The old rats appeared newly invigorated after receiving their injections. As hoped, the cardiac stem cells improved heart function yet also provided additional benefits. The rats' fur fur, shaved for surgery, grew back more quickly than expected, and their chromosomal telomeres, which commonly shrink with age, lengthened.

The old rats receiving the cardiac stem cells also had increased stamina overall, exercising more than before the infusion.

"It's extremely exciting," said Dr. Eduardo Marbn, primary investigator on the research and director of the Cedars-Sinai Heart Institute. Witnessing "the systemic rejuvenating effects," he said, "it's kind of like an unexpected fountain of youth."

"We've been studying new forms of cell therapy for the heart for some 12 years now," Marbn said.

Some of this research has focused on cardiosphere-derived cells.

"They're progenitor cells from the heart itself," Marbn said. Progenitor cells are generated from stem cells and share some, but not all, of the same properties. For instance, they can differentiate into more than one kind of cell like stem cells, but unlike stem cells, progenitor cells cannot divide and reproduce indefinitely.

Since heart failure with preserved ejection fraction is similar to aging, Marbn decided to experiment on old rats, ones that suffered from a type of heart problem "that's very typical of what we find in older human beings: The heart's stiff, and it doesn't relax right, and it causes fluid to back up some," Marbn explained.

He and his team injected cardiosphere-derived cells from newborn rats into the hearts of 22-month-old rats -- that's elderly for a rat. Similar old rats received a placebo injection of saline solution. Then, Marbn and his team compared both groups to young rats that were 4 months old. After a month, they compared the rats again.

Even though the cells were injected into the heart, their effects were noticeable throughout the body, Marbn said

"The animals could exercise further than they could before by about 20%, and one of the most striking things, especially for me (because I'm kind of losing my hair) the animals ... regrew their fur a lot better after they'd gotten cells" compared with the placebo rats, Marbn said.

The rats that received cardiosphere-derived cells also experienced improved heart function and showed longer heart cell telomeres.

Why did it work?

The working hypothesis is that the cells secrete exosomes, tiny vesicles that "contain a lot of nucleic acids, things like RNA, that can change patterns of the way the tissue responds to injury and the way genes are expressed in the tissue," Marbn said.

It is the exosomes that act on the heart and make it better as well as mediating long-distance effects on exercise capacity and hair regrowth, he explained.

Looking to the future, Marbn said he's begun to explore delivering the cardiac stem cells intravenously in a simple infusion -- instead of injecting them directly into the heart, which would be a complex procedure for a human patient -- and seeing whether the same beneficial effects occur.

Dr. Gary Gerstenblith, a professor of medicine in the cardiology division of Johns Hopkins Medicine, said the new study is "very comprehensive."

"Striking benefits are demonstrated not only from a cardiac perspective but across multiple organ systems," said Gerstenblith, who did not contribute to the new research. "The results suggest that stem cell therapies should be studied as an additional therapeutic option in the treatment of cardiac and other diseases common in the elderly."

Todd Herron, director of the University of Michigan Frankel Cardiovascular Center's Cardiovascular Regeneration Core Laboratory, said Marbn, with his previous work with cardiac stem cells, has "led the field in this area."

"The novelty of this bit of work is, they started to look at more precise molecular mechanisms to explain the phenomenon they've seen in the past," said Herron, who played no role in the new research.

One strength of the approach here is that the researchers have taken cells "from the organ that they want to rejuvenate, so that makes it likely that the cells stay there in that tissue," Herron said.

He believes that more extensive study, beginning with larger animals and including long-term followup, is needed before this technique could be used in humans.

"We need to make sure there's no harm being done," Herron said, adding that extending the lifetime and improving quality of life amounts to "a tradeoff between the potential risk and the potential good that can be done."

Capicor hasn't announced any plans to do studies in aging, but the possibility exists.

After all, the cells have been proven "completely safe" in "over 100 human patients," so it would be possible to fast-track them into the clinic, Marbn explained: "I can't tell you that there are any plans to do that, but it could easily be done from a safety viewpoint."

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Cardiac stem cells rejuvenate rats' aging hearts ... - CNN

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Human Induced Pluripotent Stem Cells (HiPSC)Top:HiPSC express pluriotency markers OCT4, Nanog, LIN28 and SSEA-4.Bottom:HiPSC differentiate into cell derivatives from the 3 embryonic layers: Neuronal marker beta III tubulin (TUJ1), Smooth Muscle Actin (SMA) and Hepatocyte Nuclear Factor 3 Beta (HNF3b).

Cutting-edge development and manufacturing provides high quality, thoroughly-characterized HiPSC cells to researchers around the world. HiPSC are generated from somatic cells, eliminating ethical considerations associated with scientific work based on embryonic stem cells. Furthermore, being donor/patient-specific, they open possibilities for a wide variety of studies in biomedical research. Donor somatic cells carry the genetic makeup of the diseased patient, hence HiPSC can be used directly to model disease on a dish.

Thus, one of the main uses of HiPSC has been in genetic disease modeling in organs and tissues, such as the brain (Alzheimers, Autism Spectrum Disorders), heart (Familial Hypertrophic, Dilated, and Arrhythmogenic Right Ventricular Cardiomyopathies), and skeletal muscle (Amyotrophic Lateral Sclerosis, Spinal Muscle Atrophy). The combination of HiPSC technology and gene editing strategies such as the CRISPR/Cas9 system creates a powerful platform in which disease-causing mutations can be created on demand and sets of isogenic cell lines (with and without mutations) serve as convenient tools for disease modeling studies.

Other applications of HiPSC and iPSC-differentiated cells include drug screening, development, efficacy and toxicity assessment. As an example, through the FDA-backed CiPA (Comprehensive in vitro Pro-Arrhythmia Assessment) initiative, HiPSC-derived cardiac muscle cells (cardiomyocytes) are poised to constitute a new standard model for the evaluation of cardiotoxicity of new drugs, which is the main reason of drug withdrawal from the market. Finally, HiPSC-differentiated cells are being used in early stage technology development for applications in regenerative medicine. Bio-printing and tissue constructs have also been considered as attractive applications for HiPSC.

