduction in the trembling and muscle rigidity associated with the disease. Brain scans taken 3-months after the transplant revealed that dopamine production had increased by 58%, however it later dropped but the Parkinsons symptoms did not return. The study is the first human study to show that stem cell transplants can help to treat Parkinsons.

The use of fetal-derived neural stem cells has shown significant promise in rodent models of Parkinsons disease, and the potential for tumorigenicity appears to be minimal. The authors report that undifferentiated human neural stem cells (hNSCs) transplanted into severely Parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates could survive, migrate, and induce behavioral recovery of Parkinsonian symptoms, which were directly related to reduced dopamine levels in the nigrostriatal system(5). Working with these cells, the researchers created dopamine neurons deficient in DJ-1, a gene mutated in an inherited form of Parkinsons. They report that DJ-1-deficient cells -- and especially DJ-1-deficient dopamine neurons -- display heightened sensitivity to oxidative stress, caused by products of oxygen metabolism that react with and damage cellular components like proteins and DNA. In a second paper, they link DJ-1 dysfunction to the aggregation of alpha-synuclein, a hallmark of Parkinsons neuropathology. (6,7)

In summary most of studies using aborted human embryonic tissue indicate that:

Clinical benefit does occur; however, the benefit is not marked and there is a delay of many months before the clinical change.

Postmortem examinations show that tissue grafts do survive and innervate the striatum.

PET scans show that there is an increase in dopamine uptake after transplantation.

Followup studies show that long term benefit does occur with transplantation.(8)

During and after a stroke, certain cellular events take place that lead to the death of brain cells. Compounds that inhibit a group of enzymes called histone deacetylases can modulate gene expression, and in some cases produce cellular proteins that are actually neuroprotective -- they are able to block cell death. Great deal of research has gone into developing histone deacetylase inhibitors as novel therapeutics (9)

One Mesenchymal stem cell (MSC) transplantation improves recovery from ischemic stroke in animals. The Researchers examined the feasibility, efficacy, and safety of cell therapy using culture-expanded autologous MSCs in patients with ischemic stroke. They prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory Serial evaluations showed no adverse cell-related, serological, or imaging-defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery.(10)

Early intravenous stem cell injection displayed anti-inflammatory functionality that promoted neuroprotection, mainly by interrupting splenic inflammatory responses after intra cranial Haemorrage.

In summary, early intravenous NSC injection displayed anti-inflammatory functionality that neural stem cell (NSC) transplantation has been investigated as a means to reconstitute the damaged brain after stroke. In this study, however, was investigated the effect on acute cerebral and peripheral inflammation after intracerebral haemorrhage (ICH). STEM CELLS from fetal human brain were injected intravenously (NSCs-iv, 5 million cells) or intracerebrally (NSCs-ic, 1 million cells) at 2 or 24 h after collagenase-induced ICH in a rat model. Only NSCs-iv-2 h resulted in fewer initial neurologic deteriorations and reduced brain edema formation, inflammatory infiltrations and apoptosis. (11)

Emerging cell therapies for the restoration of sight have focused on two areas of the eye that are critical for visual function, the cornea and the retina. The relatively easy access of the cornea, the homogeneity of the cells forming the different layers of the corneal epithelium and the improvement of cell culture protocols are leading to considerable success in corneal epithelium restoration. Rebuilding the entire cornea is however still far from reality. The restoration of the retina has recently been achieved in different animal models of retinal degeneration using immature photoreceptors (12)

Bone marrow contains stem cells, which have the extraordinary abilities to home in on injuries and possibly regenerate other cell types in the body. In this case, the cells were transplanted to confirm that bone marrow does regenerate the injured RPE. Damage to RPE is present in many diseases of the retina, including age-related macular degeneration, which affects more than 1.75 million people in the United States. (13)

Neural stem cells (NSCs) offer the potential to replace lost tissue after nervous system injury. Thus, stem cells can promote host neural repair in part by secreting growth factors, and their regeneration-promoting activities can be modified by gene delivery.

Attempted repair of human spinal cord injury by transplantation of stem cells depends on complex biological interactions between the host and graft

Extrapolating results from experimental therapy in animals to humans with spinal cord injury requires great caution.

There is great pressure on surgeons to transplant stem cells into humans with spinal cord injury. However, as the efficacy of and exact indications for this therapy are still uncertain, and morbidity (such as rejection or late tumour development) may result, only carefully designed studies based on sound experimental work which attempts to eliminate placebo effects should proceed.

Premature application of stem cell transplantation in humans with spinal cord injury should be discouraged. 14, 15, 16)

Attempted repair of human spinal cord injury by transplantation of stem cells depends on complex biological interactions between the host and graft

Extrapolating results from experimental therapy in animals to humans with spinal cord injury requires great caution.

There is great pressure on surgeons to transplant stem cells into humans with spinal cord injury. However, as the efficacy of and exact indications for this therapy are still uncertain, and morbidity (such as rejection or late tumour development) may result, only carefully designed studies based on sound experimental work which attempts to eliminate placebo effects should proceed.

Premature application of stem cell transplantation in humans with spinal cord injury should be discouraged.

Mesenchymal stem cells have also been identified and are currently being developed for bone, cartilage, muscle, tendon, and ligament repair and regeneration. These MSCs are typically harvested, isolated, and expanded from bone marrow or adipose tissue, and they have been isolated from rodents, dogs, and humans. Interestingly, these cells can undergo extensive sub cultivation in vitro without differentiation, magnifying their potential clinical use.(17) Human MSCs can be directed toward osteoblastic differentiation by adding dexamethasone, ascorbic acid, and -glycerophosphate to the tissue culture media. This osteoblastic commitment and differentiation can be clearly documented by analyzing alkaline phosphatase activity, the expression of bone matrix proteins, and the mineralization of the extracellular matrix.(18)

Children with Battens disease suffer seizures, motor control disturbances, blindness and communication problems. As many as 600 children in the US are currently diagnosed with the condition.(19)

Death can occur in children as young as 8 years old. The children lack an enzyme for breaking down complex fat and protein compounds in the brain, explains Robert Steiner, vice chair of paediatric research at the hospital. The material accumulates and interferes with tissue function, ultimately causing brain cells to die. Tests on animals demonstrated that stem cells injected into the brain secreted the missing enzyme. And the stem cells were found to survive well in the rodent brain. Once injected, the purified neural cells may develop into neurons or other nervous system tissue, including oligodendrocytes, or glial cells, which support the neurons(20).

In a study that demonstrates the promise of cell-based therapies for diseases that have proved intractable to modern medicine, a team of scientists from the University of Wisconsin-Madison has shown it is possible to rescue the dying neurons characteristic of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disorder also known as Lou Gehrigs disease. Previously there was no effective treatments for ALS, which afflicts roughly 40,000 people in the United States and which is almost always fatal within three to five years of diagnosis. Patients gradually experience progressive muscle weakness and paralysis as the motor neurons that control muscles are destroyed by the disease

In the new Wisconsin study, nascent brain cells known as neural progenitor cells derived from human fetal tissue were engineered to secrete a chemical known as glial cell line derived neurotrophic factor (GDNF), an agent that has been shown to protect neurons but that is very difficult to deliver to specific regions of the brain. The engineered cells were then implanted in the spinal cords of rats afflicted with a form of ALS. The implanted cells, in fact, demonstrated an affinity for the areas of the spinal cord where motor neurons were dying. The cells after being injected to the area of damage where they just sit and release GDNF. At the early stages of disease, almost 100 percent protection of motor neurons was seen. (21)

In other study MSCs were isolated from bone marrow of 9 patients with definite ALS. Growth kinetics, immunophenotype, telomere length and karyotype were evaluated during in vitro expansion. No significant differences between donors or patients were observed. The patients received intraspinal injections of autologous MSCs at the thoracic level and monitored for 4 years. No significant acute or late side effects were evidenced. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. The results seem to demonstrate that MSCs represent a good chance for stem cell cell-based therapy in ALS and that intraspinal injection of MSCs is safe also in the long term. A new phase 1 study is carried out to verify these data in a larger number of patients. (22)

Stem-cell-based technology offers amazing possibilities for the future. These include the ability to reproduce human tissues and potentially repair damaged organs (such as the brain, spinal cord, vertebral column the eye), where, at present, we mainly provide supportive care to prevent the situation from becoming worse. This potential almost silences the sternest critics of such technology, but the fact remains that the ethical challenges are daunting. It is encouraging that, in tackling these challenges, we stand to reflect a great deal about the ethics of our profession and our relationships with patients, industry, and each other. The experimental basis of stem-cell or OEC transplantation should be sound before these techniques are applied to humans with neurological disorders.

1. Stem cell therapy for cerebral palsy. Bartley J, Carroll JE. Department of Pediatrics of the Medical College of Georgia, Augusta, Georgia, USA

8. Department of Neurology, Mt. Sinai School of Medicine, New York, NY, Medscape journal. Stem Cell Transplantation for Parkinsons Disease

9. Journal of Medicinal Chemistry. Future Therapies For Stroke May Block Cell Death 16 Jun 2007

10. Neurosurg Focus. 2005;19(6) 2005 American Association of Neurological Surgeons

11. Brain Advance Access originally published online on December 20, 2007 Brain 2008 Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke.

13. University of Florida(2006, June 8). Bone Marrow May Restore Cells Lost In Vision Diseases. ScienceDaily.

18. Autologous mesenchymal stem cell transplantation in stroke patients Oh Young Bang, MD, PhD 1, Jin Soo Lee, MD Department of Neurology, School of Medicine, Ajou University, Suwon, South Korea Brain Disease Research Center, School of Medicine, Ajou University, Suwon, South Korea.

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Role of Stem Cells in Treatment of Neurological Disorder

Spinal Cord Stem Cells Comments Off on Role of Stem Cells in Treatment of Neurological Disorder | October 16th, 2021

Stem cell research holds great promise for biomedical sciencefrom helping us better understand how diseases develop and spread, to serving as accurate screens for new drugs, to developing cell-based therapies for diabetes, heart failure, Parkinsons disease, and many other conditions that affect millions of Americans. There are 2 basic types of human stem cells: embryonic stem (ES) cells and non-embryonic, or adult stem cells. Just a few years ago, scientists discovered how to make a third type, by reprogramming ordinary skin cells that have already grown up into those that look and act like cells from an embryo. These cells have been named induced pluripotent stem cells, or iPS cells.

NIH research is progressing on multiple fronts to learn more about the differences between the 3 stem cell types and to create patient-specific cells for in-depth study of many diseases. The ability to create iPS cells is a significant breakthrough, since the reprogramming technique is relatively simple to perform with standard laboratory methods, and because skin cells are easy to gather and grow. The most exciting aspect of this research is its potential to speed progress toward achieving personalized therapies. With refinements, this method could yield an unlimited supply of customized cells.

Regenerative medicine is moving toward a day when we can repair and replace damaged tissues. In time, we will be able to make insulin-secreting pancreatic cells, bone cells to heal breaks and defects, and eye and ear cells to restore vision and hearing. NIH researchers are hard at work using stem cells as a powerful tool to study neurological disorders like Parkinsons, Huntingtons disease, amyotrophic lateral sclerosis (ALS), and spinal cord injury, to name a few.

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Stem Cells | National Institutes of Health (NIH)

Spinal Cord Stem Cells Comments Off on Stem Cells | National Institutes of Health (NIH) | October 16th, 2021

Tests to determine how blood pressure changes during certain maneuvers

During the physical examination, doctors can check for signs of autonomic disorders, such as orthostatic hypotension. For example, they measure blood pressure and heart rate while a person is lying down or sitting and after the person stands to check how blood pressure changes when position is changed. When a person stands up, gravity makes it harder for blood from the legs to get back to the heart. Thus, blood pressure decreases. To compensate, the heart pumps harder, and the heart rate increases. However, the changes in heart rate and blood pressure are slight and brief. If the changes are larger or last longer, the person may have orthostatic hypotension.

The tilt table test and the Valsalva maneuver, done together, can help doctors determine whether a decrease in blood pressure is due to an autonomic nervous system disorder.

Doctors examine the pupils for abnormal responses or lack of response to changes in light.

Sweat testing is also done. For one sweat test, the sweat glands are stimulated by electrodes that are filled with acetylcholine and placed on the legs and forearm. Then, the volume of sweat is measured to determine whether sweat production is normal. A slight burning sensation may be felt during the test.

In the thermoregulatory sweat test, a dye is applied to the skin, and a person is placed in a closed, heated compartment to stimulate sweating. Sweat causes the dye to change color. Doctors can then evaluate the pattern of sweat loss, which may help them determine the cause of the autonomic nervous system disorder.

Other tests may be done to check for disorders that can cause the autonomic disorder.

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Overview of the Autonomic Nervous System - Brain, Spinal ...

Spinal Cord Stem Cells Comments Off on Overview of the Autonomic Nervous System – Brain, Spinal … | October 16th, 2021

DUARTE, Calif.--(BUSINESS WIRE)--As a 16-year-old high school sophomore, Julian Castaeda was focused on running track specifically, trying to run a mile in under five minutes. He was also planning to attend two camps that summer that would help him prepare for the rigors of college.

Despite being diagnosed with precursor B cell acute lymphoblastic leukemia at age 10 and receiving chemotherapy on and off for three and a half years, Castaeda had been in remission for two years. He had moved on from that difficult experience.

But in March 2017, Castaeda and his mother, Erica Palacios, again received devastating news the leukemia had returned. Castaeda received chemotherapy for a few months, but the cancer kept proliferating. Castaeda would need a hematopoietic stem cell transplant (more commonly referred to as a bone marrow transplant, or BMT) this time to put his cancer back into remission.

It was heartbreaking. I knew at that point that all my plans for sophomore year would be gone, Castaeda recalled.

But Castaeda was determined to get his life back. This was possible thanks to Johannes Eppler, 27, of Breisach, Germany, who joined the bone marrow registry via DKMS, an international nonprofit that is dedicated to the fight against blood cancers and blood disorders, including the recruitment of bone marrow donors. Castaeda received a bone marrow transplant on Aug. 2, 2017, putting the cancer into remission.

He has a big heart, Palacios said about Eppler. Hes an angel. He saved my son. I am thankful that people are willing to [donate].

Castaeda, who grew up in Bakersfield, California, and was treated by City of Hopes Joseph Rosenthal, M.D., M.H.C.M., the Barron Hilton Chair in Pediatrics, is now 20 years old and a junior at California State University Northridge. He also founded Bags of Love Foundation, a nonprofit that has delivered more than 200 care packages to young cancer patients in treatment and has provided $11,000 in scholarships to survivors.

On Friday, Oct. 15, Castaeda will meet his donor for the first time virtually during City of Hopes BMT Reunion. City of Hope, a pioneer and leader in BMT, has hosted a Celebration of Life for bone marrow, stem cell and cord blood transplant recipients, their families and donors for more than 40 years. The celebration honors children and adult cancer survivors, including those who have received autologous transplants, which use a patients own stem cells, and those who received an allogeneic procedure, which require a bone marrow or stem cell donation from a related or unrelated donor.

What began with a birthday cake and a single candle representing a patients first year free from cancer has grown into an annual extravaganza that draws thousands of cancer survivors, donors and families from around the world, as well as the doctors, nurses and staff who help them through the lifesaving therapy.

Each year, patient-donor meetings are the events emotional highlight. Many recipients, though overwhelmed with curiosity and the need to express their gratitude, can only dream of meeting the stranger who saved their lives. City of Hope is making that dream come true for Castaeda, as well as Dona Garrish, a Fullerton, California resident and retired school teacher. Her donor was Michael Fischer, 35, of Wlkau, Germany.

Garrish, 75, received her transplant on March 22, 2017, after it was delayed several times due to infections and other complications that prevented her from going through with the treatment. Garrish, who was diagnosed with acute myeloid leukemia, felt a strong connection to Fischer from the first time a City of Hope employee told her a German male, whom she had never met, was a perfect match for her. She refers to him as her gift from God and her angel on Earth.

He unknowingly encouraged me to fight harder and not to become discouraged, as someday I wanted to meet him and thank him, she added. Garrish recalled watching two patients meeting their donors at the 2017 BMT Reunion. The reunions were held in front of City of Hope Helford Clinical Research Hospital, where Garrish was recovering from her transplant.

While tethered to her IV pole, Garrish looked down from the hospitals sixth floor and said, Thats what I want to do.

City of Hope nurses, doctors and staff were constantly there supporting me every step of the way, even when I couldnt take a single step, said Garrish, who was treated by City of Hopes Liana Nikolaenko, M.D. The timing was urgent, my battle was rough and long, but I live, breathe and enjoy life today because of City of Hope.

Other event highlights include videos of grateful patients wearing the signature BMT buttons that display the number of years since their transplants, comedy by City of Hope BMT patient Sean Kent and a dance/song performed by BMT nurses, known as the Marrowettes. There will be special guest appearances by a Los Angeles Dodger and Katharina Harf, executive chairwoman of DKMS U.S., to congratulate patients, their donors and the BMT program.