Human iPSC and Derived Cells are forResearch Use Only (RUO). Not for human clinical or therapeutic use.

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iPSC | Induced Pluripotent Stem Cells | Human | HiPSC ...

Charles A. Goldthwaite, Jr., Ph.D.

Cardiovascular disease (CVD), which includes hypertension, coronary heart disease (CHD), stroke, and congestive heart failure (CHF), has ranked as the number one cause of death in the United States every year since 1900 except 1918, when the nation struggled with an influenza epidemic.1 In 2002, CVD claimed roughly as many lives as cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, influenza, and pneumonia combined. According to data from the 19992002 National Health and Nutrition Examination Survey (NHANES), CVD caused approximately 1.4 million deaths (38.0 percent of all deaths) in the U.S. in 2002. Nearly 2600 Americans die of CVD each day, roughly one death every 34 seconds. Moreover, within a year of diagnosis, one in five patients with CHF will die. CVD also creates a growing economic burden; the total health care cost of CVD in 2005 was estimated at $393.5 billion dollars.

Given the aging of the U.S. population and the relatively dramatic recent increases in the prevalence of cardiovascular risk factors such as obesity and type 2 diabetes,2,3 CVD will continue to be a significant health concern well into the 21st century. However, improvements in the acute treatment of heart attacks and an increasing arsenal of drugs have facilitated survival. In the U.S. alone, an estimated 7.1 million people have survived a heart attack, while 4.9 million live with CHF.1 These trends suggest an unmet need for therapies to regenerate or repair damaged cardiac tissue.

Ischemic heart failure occurs when cardiac tissue is deprived of oxygen. When the ischemic insult is severe enough to cause the loss of critical amounts of cardiac muscle cells (cardiomyocytes), this loss initiates a cascade of detrimental events, including formation of a non-contractile scar, ventricular wall thinning (see Figure 6.1), an overload of blood flow and pressure, ventricular remodeling (the overstretching of viable cardiac cells to sustain cardiac output), heart failure, and eventual death.4 Restoring damaged heart muscle tissue, through repair or regeneration, therefore represents a fundamental mechanistic strategy to treat heart failure. However, endogenous repair mechanisms, including the proliferation of cardiomyocytes under conditions of severe blood vessel stress or vessel formation and tissue generation via the migration of bone-marrow-derived stem cells to the site of damage, are in themselves insufficient to restore lost heart muscle tissue (myocardium) or cardiac function.5 Current pharmacologic interventions for heart disease, including beta-blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors, and surgical treatment options, such as changing the shape of the left ventricle and implanting assistive devices such as pacemakers or defibrillators, do not restore function to damaged tissue. Moreover, while implantation of mechanical ventricular assist devices can provide long-term improvement in heart function, complications such as infection and blood clots remain problematic.6 Although heart transplantation offers a viable option to replace damaged myocardium in selected individuals, organ availability and transplant rejection complications limit the widespread practical use of this approach.

Figure 6.1. Normal vs. Infarcted Heart. The left ventricle has a thick muscular wall, shown in cross-section in A. After a myocardial infarction (heart attack), heart muscle cells in the left ventricle are deprived of oxygen and die (B), eventually causing the ventricular wall to become thinner (C).

2007 Terese Winslow

The difficulty in regenerating damaged myocardial tissue has led researchers to explore the application of embryonic and adult-derived stem cells for cardiac repair. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells, mesenchymal cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells (cells that give rise to the endothelium, the interior lining of blood vessels), and umbilical cord blood cells, have been investigated to varying extents as possible sources for regenerating damaged myocardium. All have been tested in mouse or rat models, and some have been tested in large animal models such as pigs. Preliminary clinical data for many of these cell types have also been gathered in selected patient populations.

However, clinical trials to date using stem cells to repair damaged cardiac tissue vary in terms of the condition being treated, the method of cell delivery, and the primary outcome measured by the study, thus hampering direct comparisons between trials.7 Some patients who have received stem cells for myocardial repair have reduced cardiac blood flow (myocardial ischemia), while others have more pronounced congestive heart failure and still others are recovering from heart attacks. In some cases, the patient's underlying condition influences the way that the stem cells are delivered to his/her heart (see the section, quot;Methods of Cell Deliveryquot; for details). Even among patients undergoing comparable procedures, the clinical study design can affect the reporting of results. Some studies have focused on safety issues and adverse effects of the transplantation procedures; others have assessed improvements in ventricular function or the delivery of arterial blood. Furthermore, no published trial has directly compared two or more stem cell types, and the transplanted cells may be autologous (i.e., derived from the person on whom they are used) or allogeneic (i.e., originating from another person) in origin. Finally, most of these trials use unlabeled cells, making it difficult for investigators to follow the cells' course through the body after transplantation (see the section quot;Considerations for Using These Stem Cells in the Clinical Settingquot; at the end of this article for more details).

Despite the relative infancy of this field, initial results from the application of stem cells to restore cardiac function have been promising. This article will review the research supporting each of the aforementioned cell types as potential source materials for myocardial regeneration and will conclude with a discussion of general issues that relate to their clinical application.

In 2001, Menasche, et.al. described the successful implantation of autologous skeletal myoblasts (cells that divide to repair and/or increase the size of voluntary muscles) into the post-infarction scar of a patient with severe ischemic heart failure who was undergoing coronary artery bypass surgery.8 Following the procedure, the researchers used imaging techniques to observe the heart's muscular wall and to assess its ability to beat. When they examined patients 5 months after treatment, they concluded that treated hearts pumped blood more efficiently and seemed to demonstrate improved tissue health. This case study suggested that stem cells may represent a viable resource for treating ischemic heart failure, spawning several dozen clinical studies of stem cell therapy for cardiac repair (see Boyle, et.al.7 for a complete list) and inspiring the development of Phase I and Phase II clinical trials. These trials have revealed the complexity of using stem cells for cardiac repair, and considerations for using stem cells in the clinical setting are discussed in a subsequent section of this report.

The mechanism by which stem cells promote cardiac repair remains controversial, and it is likely that the cells regenerate myocardium through several pathways. Initially, scientists believed that transplanted cells differentiated into cardiac cells, blood vessels, or other cells damaged by CVD.911 However, this model has been recently supplanted by the idea that transplanted stem cells release growth factors and other molecules that promote blood vessel formation (angiogenesis) or stimulate quot;residentquot; cardiac stem cells to repair damage.1214 Additional mechanisms for stem-cell mediated heart repair, including strengthening of the post-infarct scar15 and the fusion of donor cells with host cardiomyocytes,16 have also been proposed.

Regardless of which mechanism(s) will ultimately prove to be the most significant in stem-cell mediated cardiac repair, cells must be successfully delivered to the site of injury to maximize the restored function. In preliminary clinical studies, researchers have used several approaches to deliver stem cells. Common approaches include intravenous injection and direct infusion into the coronary arteries. These methods can be used in patients whose blood flow has been restored to their hearts after a heart attack, provided that they do not have additional cardiac dysfunction that results in total occlusion or poor arterial flow.12, 17 Of these two methods, intracoronary infusion offers the advantage of directed local delivery, thereby increasing the number of cells that reach the target tissue relative to the number that will home to the heart once they have been placed in the circulation. However, these strategies may be of limited benefit to those who have poor circulation, and stem cells are often injected directly into the ventricular wall of these patients. This endomyocardial injection may be carried out either via a catheter or during open-heart surgery.18

To determine the ideal site to inject stem cells, doctors use mapping or direct visualization to identify the locations of scars and viable cardiac tissue. Despite improvements in delivery efficiency, however, the success of these methods remains limited by the death of the transplanted cells; as many as 90% of transplanted cells die shortly after implantation as a result of physical stress, myocardial inflammation, and myocardial hypoxia.4 Timing of delivery may slow the rate of deterioration of tissue function, although this issue remains a hurdle for therapeutic approaches.

Embryonic and adult stem cells have been investigated to regenerate damaged myocardial tissue in animal models and in a limited number of clinical studies. A brief review of work to date and specific considerations for the application of various cell types will be discussed in the following sections.

Because ES cells are pluripotent, they can potentially give rise to the variety of cell types that are instrumental in regenerating damaged myocardium, including cardiomyocytes, endothelial cells, and smooth muscle cells. To this end, mouse and human ES cells have been shown to differentiate spontaneously to form endothelial and smooth muscle cells in vitro19 and in vivo,20,21 and human ES cells differentiate into myocytes with the structural and functional properties of cardiomyocytes.2224 Moreover, ES cells that were transplanted into ischemically-injured myocardium in rats differentiated into normal myocardial cells that remained viable for up to four months,25 suggesting that these cells may be candidates for regenerative therapy in humans.

However, several key hurdles must be overcome before human ES cells can be used for clinical applications. Foremost, ethical issues related to embryo access currently limit the avenues of investigation. In addition, human ES cells must go through rigorous testing and purification procedures before the cells can be used as sources to regenerate tissue. First, researchers must verify that their putative ES cells are pluripotent. To prove that they have established a human ES cell line, researchers inject the cells into immunocompromised mice; i.e., mice that have a dysfunctional immune system. Because the injected cells cannot be destroyed by the mouse's immune system, they survive and proliferate. Under these conditions, pluripotent cells will form a teratoma, a multi-layered, benign tumor that contains cells derived from all three embryonic germ layers. Teratoma formation indicates that the stem cells have the capacity to give rise to all cell types in the body.

The pluripotency of ES cells can complicate their clinical application. While undifferentiated ES cells may possibly serve as sources of specific cell populations used in myocardial repair, it is essential that tight quality control be maintained with respect to the differentiated cells. Any differentiated cells that would be used to regenerate heart tissue must be purified before transplantation can be considered. If injected regenerative cells are accidentally contaminated with undifferentiated ES cells, a tumor could possibly form as a result of the cell transplant.4 However, purification methodologies continue to improve; one recent report describes a method to identify and select cardiomyocytes during human ES cell differentiation that may make these cells a viable option in the future.26

This concern illustrates the scientific challenges that accompany the use of all human stem cells, whether derived from embryonic or adult tissues. Predictable control of cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization. Furthermore, long-term cell stability must be well understood before human ES-derived cells can be used in regenerative medicine. The propensity for genetic mutation in the human ES cells must be determined, and the survival of differentiated, ES-derived cells following transplantation must be assessed. Furthermore, once cells have been transplanted, undesirable interactions between the host tissue and the injected cells must be minimized. Cells or tissues derived from ES cells that are currently available for use in humans are not tissue-matched to patients and thus would require immunosuppression to limit immune rejection.18

While skeletal myoblasts (SMs) are committed progenitors of skeletal muscle cells, their autologous origin, high proliferative potential, commitment to a myogenic lineage, and resistance to ischemia promoted their use as the first stem cell type to be explored extensively for cardiac application. Studies in rats and humans have demonstrated that these cells can repopulate scar tissue and improve left ventricular function following transplantation.27 However, SM-derived cardiomyocytes do not function in complete concert with native myocardium. The expression of two key proteins involved in electromechanical cell integration, N-cadherin and connexin 43, are downregulated in vivo,28 and the engrafted cells develop a contractile activity phenotype that appears to be unaffected by neighboring cardiomyocytes.29

To date, the safety and feasibility of transplanting SM cells have been explored in a series of small studies enrolling a collective total of nearly 100 patients. Most of these procedures were carried out during open-heart surgery, although a couple of studies have investigated direct myocardial injection and transcoronary administration. Sustained ventricular tachycardia, a life-threatening arrhythmia and unexpected side-effect, occurred in early implantation studies, possibly resulting from the lack of electrical coupling between SM-derived cardiomyocytes and native tissue.30,31 Changes in preimplantation protocols have minimized the occurrence of arrhythmias in conjunction with the use of SM cells, and Phase II studies of skeletal myoblast therapy are presently underway.