During our annual BMT reunion, we express our most heartfelt thanks to the many selfless individuals who each year donate their bone marrow or stem cells to save a persons life, said Stephen J. Forman, M.D., director of City of Hopes Hematologic Malignancies Research Institute and former chair of its Department of Hematology & Hematopoietic Cell Transplantation. Whether the donor is a patients family member or a person she or he has never met, we are all extremely grateful that these donors took the time to donate and gave someone a second chance at life.

About City of Hopes BMT program

City of Hopes BMT program has performed more than 17,000 transplants, making it one of the largest and most successful programs in the nation. The institution has the largest BMT program in California, performing over 700 transplants annually, and is among the top three hospitals in the nation in terms of total transplants performed.

Over the years, City of Hope has also helped pioneer several BMT innovations. In addition to being one of the first institutions to perform BMTs in older adults, it was one of the first programs to show that BMTs could be safely performed for patients with HIV. City of Hope has had growing success with nonrelated matched donors and, most recently, half matched family donors.

City of Hopes BMT program is the only one in the nation that has had one-year survival above the expected rate for 15 consecutive years, based on analysis by the Center for International Blood and Marrow Transplant Research.

City of Hope was also one of the first programs to develop a treatment for prevention of cytomegalovirus (CMV), a common and potentially deadly infection after transplant, which has nearly eliminated the threat of CMV for BMT patients. The institution successfully conducted clinical trials of a CMV vaccine developed at City of Hope. As a pioneer in the development of CAR T cells to treat cancer, City of Hope is also testing how this form of cancer immunotherapy can help patients have a more successful transplant.

In addition, Be The Match at City of Hope last year added more than 13,000 new volunteers willing to save a life when they match a patient who needs a bone marrow transplant. In total, nearly 300,000 potential donors have signed up via City of Hope, motivated by a patient at the cancer center. Be The Match encourages healthy individuals between the ages of 18 and 40 to take the first step of registering by texting COHSAVES to 61474. To learn more about the donation process, visit Be The Match at City of Hopes website.

The public can register to view the event here.

About City of Hope

City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hopes translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin, monoclonal antibodies and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is ranked among the nations Best Hospitals in cancer by U.S. News & World Report. Its main campus is located near Los Angeles, with additional locations throughout Southern California and in Arizona. Translational Genomics Research Institute (TGen) became a part of City of Hope in 2016. AccessHope, a subsidiary launched in 2019, serves employers and their health care partners by providing access to NCI-designated cancer center expertise. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.

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College Student and Retired Teacher to Thank Stem Cell Donors They've Never Met for Saving Their Lives During City of Hope's 45th Bone Marrow...

Bone Marrow Stem Cells Comments Off on College Student and Retired Teacher to Thank Stem Cell Donors They’ve Never Met for Saving Their Lives During City of Hope’s 45th Bone Marrow… | October 16th, 2021

Stem Cell Therapy Market Research Report by Cell Source (Adipose tissue-derived MSCs (mesenchymal stem cells),, Bone marrow-derived MSCs,, and Placental/umbilical cord-derived MSCs), by Type (Allogeneic Stem Cell Therapy and Autologous Stem Cell Therapy), by Therapeutic Application, by End-User, by Region (Americas, Asia-Pacific, and Europe, Middle East & Africa) - Global Forecast to 2026 - Cumulative Impact of COVID-19

New York, Oct. 13, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Stem Cell Therapy Market Research Report by Cell Source, by Type, by Therapeutic Application, by End-User, by Region - Global Forecast to 2026 - Cumulative Impact of COVID-19" - https://www.reportlinker.com/p06175517/?utm_source=GNW

The Global Stem Cell Therapy Market size was estimated at USD 202.87 million in 2020 and expected to reach USD 240.88 million in 2021, at a CAGR 19.07% to reach USD 578.27 million by 2026.

Market Statistics:The report provides market sizing and forecast across five major currencies - USD, EUR GBP, JPY, and AUD. It helps organization leaders make better decisions when currency exchange data is readily available. In this report, the years 2018 and 2019 are considered historical years, 2020 as the base year, 2021 as the estimated year, and years from 2022 to 2026 are considered the forecast period.

Market Segmentation & Coverage:This research report categorizes the Stem Cell Therapy to forecast the revenues and analyze the trends in each of the following sub-markets:

Based on Cell Source, the market was studied across Adipose tissue-derived MSCs (mesenchymal stem cells),, Bone marrow-derived MSCs,, and Placental/umbilical cord-derived MSCs.

Based on Type, the market was studied across Allogeneic Stem Cell Therapy and Autologous Stem Cell Therapy.

Based on Therapeutic Application, the market was studied across Cardiovascular Diseases Surgeries, Inflammatory & Autoimmune Diseases, Musculoskeletal Disorders, Neurological Disorders, Other Therapeutic Applications, and Wounds & Injuries.

Based on End-User, the market was studied across Academic and Research Centers, Ambulatory Surgical Centers (ASCs), and Hospitals & Clinics.

Based on Region, the market was studied across Americas, Asia-Pacific, and Europe, Middle East & Africa. The Americas is further studied across Argentina, Brazil, Canada, Mexico, and United States. The United States is further studied across California, Florida, Illinois, New York, Ohio, Pennsylvania, and Texas. The Asia-Pacific is further studied across Australia, China, India, Indonesia, Japan, Malaysia, Philippines, Singapore, South Korea, Taiwan, and Thailand. The Europe, Middle East & Africa is further studied across France, Germany, Italy, Netherlands, Qatar, Russia, Saudi Arabia, South Africa, Spain, United Arab Emirates, and United Kingdom.

Cumulative Impact of COVID-19:COVID-19 is an incomparable global public health emergency that has affected almost every industry, and the long-term effects are projected to impact the industry growth during the forecast period. Our ongoing research amplifies our research framework to ensure the inclusion of underlying COVID-19 issues and potential paths forward. The report delivers insights on COVID-19 considering the changes in consumer behavior and demand, purchasing patterns, re-routing of the supply chain, dynamics of current market forces, and the significant interventions of governments. The updated study provides insights, analysis, estimations, and forecasts, considering the COVID-19 impact on the market.

Competitive Strategic Window:The Competitive Strategic Window analyses the competitive landscape in terms of markets, applications, and geographies to help the vendor define an alignment or fit between their capabilities and opportunities for future growth prospects. It describes the optimal or favorable fit for the vendors to adopt successive merger and acquisition strategies, geography expansion, research & development, and new product introduction strategies to execute further business expansion and growth during a forecast period.

FPNV Positioning Matrix:The FPNV Positioning Matrix evaluates and categorizes the vendors in the Stem Cell Therapy Market based on Business Strategy (Business Growth, Industry Coverage, Financial Viability, and Channel Support) and Product Satisfaction (Value for Money, Ease of Use, Product Features, and Customer Support) that aids businesses in better decision making and understanding the competitive landscape.

Market Share Analysis:The Market Share Analysis offers the analysis of vendors considering their contribution to the overall market. It provides the idea of its revenue generation into the overall market compared to other vendors in the space. It provides insights into how vendors are performing in terms of revenue generation and customer base compared to others. Knowing market share offers an idea of the size and competitiveness of the vendors for the base year. It reveals the market characteristics in terms of accumulation, fragmentation, dominance, and amalgamation traits.

Competitive Scenario:The Competitive Scenario provides an outlook analysis of the various business growth strategies adopted by the vendors. The news covered in this section deliver valuable thoughts at the different stage while keeping up-to-date with the business and engage stakeholders in the economic debate. The competitive scenario represents press releases or news of the companies categorized into Merger & Acquisition, Agreement, Collaboration, & Partnership, New Product Launch & Enhancement, Investment & Funding, and Award, Recognition, & Expansion. All the news collected help vendor to understand the gaps in the marketplace and competitors strength and weakness thereby, providing insights to enhance product and service.

Company Usability Profiles:The report profoundly explores the recent significant developments by the leading vendors and innovation profiles in the Global Stem Cell Therapy Market, including Advanced Cell Technology, Inc., AlloSource, Inc., Anterogen Co., Ltd., Bioheart Inc., BioTime, Inc., BrainStorm Cell Therapeutics Inc., Celgene Corporation, Cellartis AB, CellGenix GmbH, Cellular Engineering Technologies Inc., Gamida Cell Ltd, Gilead Sciences, Inc., Holostem Terapie Avanzate Srl, JCR Pharmaceuticals Co., Ltd., Lonza Group AG, Medipost Co., Ltd., Nuvasive, Inc., Osiris Therapeutics, Inc., Pharmicell Co., Ltd., Pluristem Therapeutics Inc., PromoCell GmbH, RTI Surgical, Inc., STEMCELL Technologies, Inc., Takeda Pharmaceutical Company Limited, Vericel Corporation, and VistaGen Therapeutics, Inc..