In 2001, Jackson, et.al. demonstrated that cardiomyocytes and endothelial cells could be regenerated in a mouse heart attack model through the introduction of adult mouse bone marrow-derived stem cells.9 That same year, Orlic and colleagues showed that direct injection of mouse bone marrow-derived cells into the damaged ventricular wall following an induced heart attack led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells.11 Nine days after transplanting the stem cells, the newly-formed myocardium occupied nearly 70 percent of the damaged portion of the ventricle, and survival rates were greater in mice that received these cells than in those that did not. While several subsequent studies have questioned whether these cells actually differentiate into cardiomyocytes,32,33 the evidence to support their ability to prevent remodeling has been demonstrated in many laboratories.7

Based on these findings, researchers have investigated the potential of human adult bone marrow as a source of stem cells for cardiac repair. Adult bone marrow contains several stem cell populations, including hematopoietic stem cells (which differentiate into all of the cellular components of blood), endothelial progenitor cells, and mesenchymal stem cells; successful application of these cells usually necessitates isolating a particular cell type on the basis of its' unique cell-surface receptors. In the past three years, the transplantation of bone marrow mononuclear cells (BMMNCs), a mixed population of blood and cells that includes stem and progenitor cells, has been explored in more patients and clinical studies of cardiac repair than any other type of stem cell.7

The results from clinical studies of BMMNC transplantation have been promising but mixed. However, it should be noted that these studies have been conducted under a variety of conditions, thereby hampering direct comparison. The cells have been delivered via open-heart surgery and endomyocardial and intracoronary catheterization. Several studies, including the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) and the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trials, have shown that intracoronary infusion of BMMNCs following a heart attack significantly improves the left ventricular (LV) ejection fraction, or the volume of blood pumped out of the left ventricle with each heartbeat.3436 However, other studies have indicated either no improvement in LV ejection fraction upon treatment37 or an increased LV ejection fraction in the control group.38 An early study that used endomyocardial injection to enhance targeted delivery indicated a significant improvement in overall LV function.39 Discrepancies such as these may reflect differences in cell preparation protocols or baseline patient statistics. As larger trials are developed, these issues can be explored more systematically.

Mesenchymal stem cells (MSCs) are precursors of non-hematopoietic tissues (e.g., muscle, bone, tendons, ligaments, adipose tissue, and fibroblasts) that are obtained relatively easily from autologous bone marrow. They remain multipotent following expansion in vitro, exhibit relatively low immunogenicity, and can be frozen easily. While these properties make the cells amenable to preparation and delivery protocols, scientists can also culture them under special conditions to differentiate them into cells that resemble cardiac myocytes. This property enables their application to cardiac regeneration. MSCs differentiate into endothelial cells when cultured with vascular endothelial growth factor40 and cardiomyogenic (CMG) cells when treated with the dna-demethylating agent, 5-azacytidine.41 More important, however, is the observation that MSCs can differentiate into cardiomyocytes and endothelial cells in vivo when transplanted to the heart following myocardial infarct (MI) or non-injury in pig, mouse, or rat models.4245 Additionally, the ability of MSCs to restore functionality may be enhanced by the simultaneous transplantation of other stem cell types.43

Several animal model studies have shown that treatment with MSCs significantly increases myocardial function and capillary formation.5,41 One advantage of using these cells in human studies is their low immunogenicity; allogeneic MSCs injected into infarcted myocardium in a pig model regenerated myocardium and reduced infarct size without evidence of rejection.46 A randomized clinical trial implanting MSCs after MI has demonstrated significant improvement in global and regional LV function,47 and clinical trials are currently underway to investigate the application of allogeneic and autologous MSCs for acute MI and myocardial ischemia, respectively.

Recent evidence suggests that the heart contains a small population of endogenous stem cells that most likely facilitate minor repair and turnover-mediated cell replacement.7 These cells have been isolated and characterized in mouse, rat, and human tissues.48,49 The cells can be harvested in limited quantity from human endomyocardial biopsy specimens50 and can be injected into the site of infarction to promote cardiomyocyte formation and improvements in systolic function.49 Separation and expansion ex vivo over a period of weeks are necessary to obtain sufficient quantities of these cells for experimental purposes. However, their potential as a convenient resource for autologous stem cell therapy has led the National Heart, Lung, and Blood Institute to fund forthcoming clinical trials that will explore the use of cardiac stem cells for myocardial regeneration.

The endothelium is a layer of specialized cells that lines the interior surface of all blood vessels (including the heart). This layer provides an interface between circulating blood and the vessel wall. Endothelial progenitor cells (EPCs) are bone marrow-derived stem cells that are recruited into the peripheral blood in response to tissue ischemia.4 EPCs are precursor cells that express some cell-surface markers characteristic of mature endothelium and some of hematopoietic cells.19,5153 EPCs home in on ischemic areas, where they differentiate into new blood vessels; following a heart attack, intravenously injected EPCs home to the damaged region within 48 hours.12 The new vascularization induced by these cells prevents cardiomyocyte apoptosis (programmed cell death) and LV remodeling, thereby preserving ventricular function.13 However, no change has been observed in non-infarcted regions upon EPC administration. Clinical trials are currently underway to assess EPC therapy for growing new blood vessels and regenerating myocardium.

Several other cell populations, including umbilical cord blood (UCB) stem cells, fibroblasts (cells that synthesize the extracellular matrix of connective tissues), and peripheral blood CD34+ cells, have potential therapeutic uses for regenerating cardiac tissue. Although these cell types have not been investigated in clinical trials of heart disease, preliminary studies in animal models indicate several potential applications in humans.

Umbilical cord blood contains enriched populations of hematopoietic stem cells and mesencyhmal precursor cells relative to the quantities present in adult blood or bone marrow.54,55 When injected intravenously into the tail vein in a mouse model of MI, human mononuclear UCB cells formed new blood vessels in the infarcted heart.56 A human DNA assay was used to determine the migration pattern of the cells after injection; although they homed only to injured areas within the heart, they were also detected in the marrow, spleen, and liver. When injected directly into the infarcted area in a rat model of MI, human mononuclear UCB cells improved ventricular function.57 Staining for CD34 and other markers found on the cell surface of hematopoietic stem cells indicated that some of the cells survived in the myocardium. Results similar to these have been observed following the injection of human unrestricted somatic stem cells from UCB into a pig MI model.58

Adult peripheral blood CD34+ cells offer the advantage of being obtained relatively easily from autologous sources.59 Although some studies using a mouse model of MI claim that these cells can transdifferentiate into cardiomyocytes, endothelial cells, and smooth muscle cells at the site of tissue injury,60 this conclusion is highly contested. Recent studies that involve the direct injection of blood-borne or bone marrow-derived hematopoietic stem cells into the infarcted region of a mouse model of MI found no evidence of myocardial regeneration following injection of either cell type.33 Instead, these hematopoietic stem cells followed traditional differentiation patterns into blood cells within the microenvironment of the injured heart. Whether these cells will ultimately find application in myocardial regeneration remains to be determined.