The report provides insights on the following pointers:1. Market Penetration: Provides comprehensive information on the market offered by the key players2. Market Development: Provides in-depth information about lucrative emerging markets and analyze penetration across mature segments of the markets3. Market Diversification: Provides detailed information about new product launches, untapped geographies, recent developments, and investments4. Competitive Assessment & Intelligence: Provides an exhaustive assessment of market shares, strategies, products, certification, regulatory approvals, patent landscape, and manufacturing capabilities of the leading players5. Product Development & Innovation: Provides intelligent insights on future technologies, R&D activities, and breakthrough product developments

The report answers questions such as:1. What is the market size and forecast of the Global Stem Cell Therapy Market?2. What are the inhibiting factors and impact of COVID-19 shaping the Global Stem Cell Therapy Market during the forecast period?3. Which are the products/segments/applications/areas to invest in over the forecast period in the Global Stem Cell Therapy Market?4. What is the competitive strategic window for opportunities in the Global Stem Cell Therapy Market?5. What are the technology trends and regulatory frameworks in the Global Stem Cell Therapy Market?6. What is the market share of the leading vendors in the Global Stem Cell Therapy Market?7. What modes and strategic moves are considered suitable for entering the Global Stem Cell Therapy Market?Read the full report: https://www.reportlinker.com/p06175517/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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Stem Cell Therapy Market Research Report by Cell Source, by Type, by Therapeutic Application, by End-User, by Region - Global Forecast to 2026 -...

Bone Marrow Stem Cells Comments Off on Stem Cell Therapy Market Research Report by Cell Source, by Type, by Therapeutic Application, by End-User, by Region – Global Forecast to 2026 -… | October 16th, 2021

250 Pages Rheumatoid Arthritis Stem Cell Therapy Market Survey by Fact MR, A Leading Business and Competitive Intelligence Provider

Rheumatoid arthritis stem cell therapy has been demonstrated to induce profound healing activity, halt arthritic conditions, and in many cases, reverse and regenerate joint tissue. Today, bone marrow transplant, adipose or fat-derived stem cells, and allogeneic mesenchymal stem cells (human umbilical cord tissue) are used for rheumatoid arthritis stem cell therapy.

The Market Research Survey by Fact.MR, highlights the key reasons behind increasing demand and sales of Rheumatoid Arthritis Stem Cell Therapy.Rheumatoid Arthritis Stem Cell Therapy market driversand constraints, threats and opportunities, regional segmentation and opportunity assessment, end-use/application prospects review are addressed in the Rheumatoid Arthritis Stem Cell Therapy market survey report. The survey report provides a comprehensive analysis of Rheumatoid Arthritis Stem Cell Therapy market key trends and insights on Rheumatoid Arthritis Stem Cell Therapy market size and share.

To Get In-depth Insights Request for Brochure here https://www.factmr.com/connectus/sample?flag=B&rep_id=1001

Rheumatoid Arthritis Stem Cell Therapy Market: Segmentation

Tentatively, the global rheumatoid arthritis stem cell therapy market can be segmented on the basis of treatment type, application, end user and geography.

Based on treatment type, the global rheumatoid arthritis stem cell therapy market can be segmented into:

Based on application, the global rheumatoid arthritis stem cell therapy market can be segmented into:

Based on distribution channel, the global rheumatoid arthritis stem cell therapy market can be segmented into:

Key questions answered in Rheumatoid Arthritis Stem Cell Therapy Market Survey Report:

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Rheumatoid Arthritis Stem Cell Therapy Market: Key Players

The global market for rheumatoid arthritis stem cell therapy is highly fragmented. Examples of some of the key players operating in the global rheumatoid arthritis stem cell therapy market include Mesoblast Ltd., Roslin Cells, Regeneus Ltd, ReNeuron Group plc, International Stem Cell Corporation, TiGenix and others.

The report is a compilation of first-hand information, qualitative and quantitative assessment by industry analysts, inputs from industry experts and industry participants across the value chain.

Essential Takeaways from the this Market Report

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Hemostasis Valves MarketAccording to the latest research by Fact.MR, the Hemostasis Valves Market is set to witness steady growth during 2021-2031. The increasing advancement in the hemostasis valves industry will offer lucrative opportunities and an increasing number of interventional procedures is propelling the market growth.

Cosmetic Dentistry MarketThe global cosmetic dentistry market is estimated to witness significant growth during the forecast period of 2021-2031. This growth is factored in due to the rising consumer awareness and well-defined grooming interest in the aesthetical value of oral care.

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The post Rheumatoid Arthritis Stem Cell Therapy Market By Type (Allogeneic Mesenchymal Stem Cells, Bone Marrow Transplant, Adipose Tissue Stem Cells) and By Application (Rheumatoid Arthritis Stem Cell Therapy) Forecast to 2021-2031 appeared first on The Swiss Times.

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Rheumatoid Arthritis Stem Cell Therapy Market By Type (Allogeneic Mesenchymal Stem Cells, Bone Marrow Transplant, Adipose Tissue Stem Cells) and By...

Bone Marrow Stem Cells Comments Off on Rheumatoid Arthritis Stem Cell Therapy Market By Type (Allogeneic Mesenchymal Stem Cells, Bone Marrow Transplant, Adipose Tissue Stem Cells) and By… | October 16th, 2021

By Alycea Wood and Kamran Zamanian, Ph.D., iData Research Inc.

When choosing a treatment option for orthopedic procedures, biomaterials have become widely popular. Biomaterials are biomedical materials that can be safely implanted or injected into the body and are, more often than not, a form of biologically active tissue themselves.1 Their prevalence in orthopedic procedures is largely attributed to their ability to mimic the structure or properties of osseous tissue. Many products can offer a number of beneficial properties, such as promoting bone growth within the body (osteoinduction), promoting bone growth on the biomaterials scaffold (osteoconduction), or inducing the differentiation of stem cells into osseous tissue (osteogenesis).2,3 The orthopedic biomaterials market includes bone graft substitutes, growth factors, cellular allografts, cell therapy, hyaluronic acid viscosupplementation, and even cartilage repair devices. The U.S. orthopedic biomaterials market saw a dramatic dip and subsequent rebound in market value in 2020 and 2021 as a result of the COVID-19 pandemic. After recovery, the market is projected to see a consistently steady growth in value within the next few years. This growth is expected to be seen across all market segments apart from cellular allograft devices (Figure 1).4

Figure 1: Orthopedic biomaterials market growth trends by market segment, U.S., 20192028. Access iDatas U.S. Orthopedic Biomaterials report to view more granular data.

Cellular allografts may consist of either allograft bone (donated bone tissue) in conjunction with adipose-derived adult stem cells or viable cells within a cortical cancellous bone matrix.4,5 In both scenarios, the devices provide osteoconduction, osteoinduction, and osteogenesis to the site of implantation. Historically, this market had seen promising growth because of the optimal environment for bone growth they can provide.6 The cellular allograft market is projected to see a much slower rate of growth in market value in the next few years despite its market potential due to increased constraints on the market itself. These include, but are not limited to, direct federal restriction on product research, cost of product development, and product recalls.4

There is a strong interest in the scientific community in embryonic stem cell (ESC) research, which is largely due to ESCs high differentiability when compared to adult stem cell (ASC) lines.7 The development of new cellular allograft products, and the resulting growth in the market, is dependent on continued research into realizing the full medical potential of stem cell use. In 2019, the Trump administration eliminated federal funding of research relying on ESC tissue and instituted the National Institutes of Health (NIH) Human Fetal Tissue Research Ethics Advisory Board. This negatively impacted a large number of studies in progress while restricting the ability of new projects to commence.8,9,10 While the board was in effect, it rejected all but one application for funding.11 In April 2021, the Biden administration removed both the board and the restrictions on current projects, allowing federally funded research using ESC to continue.12 This was not the first instance where restrictions were placed and then removed on ESC research. In March 2009, President Obama signed an executive order to overturn the Bush administrations restriction on ESC research.13

The repeated restrictions on ESC research have a number of long-term ramifications in the development and implementation of new, effective cellular allograft treatments. Scientists may need to divert their research efforts away from stem cells and into less turbulent fields, and the progress of product development slows down as studies have funding pulled; this may contribute to increased hesitancy by end users to use stem cell products. Reduced research efforts, funding, and faith in stem cell products will continue to limit the growth of the cellular allograft market.

Cellular allografts tend to be notably more expensive than others within the broader cell-based biomaterials market. When compared to the cell therapy market, which uses either concentrated platelet-rich plasma (PRP) or bone marrow aspirate concentrate (BMAC) in its treatment, the cellular allograft average selling price (ASP) sits over three times higher (Figure 2).3

Figure 2: The average selling price (ASP) of the cellular allograft & cell therapy markets, U.S., 20182028. Access iDatas U.S. Orthopedic Biomaterials report to view more granular data.

The ASP of the cellular allograft market is so high because of the prohibitively expensive cost of developing new products. During the development process, reliable efficacy of a new product is uncertain, and using protein markers to help distinguish stem cell types can be very challenging.4,14 The increased cost of product development acts as a significant barrier to parties looking to enter the U.S. cellular allograft market. The result is fewer products entering and rejuvenating the market, and existing products sit at prohibitively high prices as they have low direct competition.4 The high cost of cellular allograft products hinders new entrants from introducing products and prevents end users from being able to afford existing ones. A broader consequence of this is end users turning to more affordable orthopedic biomaterial types to reduce procedural costs.

Any product recalls within the U.S. orthopedic biomaterials market, especially within cell-based therapies, will negatively impact the use of cellular allografts. This impact is amplified when a recall occurs within the market segment itself, which was seen in the cellular allograft market as recently as June 2021. On June 2, 2021, Aziyo Biologics recalled its product FiberCel following a number of patients contracting tuberculosis.15 Recalls deter the use of cell-based products through increased distrust in the safety of the products themselves, potential public backlash against the specific product itself or, in the market more broadly, reduced reimbursement from health insurance providers as well as the introduction of more restrictive FDA protocols. This is another reason why effective, safe, cell-based products are necessary for the cellular allograft market to move forward.

Conclusion

Federal research restrictions, high development costs, and product recalls all negatively impact the growth of the cellular allograft market in the United States. These constraints contribute to the projected low growth rate in market value in the coming years despite the potential uses for stem cell therapies. To shift the tide back toward growth, the cellular allograft space will need consistent research progress through large-scale studies, more affordable product development, and strict enforcement of sanitization protocols for existing products to prevent future product recalls. The large therapeutic potential of stem cell therapy has been discussed extensively in scientific and popular literature, but it may take a while to realize it.

References

About The Authors:

Alycea Wood is a research analyst at iData Research. She develops and composes syndicated research projects regarding the medical device industry, and published the U.S. Orthopedic Biomaterials report series.

Kamran Zamanian, Ph.D., is CEO and founding partner of iData Research. He has spent over 20 years working in the market research industry with a dedication to the study of medical devices used in the health of patients all over the globe.

About iData Research

For 16 years, iData Research has been a strong advocate for data-driven decision-making within the global medical device, dental, and pharmaceutical industries. By providing custom research and consulting solutions, iData empowers its clients to trust the source of data and make important strategic decisions with confidence.

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The Impact Of Market Restrictions On The US Stem Cell Biomaterials Market - Med Device Online

Bone Marrow Stem Cells Comments Off on The Impact Of Market Restrictions On The US Stem Cell Biomaterials Market – Med Device Online | October 16th, 2021

By Sam Boughedda

Investing.com Shares of biotechnology firm Jasper Therapeutics (NASDAQ:JSPR) soared 112% after Oppenheimer analyst Jay Olson initiated coverage of the company with a buy-equivalent outperform rating and $21 price target.

In a research note released after the close on Tuesday, Olson told investors that he sees Jasper as an "emerging leader" in developing novel targeted conditioning agents for hematopoietic stem cell transplantation.

The company's lead candidate, JSP191, is used to remove hematopoietic stem cells from bone marrow before a transplant.

Olsen believes Jasper Therapeutics is well-positioned to conceivably change what he describes as the "decades-old standard" hematopoietic stem cell transplantation for various diseases "either as a standalone conditioning agent or as the backbone of the conditioning regimen."

At the beginning of October, biopharmaceutical firm Amgen (NASDAQ:AMGN) disclosed a 7.4% stake in Jasper.

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Jasper Therapeutics Stock Soars after Oppenheimer Calls it a Buy - Yahoo Finance

Bone Marrow Stem Cells Comments Off on Jasper Therapeutics Stock Soars after Oppenheimer Calls it a Buy – Yahoo Finance | October 16th, 2021

Every week there are numerous scientific studies published. Heres a look at some of the more interesting ones.

T-Cell Immune Response to COVID-19 Vaccines and Natural Infections

Much of the discussions and news reports about immune responses to vaccines and COVID-19 revolve around antibody levels. Much less has been said about T-cells, which provide longer-term protection. Researchers atGladstone Institutesconducteda detailed T-cell survey before and after COVID-19 immunization, which they published ineLife. They concluded that the Pfizer-BioNTech and Moderna mRNA vaccines create long-term populations of T-cells that recognize multiple SARS-COV-2 virus variants. They also found key differences in the T-cell responses in people who had COVID-19 infections before vaccination compared to people who had never been infected.

Overall, our data support the idea that vaccines are eliciting a very robust T-cell response in healthy individuals, said Nadia Roan, senior author of the study and Gladstone Associate Investigator. But they also suggest there may be some ways to improve them further, by getting more of the vaccine-elicited T-cells to park themselves in the respiratory tract.

Antibodies produced by B-cells quickly recognize viruses, target them, and prevent infection by destroying the viruses. T-cells, however, identify and destroy cells that are already infected. Antibodies are better at stopping initial infection, but T-cells typically last longer after an initial infection or vaccine. At that point they are better at fighting off disease in its early stages, which prevents severe symptoms. But T-cells are very diverse and difficult to analyze. Some subsets respond differently to infected cells and behave differently, while others have different functions within the overall T-cell immune response.

One key finding was that in people who had not been previously infected, the T-cell responses become stronger in quantity and quality after the second dose of the vaccine. But in people who had previously had COVID-19, there was not much of a change between the first and second vaccine dose.

Blood Biomarkers Provide Warning Signs of Dementia

Investigators at theGerman Center for Neurodegenerative Diseases (DZNE)identifiedmolecules in the blood that potentially warn of impending dementia. The research study included several university hospitals across Germany. The biomarkers were based on measuring levels of microRNAs. They say that the technique isnt ready yet for practical use, but they hope to develop a simple blood test. MicroRNAs have regulatory properties, influencing protein production and metabolism. In tests in humans, mice and cell cultures, they found three microRNAs whose levels were linked to mental performance. The three microRNAs also influence neuro-inflammation and neuroplasticity, including the ability of neurons to establish connections with each other.

Stem Cell Population Essential for Bone Regeneration

Researchers at theUniversity of Tsukuba, Japan,identifieda subpopulation of mesenchymal stem cells that play a major role in bone healing. The stem cells are found in the bone marrow and express the marker CD73. When a bone fracture heals, it moves through a series of stages, including clotted blood forming at the fracture. This clot is replaced by fibrous tissue and cartilage, then by a hard bony callus. The bone is then remodeled, with regular bone replacing the hard callus. They found that the generation of the callus is critically dependent on recruiting MSCs from the surrounding tissue and bone marrow. They observed the CD73-positive MSCs migrating toward the fracture site and forming new cartilage and bone cells. When they grafted CD73-positive MSCs into the fracture, they noted enhanced healing processes.

Antiviral Molecule Prevents SARS-CoV-2 from Entering Cells

Scientists atWashington University School of Medicinein St. Louisdevelopeda compound that prevents the SARS-CoV-2 virus, which causes COVID-19, from entering cells. The compound is called MM3122 and has been studied in cell cultures and in mice. MM3122 targets a key human protein called transmembrane serine protease 2 (TMPRSS2), which coronaviruses use to enter and infect human cells. Once the virus attached onto a cell in the epithelia of the airway, the TMPRSS2 protein cuts the viral spike protein, which activates the spike protein to mediate fusion of the viral and cellular membranesstarting the infection process. In cell cultures, MM3122 protected cells from viral damage better than remdesivir,Gilead Sciences antiviral against COVID-19; and an acute safety assay in mice demonstrated that large doses of MM3122 given for seven days did not cause noticeable issues. The compound also was effective against SARS-CoV, the virus behind SARS, and MERS-CoV, the coronavirus that causes MERS. The researchers are now working with researchers at the NIH to test it in animal models of COVID-19. They are also working on an oral version of the injectable compound.