Autologous fibroblasts offer a different strategy to combat myocardial damage by replacing scar tissue with a more elastic, muscle-like tissue and inhibiting host matrix degradation.4 The cells may be manipulated to express muscle-specific transcription factors that promote their differentiation into myotubes such as those derived from skeletal myoblasts.61 One month after these cells were implanted into the post-infarction scar in a rat model of MI, they occupied a large portion of the scar but were not functionally integrated.61 Although the effects on ventricular function were not evaluated in this study, authors noted that modified autologous fibroblasts may ultimately prove useful in elderly patients who have a limited population of autologous skeletal myoblasts or bone marrow stem cells.

As these examples indicate, many types of stem cells have been applied to regenerate damaged myocardium. In select applications, stem cells have demonstrated sufficient promise to warrant further exploration in large-scale, controlled clinical trials. However, the current breadth of application of these cells has made it difficult to compare and contextualize the results generated by the various trials. Most studies published to date have enrolled fewer than 25 patients, and the studies vary in terms of cell types and preparations used, methods of delivery, patient populations, and trial outcomes. However, the mixed results that have been observed in these studies do not necessarily argue against using stem cells for cardiac repair. Rather, preliminary results illuminate the many gaps in understanding of the mechanisms by which these cells regenerate myocardial tissue and argue for improved characterization of cell preparations and delivery methods to support clinical applications.

Future clinical trials that use stem cells for myocardial repair must address two concerns that accompany the delivery of these cells: 1) safety and 2) tracking the cells to their ultimate destination(s). Although stem cells appear to be relatively safe in the majority of recipients to date, an increased frequency of non-sustained ventricular tachycardia, an arrhythmia, has been reported in conjunction with the use of skeletal myoblasts.30,6264 While this proarrhythmic effect occurs relatively early after cell delivery and does not appear to be permanent, its presence highlights the need for careful safety monitoring when these cells are used. Additionally, animal models have demonstrated that stem cells rapidly diffuse from the heart to other organs (e.g., lungs, kidneys, liver, spleen) within a few hours of transplantation,65,66 an effect observed regardless of whether the cells are injected locally into the myocardium. This migration may or may not cause side-effects in patients; however, it remains a concern related to the delivery of stem cells in humans. (Note: Techniques to label stem cells for tracking purposes and to assess their safety are discussed in more detail in other articles in this publication).

In addition to safety and tracking, several logistical issues must also be addressed before stem cells can be used routinely in the clinic. While cell tracking methodologies allow researchers to determine migration patterns, the stem cells must target their desired destination(s) and be retained there for a sufficient amount of time to achieve benefit. To facilitate targeting and enable clinical use, stem cells must be delivered easily and efficiently to their sites of application. Finally, the ease by which the cells can be obtained and the cost of cell preparation will also influence their transition to the clinic.

The evidence to date suggests that stem cells hold promise as a therapy to regenerate damaged myocardium. Given the worldwide prevalence of cardiac dysfunction and the limited availability of tissue for cardiac transplantation, stem cells could ultimately fulfill a large-scale unmet clinical need and improve the quality of life for millions of people with CVD. However, the use of these cells in this setting is currently in its infancymuch remains to be learned about the mechanisms by which stem cells repair and regenerate myocardium, the optimal cell types and modes of their delivery, and the safety issues that will accompany their use. As the results of large-scale clinical trials become available, researchers will begin to identify ways to standardize and optimize the use of these cells, thereby providing clinicians with powerful tools to mend a broken heart.

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Mending a Broken Heart: Stem Cells and Cardiac Repair ...

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This is a phase II, randomized, placebo-controlled clinical trial designed to assess feasibility, safety, and effect of autologous bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) both alone and in combination (Combo), compared to placebo (cell-free Plasmalyte-A medium) as well as each other, administered by transendocardial injection in subjects with ischemic cardiomyopathy.

This is a randomized, placebo-controlled clinical trial designed to evaluate the feasibility, safety, and effect of Combo, MSCs alone, and CSCs alone compared with placebo as well as each other in subjects with heart failure of ischemic etiology. Following a successful lead-in phase, a total of one hundred forty-four (144) subjects will be randomized (1:1:1:1) to receive Combo, MSCs, CSCs, or placebo. After randomization, baseline imaging, relevant harvest procedures, and study product injection, subjects will be followed up at 1 day, 1 week, 1 month, 3 months, 6 months and 12 months post study product injection. All subjects will receive study product injection (cells or placebo) using the NOGA XP Mapping and Navigation System. Subjects will have delayed-enhanced magnetic resonance imaging (DEMRI) scans to assess scar size and LV function and structure at baseline and at 6 and 12 months post study product administration. All endpoints will be assessed at the 6 and 12 month visits which will occur 180 30 days and 365 30 days respectively from the day of study product injection (Day 0). For the purpose of the endpoint analysis and safety evaluations, the Investigators will utilize an "intention-to-treat" study population, however an as treated analysis will also be conducted.

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Combination of Mesenchymal and C-kit+ Cardiac Stem Cells ...

To determine why the first stem cell trials were not providing the anticipated therapeutic potential, all variables, such as which stem cells were used, and how they were developed and administered, were open to consideration, says Dr. Epstein.

A key issue was the use of autologous stem cells in all previous studies. Studies demonstrated these old stem cells are functionally defective when compared to stem cells obtained from young healthy individuals. So harvesting a healthy young donors bone marrow and growing the resident stem cells might produce more robust cells.