Specific Personality Traits Might Signal Pending Alzheimers

Researchers atFlorida State Universityfoundthat specific changes in the brain linked with Alzheimers disease are often visible earlier in people with personality traits associated with the disease. The research focused on two traits: neuroticism, or a predisposition for negative emotions, and conscientiousness, linked to a tendency to be careful, organized, goal-directed and responsible. They found that people with amyloid and tau deposits, proteins linked to Alzheimers disease in the brain, were identified in participants who scored higher in neuroticism levels and lower in conscientiousness. The study suggests that personality traits might help protect against Alzheimers and other brain diseases by delaying or preventing the neuropathology for people strong in conscientiousness and low in neuroticism.

Why We Overeat

Astudyfrom theUniversity of Washington School of Medicine/UW Medicinereported on the function of glutamatergic neurons in mice. These neurons communicate to the lateral habenula, a brain region associated with the pathophysiology of depression, and the ventral tegmental area, which is involved in motivation, reward and addiction. They found that when mice are eating, the neurons in the lateral habenula are more responsive than the neurons in the ventral tegmental area. They suggest that these neurons might play a bigger role in guiding feeding. In addition, they studied the influence of the leptin and ghrelin hormones, which are believed to regulate behavior via the mesolimbic dopamine system, part of the reward pathway. The research adds additional insight into satiety and why people or at least mice overeat.

We found these cells are not a monolithic group, and that different flavors of these cells do different things, said Garret Stuber, a joint UW professor of anesthesiology and pain medicine and pharmacology, the papers senior author.

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Research Roundup: T-Cell Immune Response to COVID-19 Vaccines and More - BioSpace

Bone Marrow Stem Cells Comments Off on Research Roundup: T-Cell Immune Response to COVID-19 Vaccines and More – BioSpace | October 16th, 2021

TEL AVIV, Israel, Oct. 13, 2021 /PRNewswire/ --BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a late clinical-stage biopharmaceutical company focused on oncology, today announced positive results from a pharmacoeconomic study evaluating the cost-effectiveness of using investigational drug Motixafortide as a primary stem cell mobilization (SCM) agent on top of granulocyte colony stimulating factor (G-CSF), versus G-CSF alone, in multiple myeloma patients undergoing autologous stem cell transplantation (ASCT). The study was performed by the Global Health Economics and Outcomes Research (HEOR) team of IQVIA, and was a pre-planned study conducted in parallel with the GENESIS Phase 3 trial. These results, together with the highly significant and clinically meaningful data from the GENESIS trial, strongly support the potential use of Motixafortide, on top of G-CSF, as the standard of care in SCM for ASCT.

The study concluded that the addition of Motixafortide to G-CSF (the current standard of care) is associated with a statistically significant decrease in health resource utilization (HRU) during the ASCT process, compared to G-CSF alone. Based on the significantly higher number of mobilized cells and the lower number of apheresis sessions, lifetime estimates show quality-adjusted-life-year (QALY) benefits and net cost savings of ~$17,000 (not including the cost of Motixafortide), versus G-CSF alone. The study findings, combined with model estimates, suggest that the use of Motixafortide, on top of G-CSF, as the standard of care in mobilization for ASCT, could be a cost-effective option in the US, based on accepted willingness-to-pay (WTP) values for healthcare payers.

"The compelling cost savings identified by this rigorously designed study strongly support the Company's view that Motixafortide, in combination with G-CSF, can become the new standard of care as an upfront, or primary, therapy for all multiple myeloma patients undergoing autologous stem cell transplantation," stated Philip Serlin, Chief Executive Officer of BioLineRx. "Based on data from the GENESIS trial showing that nearly 90% of patients collected an optimal number of cells for transplantation following a single administration of Motixafortide and in only one apheresis session, versus less than 10% for G-CSF alone, the pharmacoeconomic study demonstrates that use of Motixafortide on top of G-CSF can save $17,000 per patient, not including the cost of Motixafortide. These cost savings should leave substantial room in the future to optimize our pricing strategy for Motixafortide at product launch and thereafter, if approved.

"It is also important to note that fewer administrations and apheresis sessions confer meaningful safety and time benefits to patients. In addition, the significantly higher median number of cells collected in one apheresis session ~11 million using Motixafortide on top of G-CSF versus ~2 million for G-CSF alone not only enables transplantation of an optimal number of cells, with the potential to significantly save on time to engraftment, it also permits the retention of enough cells for cryopreservation in the event that an additional transplantation is required in the future. Lastly, higher levels of certainty regarding the number of apheresis sessions required for mobilization could enable more efficient utilization of apheresis units at transplantation institutions, where there is often a shortage of available machines.

"We believe the data from the GENESIS study, together with the results from this pharmacoeconomic study, set Motixafortide apart from all other mobilization agents either currently available or in development. If approved, Motixafortide represents a significant advancement in SCM to the benefit of patients and payers alike, and, to that end, we remain on track to submit a New Drug Application (NDA) to the FDA in the first half of next year," Mr. Serlin concluded.

About the Pharmacoeconomic Study

The pharmacoeconomic study analyzed healthcare resource utilization (HRU) observed during the Phase 3 GENESIS trial, which randomized 122 patients into two arms: Motixafortide plus G-CSF (n=80) or placebo plus G-CSF (n=42). HRU data points collected include: (1) the number of Motixafortide and G-CSF doses, as well as the number of apheresis sessions performed, in primary mobilization; (2) the percentage of patients needing rescue mobilization due to poor primary mobilization, including the number of apheresis sessions needed and the number of G-CSF and plerixafor doses required; and (3) hospitalization costs related to conditioning and transplantation, including length of stay. Quality-adjusted life years gained (QALY) from published literature were also incorporated into the model. Motixafortide plus G-CSF was associated with a statistically significant HRU decrease during the autologous stem cell transplantation process compared to standard-of-care G-CSF alone. Given the higher number of mobilized cells and lower number of apheresis sessions, lifetime estimates show quality-adjusted-life-year (QALY) benefits and net cost savings of ~$17,000 (not including the cost of Motixafortide), versus the current standard of care.

About the GENESIS Phase 3 Trial

The GENESIS Phase 3 trial (NCT03246529) was initiated in December 2017. GENESIS was a randomized, placebo-controlled, multicenter study, evaluating the safety, tolerability and efficacy of Motixafortide and G-CSF, compared to placebo and G-CSF, for the mobilization of hematopoietic stem cells for autologous transplantation in multiple myeloma patients. The primary objective of the study was to demonstrate that only one dose of Motixafortide on top of G-CSF is superior to G-CSF alone in the ability to mobilize 6 million CD34+ cells in up to two apheresis sessions. Additional objectives included time to engraftment of neutrophils and platelets and durability of engraftment, as well as other efficacy and safety parameters. The study successfully met all primary and secondary endpoints with an exceptionally high level of statistical significance (p<0.0001), including approximately 90% of patients who mobilized the target number of cells for transplantation with only one administration of Motixafortide and in only one apheresis session.

About Stem Cell Mobilization for Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) is part of the standard treatment paradigm for a number of blood cancers, including multiple myeloma, non-Hodgkin's lymphoma and other lymphomas. In eligible patients, ASCT is performed after initial (induction) therapy, and, in most cases, requires consecutive-day clinic visits for the mobilization and apheresis (harvesting) phases, and full hospitalization for the conditioning chemotherapy and transplantation phases until engraftment. The associated burden is therefore significant patients experience clinically relevant deteriorations in their quality of life during ASCT, and healthcare resource use throughout the ASCT phases is particularly intense. Therefore, new interventions impacting the ASCT process have the potential for relieving some of the clinical burden for transplanted patients, the logistical burden for the apheresis units, and the financial burden for healthcare providers and payers.

Described simply, ASCT consists of: (1) mobilizing the patient's own stem cells from his/ her bone marrow to the peripheral blood for removing (harvesting) via an apheresis procedure; (2) freezing and storing the harvested cells until they are needed for transplantation; (3) providing a conditioning treatment, such as high-dose chemotherapy or radiation, to kill the remaining cancer cells the day before transplant; and (4) infusing the stored stem cells back to the patient intravenously via a catheter.

To mobilize the patient's stem cells from the bone marrow to the peripheral blood for harvesting, the current standard of care includes the administration of 5-8 daily doses of granulocyte colony stimulating factor (G-CSF), and the performance of 1-4 apheresis sessions. For patients unable to mobilize sufficient numbers of cells for harvesting during this primary mobilization phase, rescue therapy is carried out, consisting of 1-4 doses of plerixafor on top of G-CSF, and the performance of an additional number of apheresis sessions as necessary. In light of this, an agent with superior mobilization activity may significantly reduce the mobilization and harvesting burden and associated risks of the ASCT process and lead to significant clinical and resource benefits.

About BioLineRx

BioLineRx Ltd. (NASDAQ/TASE: BLRX) is a late clinical-stage biopharmaceutical company focused on oncology. The Company's business model is to in-license novel compounds, develop them through clinical stages, and then partner with pharmaceutical companies for further clinical development and/or commercialization.

The Company's lead program, Motixafortide (BL-8040), is a cancer therapy platform that was successfully evaluated in a Phase 3 study in stem cell mobilization for autologous bone-marrow transplantation, as well as reporting positive results from a pre-planned pharmacoeconomic study, and is currently in preparations for an NDA submission. Motixafortide was also successfully evaluated in a Phase 2a study for the treatment of pancreatic cancer in combination with KEYTRUDA and chemotherapy under a clinical trial collaboration agreement with MSD (BioLineRx owns all rights to Motixafortide), and is currently being studied in combination with LIBTAYO and chemotherapy as a first-line PDAC therapy.

BioLineRx is also developing a second oncology program, AGI-134, an immunotherapy treatment for multiple solid tumors that is currently being investigated in a Phase 1/2a study.

For additional information on BioLineRx, please visit the Company's website at http://www.biolinerx.com, where you can review the Company's SEC filings, press releases, announcements and events.

Various statements in this release concerning BioLineRx's future expectations constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include words such as "may," "expects," "anticipates," "believes," and "intends," and describe opinions about future events. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Factors that could cause BioLineRx's actual results to differ materially from those expressed or implied in such forward-looking statements include, but are not limited to: the initiation, timing, progress and results of BioLineRx's preclinical studies, clinical trials and other therapeutic candidate development efforts; BioLineRx's ability to advance its therapeutic candidates into clinical trials or to successfully complete its preclinical studies or clinical trials; BioLineRx's receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings and approvals; the clinical development, commercialization and market acceptance of BioLineRx's therapeutic candidates; BioLineRx's ability to establish and maintain corporate collaborations; BioLineRx's ability to integrate new therapeutic candidates and new personnel; the interpretation of the properties and characteristics of BioLineRx's therapeutic candidates and of the results obtained with its therapeutic candidates in preclinical studies or clinical trials; the implementation of BioLineRx's business model and strategic plans for its business and therapeutic candidates; the scope of protection BioLineRx is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; estimates of BioLineRx's expenses, future revenues, capital requirements and its needs for additional financing; risks related to changes in healthcare laws, rules and regulations in the United States or elsewhere; competitive companies, technologies and BioLineRx's industry; risks related to the COVID-19 pandemic; and statements as to the impact of the political and security situation in Israel on BioLineRx's business. These and other factors are more fully discussed in the "Risk Factors" section of BioLineRx's most recent annual report on Form 20-F filed with the Securities and Exchange Commission on February 23, 2021. In addition, any forward-looking statements represent BioLineRx's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law.

Contact:Tim McCarthyLifeSci Advisors, LLC+1-212-915-2564[emailprotected]

or

Moran MeirLifeSci Advisors, LLC+972-54-476-4945[emailprotected]

SOURCE BioLineRx Ltd.

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BioLineRx Announces Positive Results from Pharmacoeconomic Study Positioning Motixafortide as Potential Standard of Care in Stem Cell Mobilization -...

Bone Marrow Stem Cells Comments Off on BioLineRx Announces Positive Results from Pharmacoeconomic Study Positioning Motixafortide as Potential Standard of Care in Stem Cell Mobilization -… | October 16th, 2021

Nine accepted abstracts demonstrate broad potential of the companys HSC gene therapy approach to treat severe neurodegenerative diseases and immunological disorders

BOSTON and LONDON, Oct. 13, 2021 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today announced the acceptance of nine abstracts at the upcoming European Society of Gene & Cell Therapy Congress (ESGCT) taking place virtually from October 19-22.

Clinical and pre-clinical data from across the companys hematopoietic stem cell (HSC) gene therapy portfolio will be featured in two oral and seven poster presentations, including an update on the ongoing proof-of-concept study of OTL-201 for the treatment of Mucopolysaccharidosis type IIIA (MPS-IIIA, also known as Sanfilippo syndrome type A), pre-clinical data from OTL-204 in frontotemporal dementia (FTD), as well as proof-of-principle for longitudinal monitoring of vector integration sites using Liquid Biopsy Integration Site sequencing (LiBIS-seq).

Additionally, Orchards scientific advisory board member and clinical collaborator Alessandra Biffi, M.D., professor of pediatrics, University of Padua and chief of the Pediatric Onco-hematology Unit of Padua Hospital, will be giving an invited presentation on the HSC gene therapy landscape for the treatment of neurodegenerative disorders, which will include an overview of several of the companys investigational programs.

The presentations are listed below, and the full program is available online on the ESGCT website. All times are Central European Summer Time (CEST).

Oral Presentation Details:

Haematopoietic reconstitution dynamics of mobilized peripheral blood- and bone marrow-derived haematopoietic stem/progenitor cells after gene therapyPresenting Author: Andrea Calabria, Ph.D., San Raffaele Telethon Institute for Gene TherapyAbstract Number: OR049Date/Time: Friday, October 22, 2021 at 10:01 CEST

Longitudinal monitoring of vector integration sites in in vivo GT approaches by Liquid-Biopsy-Integration-Site-SequencingPresenting Author: Daniela Cesana, Ph.D., San Raffaele Telethon Institute for Gene TherapyAbstract Number: OR058Date/Time: Friday, October 22, 2021 at 12:46 CEST

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Poster Presentation Details:

All posters will be available on demand starting October 19, 2021 on the ESGCT website.

Development of an ex vivo Gene Therapy for Frontotemporal Dementia (FTD)Presenting Author: Yuri Ciervo, Ph.D., division of pediatric Hematology,Oncology and Stem Cell Transplantation, Womans and Child Health Department, University of Padova, Padova, ItalyAbstract Number: P077

Optimized Lentiviral Transduction Process for ex vivo CD34+ Hematopoietic Stem Cell Gene Therapy Drug Product ManufacturePresenting Author: Saranya Elavazhagan, Orchard TherapeuticsAbstract Number: P271

Clinical Trial Update: Ex-vivo autologous stem cell gene therapy in MPSIIIAPresenting Author: Brian Bigger, Ph.D., University of ManchesterAbstract Number: P361

Dissecting bone remodelling mechanisms and hematopoietic stem cell gene therapy impact in Mucopolysaccharidosis type I Hurler bone defectsPresenting Author: Ludovica Santi, Ph.D., San Raffaele Telethon Institute for Gene TherapyAbstract Number: P157

Hematopoietic reconstitution and lineage commitment in HSC GT patients are influenced by the disease backgroundPresenting Author: Andrea Calabria, Ph.D., San Raffaele Telethon Institute for Gene TherapyAbstract Number: P181

Kinetics and composition of haematopoietic stem/progenitors mobilized cells upon G-CSF and Plerixafor administration in transplant donor or patients undergoing autologous gene therapyPresenting Author: Luca Basso-Ricci, San Raffaele Telethon Institute for Gene TherapyAbstract Number: P174

Role of peripheral blood circulating haematopoietic stem/progenitor cells during physiological haematopoietic maturation and after gene therapyPresenting Author: Pamela Quaranta, San Raffaele Telethon Institute for Gene TherapyAbstract Number: P186

About Orchard TherapeuticsAt Orchard Therapeutics, our vision is to end the devastation caused by genetic and other severe diseases. We aim to do this by discovering, developing and commercializing new treatments that tap into the curative potential of hematopoietic stem cell (HSC) gene therapy. In this approach, a patients own blood stem cells are genetically modified outside of the body and then reinserted, with the goal of correcting the underlying cause of disease in a single treatment.

In 2018, the company acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Today, Orchard has a deep pipeline spanning pre-clinical, clinical and commercial stage HSC gene therapies designed to address serious diseases where the burden is immense for patients, families and society and current treatment options are limited or do not exist.

Orchard has its global headquarters in London and U.S. headquarters in Boston. For more information, please visit http://www.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About OrchardInvestors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (Twitter and LinkedIn), including but not limited to investor presentations and investor fact sheets, U.S. Securities and Exchange Commission filings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaBenjamin NavonDirector, Corporate Communications+1 857-248-9454Benjamin.Navon@orchard-tx.com

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Orchard Therapeutics Outlines Comprehensive Presence at the European Society of Gene & Cell Therapy Congress - Yahoo Finance

Bone Marrow Stem Cells Comments Off on Orchard Therapeutics Outlines Comprehensive Presence at the European Society of Gene & Cell Therapy Congress – Yahoo Finance | October 16th, 2021

GRAND RAPIDS, Mich. As day turned to darkness, a crowd gathered at Monroe North on Saturday in Grand Rapids for the annual Light the Night celebration.