However, giving a patient allogenic stem cells raised an important issue: whether such cells will be rejected by an immune response. But research showed mesenchymal stem cells (MSCs), a type of adult stem cell, have been designed by nature to be stealth bombers, explainsDr. Epstein. They express molecules on their surface that prevent the body from recognizing the cells as foreign, so the patient does not reject the donated MSCs.

To further explore and refine potential stem cell cardiovascular therapies, MHVI expanded the translational research team to include Michael Lipinski, MD, PhD, an expert in molecular biology and scientific lead for preclinical research at the MedStar Cardiovascular Research Network, and Dror Luger, PhD, an expert in immunology and inflammatory responses. By bringing together these diverse areas of expertise, we forged a team with the potential to produce research that could lead to important breakthroughs in understanding how stem cells might work and thereby provide more successful treatment of patients with cardiac disease, says Dr. Epstein.

CardioCell, a San Diego-based stem cell company focused on stem cell therapy for cardiovascular disease, found that MSCs grew faster and showed improved function when cultured in a reduced oxygen environment. Stem cells typically grow in the body, in bone marrow and other tissues, in a low oxygen environmentonly five percent oxygen, as opposed to room air, which is about 20 percent, explains Dr. Lipinski. All previous stem cell trials used cells exposed to, and grown under, room air oxygen conditions.

Using CardioCells low oxygen-grown MSCs, the MHVI scientists demonstrated biologically important effects occurred, even when the MSCs were administered intravenously. This mode of administration was previously rejected by scientists who thought cells would be trapped in the first capillary bed they traversedthe lungsand never reach the heart.

However, the MHVI team demonstrated a small percentage of these IV administered MSCs did reach the heart, where they could exert beneficial effects. The cells seek out inflamed cardiac tissue after a heart attack because they upregulate receptors that allow them to be attracted to and penetrate inflamed tissue in high numbers, says Dr. Luger.

The investigators also found the cells residing in other tissues could provide other benefits. It has been shown that a heart attack activates the immune and inflammatory systems, including those in the spleen, explains Dr. Luger. The systemic anti-inflammatory effects produced by MSCs in the spleen, lungs and other tissues caused by the molecules secreted by the MSCs could exert positive effects as well. Dr. Epstein added that such anti-inflammatory effects could also benefit the excessive inflammatory activities that exist in many heart failure patients.

For the clinical heart failure trial, MHVI is partnering with CardioCell, which will grow and provide stem cells already used in Phase I and 2a clinical trials and approved by the Food and Drug Administration.

As an extension of their stem cell work, the MHVI investigators are building on the fact that any beneficial effect of adult stem cells will not derive from their transformation into heart muscle, but rather from the molecules they secrete; these, in turn, stimulate pathways favoring tissue healing. The team is investigating the use of liposomes as therapeutic delivery vehicles for these secreted products, which include those with anti-inflammatory and angiogenesis activities.

If successful, using MSCs for anti-inflammatory and immune-modulatory effects could have implicationsfor many different diseases, including arthritis and autoimmune diseases like rheumatoid arthritis. Dr. Epstein cautions that a great deal of research is yet to be done before such applications can be routinely used to treat patients with these conditions. For now, they hope the current studies in heart failure patients will demonstrate effectiveness. If so, Dr. Epstein says, it changes the whole playing field for stem cells.

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Next Steps for Cardiac Stem Cells - MedStar Heart ...

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On a June day in 2009, a 39-year-old man named Ken Milles lay on an exam table at Cedars-Sinai Medical Center in Los Angeles. A month earlier, he'd suffered a massive heart attack that destroyed nearly a third of his heart.

"The most difficult part was the uncertainty," he recalls. "Your heart is 30% damaged, and they tell you this could affect you the rest of your life." He was about to receive an infusion of stem cells, grown from cells taken from his own heart a few weeks earlier. No one had ever tried this before.

About three weeks later, in Kentucky, a patient named Mike Jones underwent a similar procedure at the University of Louisville's Jewish Hospital. Jones suffered from advanced heart failure, the result of a heart attack years earlier. Like Milles, he received an infusion of stem cells, grown from his own heart tissue.

"Once you reach this stage of heart disease, you don't get better," says Dr. Robert Bolli, who oversaw Jones' procedure, explaining what doctors have always believed and taught. "You can go down slowly, or go down quickly, but you're going to go down."

Conventional wisdom took a hit Monday, as Bolli's group and a team from Cedars-Sinai each reported that stem cell therapies were able to reverse heart damage, without dangerous side effects, at least in a small group of patients.

In Bolli's study, published in The Lancet, 16 patients with severe heart failure received a purified batch of cardiac stem cells. Within a year, their heart function markedly improved. The heart's pumping ability can be quantified through the "Left Ventricle Ejection Fraction," a measure of how much blood the heart pumps with each contraction. A patient with an LVEF of less than 40% is considered to suffer severe heart failure. When the study began, Bolli's patients had an average LVEF of 30.3%. Four months after receiving stem cells, it was 38.5%. Among seven patients who were followed for a full year, it improved to an astounding 42.5%. A control group of seven patients, given nothing but standard maintenance medications, showed no improvement at all.

"We were surprised by the magnitude of improvement," says Bolli, who says traditional therapies, such as placing a stent to physically widen the patient's artery, typically make a smaller difference. Prior to treatment, Mike Jones couldn't walk to the restroom without stopping for breath, says Bolli. "Now he can drive a tractor on his farm, even play basketball with his grandchildren. His life was transformed."

At Cedars-Sinai, 17 patients, including Milles, were given stem cells approximately six weeks after suffering a moderate to major heart attack. All had lost enough tissue to put them "at big risk" of future heart failure, according to Dr. Eduardo Marban, the director of the Cedars-Sinai Heart Institute, who developed the stem cell procedure used there.

The results were striking. Not only did scar tissue retreat -- shrinking 40% in Ken Milles, and between 30% and 47% in other test subjects -- but the patients actually generated new heart tissue. On average, the stem cell recipients grew the equivalent of 600 million new heart cells, according to Marban, who used MRI imaging to measure changes. By way of perspective, a major heart attack might kill off a billion cells.