Its an inspirational community event, said Anne Bradley, Light the Night campaign development manager.

People eventually made their way to the street and showed support in each stride for blood cancer patients, their families and the countless others impacted by the disease.

Among the participants was Colette Smiley. Her white light gave a hint as to why she showed up.

I am a leukemia survivor, said Smiley. It completely alters your life.

In 2014, doctors diagnosed Smiley with Acute Myeloid Leukemia, or AML. Its an often fatal cancer that forms in a persons blood and bone marrow.

Smiley credits her treatment plan and a strangers stem cells for helping her enter remission within weeks of her diagnosis.

I come here to celebrate, to celebrate each re-birthday that I have, but to also thank LLS for [what] they do each and every day and each and every year for blood cancer patients, said Smiley.

According to the Leukemia and Lymphoma Society, blood cancers impact an estimated 1.5 million people in the United States, with a person diagnosed once every three minutes.

Leukemia is the most common cancer diagnosed in children and adolescents younger than 20 years old. It accounts for 25.1 percent of all cancer cases in the age group.

Symptoms of blood cancers often only appear in advanced stages, but can include ones similar to a severe cold or flu. Survival rates at one point hovered around 3 percent, but now, its up to 95 percent.

Its our goal and our mission to end blood cancer and to improve the quality of life for patients and their families, said Bradley.

All proceeds from Light the Night benefit LLS, which says 80 cents of every dollars goes directly to their mission.

Attendees, though, found a deeper value in the night.

We all live different stories, said Smiley. We all work in different places and our families are different and our backgrounds are different, but something brought us together that we certainly didnt wish for, blood cancer, but its brought us together and we can support each other now.

Light the Night hopes to collect $1 million in Michigan.

To donate, click here.

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'Light the Night' returns to Grand Rapids, raising awareness, donations for blood cancers - Fox17

Bone Marrow Stem Cells Comments Off on ‘Light the Night’ returns to Grand Rapids, raising awareness, donations for blood cancers – Fox17 | October 16th, 2021

NEW YORK, Oct. 14, 2021 /PRNewswire/ --BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, will present findings from a multicenter, open label clinical trial of NurOwn in progressive multiple sclerosis. The study, "Phase 2 Safety and Efficacy Study of Intrathecal MSC-NTF cells in Progressive Multiple Sclerosis," will be delivered in an oral presentation today at the fully digital37thCongress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The Phase 2 clinical trial was designed to evaluate intrathecal administration of NurOwn (autologous MSC-NTF cells) in participants with progressive MS. The study achieved the primary endpoint of safety and tolerability. It demonstrated a reduction of neuroinflammatory biomarkers and an increase in neuroprotective biomarkers in the cerebrospinal fluid (CSF) and consistent improvement across MS functional outcome measures, including measures of walking, upper extremity function, vision and cognition.

"We were pleased that this study demonstrated safety, preliminary evidence of efficacy and relevant biomarker outcomes in patients with progressive multiple sclerosis, in an area of high unmet need," said Jeffrey Cohen, M.D., Director of Experimental Therapeutics at the Cleveland Clinic Mellen Center for MS and principal investigator for the trial. "These results should be confirmed in a randomized placebo-controlled trial."

The study was sponsored by Brainstorm Cell Therapeutics with additional financial support for biomarker analyses from the National Multiple Sclerosis Society Fast-Forward Program. It was conducted at four U.S. MS centers of excellence:

"We very much appreciate the tremendous collaboration among many premier organizations, for their generous sharing of expertise, support and data, which enabled the important balance between scientific rigor and ethical treatment of progressive MS participants in the trial," said Ralph Kern, M.D., MHSc., President and Chief Medical Officer, Brainstorm Cell Therapeutics. "We are holding discussions with key MS experts, and seeking guidance from the FDA to determine next steps for the development of NurOwn in progressive MS."

"The National MS Society is pleased to support the biomarker portion of this study through our commercial funding program Fast Forward," said Mark Allegretta, Ph.D., Vice President, Research. "We're encouraged to see evidence that the biomarker analysis showed proof of concept for detecting neuroprotection and reduced inflammation."

About the trial

The Phase 2 open-label studyevaluated the safety and efficacy of intrathecal administration of autologous MSC-NTF cells in patients with primary or secondary progressive MS. The primary study endpoint was safety and tolerability. Secondary efficacy endpoints included: timed 25-foot walk (T25FW); 9-Hole Peg Test (9-HPT); Low Contrast Letter Acuity (LCLA); Symbol Digit Modalities Test (SDMT); 12 item MS Walking Scale (MSWS-12); as well as cerebrospinal fluid (CSF) and blood biomarkers. Clinical efficacy outcomes were compared with matched (n=48) participants in the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB) registry, Tanuja Chitnis, MD Brigham and Women's Hospital and the Ann Romney Center for Neurologic Diseases, and 255 patient randomized double blind placebo controlled NN-102 SPRINT-MS Study, courtesy NIH/NINDS, PI: Robert J. Fox, MD, MS, FAAN, Cleveland Clinic, CTR: NCT01982942. Baseline characteristics from these two cohorts were similar allowing for comparison of efficacy results, comparisons with SPRINT-MS were with the placebo arm of this study.

Mean age of participants was 47 years, 56% were female, and mean baseline EDSS score was 5.4. 18 participants were treated, 16 (80%) received all 3 treatments and completed the entire study; 2 study discontinuations were due to procedure-related adverse events. No deaths or treatment-related adverse events due to worsening of MS were observed.

In responder analyses, 14% and 13% of MSC-NTF treated participants showed at least a 25% improvement in T25FW and 9-HPT (combined hands) respectively, compared to 5% and 0% in matched CLIMB patients and 9% and 3% in SPRINT. Twenty-seven percent (27%) showed at least an 8-letter improvement in LCLA (binocular, 2.5% threshold) and 67% showed at least a 3-point improvement in SDMT, compared to 6% and 18% in CLIMB and 13% and 35% in SPRINT, respectively.

Mean improvements of +0.10 ft/sec in T25FW and -0.23 sec in 9-HPT (combined hands), were observed in MSC-NTF treated participants, compared to a mean worsening of -0.07 ft/sec and +0.49 sec in CLIMB and -0.06 ft/sec and +0.28 sec in SPRINT, respectively. MSC-NTF treated participants showed a mean improvement of +3.3 letters in LCLA (binocular, 2.5% threshold) and 3.8 points in SDMT, compared to a mean worsening of -1.07 letters in LCLA (binocular, 2.5% threshold) and mean improvement of +0.10 in SDMT, in CLIMB and -0.6 and -0.1 in SPRINT. In addition the MSFC-4 Composite Z-score of T25W, 9-HPT, SDMT and LCLA showed a 0.18 point improvement in MSC-NTF treated participants, while CLIMB and SPRINT showed decreases of -0.02 and -0.05.

Furthermore, 38% of treated patients showed at least a 10-point improvement in the MSWS-12 a patient reported outcome that evaluates the impact of MS on walking function, whereas this outcome was not evaluated in CLIMB or SPRINT.

CSF biomarkers obtained at 3 consecutive time points, showed increases in neuroprotective molecules (VEGF, HGF, NCAM-1,Follistatin, Fetuin-A) and decreases in neuroinflammatory biomarkers (MCP-1, SDF-1, sCD27 and Osteopontin).

About NurOwn

The NurOwntechnology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells are designed to effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwntechnology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug designation status from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a Phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm completed under an investigational new drug application a Phase 2 open-label multicenter trial (NCT03799718) of autologous MSC-NTF cells in progressive multiple sclerosis (MS) and was supported by a grant from the National MS Society (NMSS).

For more information, visit the company's website atwww.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future NurOwnmanufacturing and clinical development plans, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, the prospects for regulatory approval of BrainStorm's NurOwntreatment candidate, the initiation, completion, and success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwntreatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture, or to use third parties to manufacture, and commercialize the NurOwntreatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

Contacts:

Investor Relations:Eric GoldsteinLifeSci Advisors, LLCPhone: +1 (646) 791-9729egoldstein@lifesciadvisors.com

Media:Mariesa Kemble kemblem@mac.com

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SOURCE Brainstorm Cell Therapeutics Inc

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