"This is unprecedented, the first time anyone has grown living heart muscle," says Marban. "No one else has demonstrated that. It's very gratifying, especially when the conventional teaching has been that the damage is irreversible."

Perhaps even more important, no treated patient in either study suffered a significant health setback.

The twin findings are a boost to the notion that the heart contains the seeds of its own rebirth. For years, doctors believed that heart cells, once destroyed, were gone forever. But in a series of experiments, researchers including Bolli's collaborator, Dr. Piero Anversa, found that the heart contains a type of stem cell that can develop into either heart muscle or blood vessel components -- in essence, whatever the heart requires at a particular point in time. The problem for patients like Mike Jones or Ken Milles is that there simply aren't enough of these repair cells waiting around. The experimental treatments involve removing stem cells through a biopsy, and making millions of copies in a laboratory.

The Bolli/Anversa group and Marban's team both used cardiac stem cells, but Bolli and Anversa "purified" the CSCs, so that more than 90% of the infusion was actual stem cells. Marban, on the other hand, used a mixture of stem cells and other types of cells extracted from the patient's heart. "We've found that the mixture is more potent than any subtype we've been able to isolate," he says. He says the additional cells may help by providing a supportive environment for the stem cells to multiply.

Other scientists, including Dr. Douglas Losordo, have produced improvements in cardiac patients using stem cells derived from bone marrow. "The body contains cells that seem to be pre-programmed for repair," explains Losordo. "The consistent thing about all these approaches is that they're leveraging what seems to be the body's own repair mechanism."

Losordo praised the Lancet paper, and recalls the skepticism that met Anversa's initial claims, a decade ago, that there were stem cells in the adult heart. "Some scientists are always resistant to that type of novelty. You know the saying: First they ignore you, then they attack you and finally they imitate you."

Denis Buxton, who oversees stem cell research at the National Heart, Lung and Blood Institute at the National Institutes of Health, calls the new studies "a paradigm shift, harnessing the heart's own regenerative processes." But he says he would like to see more head-to-head comparisons to determine which type of cells are most beneficial.

Questions also remain about timing. Patients who suffer large heart attacks are prone to future damage, in part because the weakened heart tries to compensate by dilating -- swelling -- and by changing shape. In a vicious circle, the changes make the heart a less efficient pump, which leads to more overcompensation, and so on, until the end result is heart failure. Marban's study aimed to treat patients before they could develop heart failure in the first place.

In a third study released Monday, researchers treated patients with severe heart failure with stem cells derived from bone marrow. In a group of 60 patients, those receiving the treatment had fewer heart problems over the course of a year, as well as improved heart function.

A fourth study also used cells derived from bone marrow, but injected them into patients two to three weeks after a heart attack. Previous studies, with the cells given just days afterward, found a modest improvement in heart function. But Monday, the lead researcher, Dr. Dan Simon of UH Case Medical Center, reported that with the three-week delay, patients did not see the same benefit.

With other methods, there may be a larger window of opportunity. At least in initial studies, Losordo's bone marrow treatments helped some patients with long-standing heart problems. Bolli's Lancet paper suggests that CSCs, too, might help patients with advanced disease. "These patients had had heart failure for several years. They were a wreck!" says Bolli. "But we found their stem cells were still very competent." By that, he means the cells were still capable of multiplying and of turning into useful muscle and blood vessel walls.

Marban has an open mind on the timing issue. In fact, one patient from his control group e-mailed after the study was complete, saying he felt terrible and pleading for an infusion of stem cells. At Marban's request, the FDA granted special approval to treat him. "He had a very nice response. That was 14 months after his heart attack. Of course that's just one person, and we need bigger studies," says Marban.

For Ken Milles, the procedure itself wasn't painful, but it was unsettling. The biopsy to harvest the stem cells felt "weird," he recalls, as he felt the doctor poking around inside his heart. The infusion, a few weeks later, was harder. The procedure -- basically the same as an angioplasty -- involved stopping blood flow through the damaged artery for three minutes, while the stem cells were infused. "It felt exacfly like I was having a heart attack again," Milles remembers.

Milles had spent the first weeks after his heart attack just lying in bed re-watching his "Sopranos" DVDs, but within a week of the stem cell infusion, he says, "I was reinvigorated." Today he's back at work full time, as an accounting manager at a construction company. He's cut out fast food and shed 50 pounds. His wife and two teenage sons are thrilled.

Denis Buxton says the new papers could prove a milestone. "We don't have anything else to actually regenerate the heart. These stem cell therapies have the possibility of actually reversing damage."

Bolli says he'll have to temper his enthusiasm until he can duplicate the results in larger studies, definitive enough to get stem cell therapy approved as a standard treatment. "If a phase 3 study confirmed this, it would be the biggest advance in cardiology in my lifetime. We would possibly be curing heart failure. It would be a revolution."

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Studies: Stem cells reverse heart damage - CNN

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Video abstract from Drs. Banerjee, Surendran, Bharti, Morishita, Varshney, and Pal on their recently published STEM CELLS paper entitled, "Long non-coding RNA RP11-380D23.2 drives distal-proximal patterning of the lung by regulating PITX2 expression." Read the paper here.

Video abstract from Drs. Sayed, Ospino, Himmati, Lee, Chanda, Mocarski, and Cooke on their recently published STEM CELLS paper entitled, "Retinoic Acid Inducible Gene 1 Protein (RIG1)-like Receptor Pathway is Required for Efficient Nuclear Reprogramming." Read the paper here.

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STEM CELLS - Issue - Wiley Online Library

Nearly 500,000 people in the US die of sudden cardiac death each year, and long QT syndrome (LQTS) is a major form of sudden cardiac death. LQTS can be triggered by drug exposure or stresses. Drug-induced LQTS is the single most common reason for drugs to be withdrawn from clinical trials, causing major setbacks to drug discovery efforts and exposing people to dangerous drugs. In most cases, the mechanism of drug-induced LQTS is unknown. However, there are genetic forms of LQTS that should allow us to make iPS cellderived heart cells that have the key features of LQTS. Our objective is to produce a cell-based test for LQTS with induced pluripotent stem (iPS) cell technology, which allows adult cells to be reprogrammed to be stem celllike cells.Despite the critical need, current tests for drug-induced LQTS are far from perfect. As a result, potentially unsafe drugs enter clinical trials, endangering people and wasting millions of dollars in research funds. When drugs that cause LQTS, such as terfenadine (Seldane), enter the market, millions of people are put at serious risk. Unfortunately, it is very difficult to know when a drug will cause LQTS, since most people who develop LQTS have no known genetic risk factors. The standard tests for LQTS use animal models or hamster cells that express human heart genes at high levels. Unfortunately, cardiac physiology in animal models (rabbits and dogs) differs from that in humans, and hamster cells lack many key features of human heart cells. Human embryonic stem cells (hESCs) can be differentiated into heart cells, but we do not know the culture conditions that would make the assay most similar to LQTS in a living person. These problems could be solved if we had a method to grow human heart cells from people with genetic LQTS mutations, so that we know the exact test conditions that would reflect the human disease. This test would be much more accurate than currently available tests and would help enable the development of safer human pharmaceuticals.Our long-term goal is to develop a panel of iPS cell lines that better represent the genetic diversity of the human population. Susceptibility to LQTS varies, and most people who have life-threatening LQTS have no known genetic risk factors. We will characterize iPS cells with well-defined mutations that have clinically proven responses to drugs that cause LQTS. These iPS cell lines will be used to refine testing conditions. To validate the iPS cellbased test, the results will be directly compared to the responses in people. These studies will provide the foundation for an expanded panel of iPS cell lines from people with other genetic mutations and from people who have no genetically defined risk factor but still have potentially fatal drug-induced LQTS. This growing panel of iPS cell lines should allow for testing drugs for LQTS more effectively and accurately than any current test.To meet these goals, we made a series of iPS cells that harbor different LQTS mutations. These iPS cells differentiate into beating cardiomyocytes. We are now evaluating these LQTS cell lines in cellular assays. We are hopeful that our studies will meet or exceed all the aims of our original proposal.

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Induced Pluripotent Stem Cells for Cardiovascular ...

In this project, we aim to develop a 3D bioprinting technology to create functional cardiac tissues via encapsulation of cardiomyocytes derived from hESCs. To further improve their viability and cardiac functionality, we are developing a new vascularization technique to enhance the cardiac tissue model through the incorporation of functional vasculature using 3D bioprinting. In Specific Aim 1, we have successfully developed and optimized a rapid 3D bioprinting technique to create biomimetic 3D micro-architectures using hyaluronic acid (HA)-based biomaterials and hESC-derived cardiomyocytes. A protocol for the synthesis of the photopolymeriable hydrogel biomaterial (hyaluronic acid-glycidyl methacrylate (HA-GM)) proposed for use with the 3D bioprinting platform has been created and refined. HA-GM chemical synthesis efficiency was evaluated. H7 human embryonic stem cells (hESC) were used. These hESC derived cardiomyoctes (hESC-CMs) were shown to be well differentiated based on examining surface markers (Nkx2.5 & cardiac troponin T) and mRNA expression (Nkx2.5, ISL1, MYL2, and MYL7). These cells have been encapsulated within a 3D vasculature pattern of photopolymerized HA-GM hydrogel biomaterial. Digital images derived from a 3D model of the heart have been printed and the direct printing of biomaterials and cell-laden materials has been successfully achieved. Fluorescent staining showed encapsulated cell survival of this structure after 2-weeks of incubation. We have successfully measured the physiological function of cells embedded within the hydrogel constructs. We assessed changes in the cell viability, alignment and function of cells within hydrogel constructs. We successfully characterized electrical function of cardiomyocytes by optical mapping of Spontaneous Beats in unpatterned and patterned tissue constructs. We further measured mechanical function in the tissue constructs by cantilever displacement. We have also measured calcium transients in our 3D printed tissue constructs by live confocal imaging at varying frequencies. In Specific Aim 2, we have created an advanced vascularization technique for 3D pre-vascularized cardiac tissues with precise control of spatial organization. Human umbilical vein endothelial cells (HUVECs) were encapsulated within a mesh of hexagonal channels and cardiomyocytes were encapsulated within islands between these channels to demonstrate the capability of spatially printing distinct cell populations into a simple prevascularized co-culture model. Cells in this bioprinted configuration showed proliferation and viability. To investigate the formation of the endothelial network, we performed immunofluorescence staining on the prevascularized tissues after 1-week culture in vitro. Human-specific CD31 staining (green) in confocal microscopy shows the conjunctive network formation of HUVECs at different patterned channel widths.

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Development of 3D Bioprinting Techniques using Human ...

Stem cell can be isolated from the the bone marrow and adipose tissue in the abdomen that are capable of forming new blood vessels and heart muscle cells. The cell number is so small in the tissues that the cells should be grown for several weeks before there is enough for the treatment of patients.

We have conducted three clinical stem cell therapy studies in which patients with coronary artery disease havebeen treated with their own mesenchymal stem cells from either the bone marrow or adipose tissue. Encouraging results are available from two studies and there is ongoing follow-up in the third study. Treatments with stem cells have in all previous studies been without any side effects.

During the course of the SCIENCE study a total of 138 patients with heart failure will be included and treated in a so-called blinded placebo-controlled design. This means that 92 patients will receive stem cells and 46 patients placebo (inactive medication, saline). Choice of treatment will be done by drawing lots. The study is carried out by an international collaboration between cardiac centers in Denmark, Poland, Germany, Netherlands, Austria and Sloveniaand the industrial partners Terumo BCT and COOK Tegentec.

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Disease Team Award DR1-01461, autologous cardiac-derived cells for advanced ischemic cardiomyopathy, is targeted at developing novel therapies for the treatment of heart failure, a condition which afflicts 7 million Americans. Heart failure, when symptomatic, has a mortality exceeding that of many malignant tumors; new therapies are desperately needed. In the second year of CIRM support, pivotal pre-clinical studies have been completed. We have found that dose-optimized injection of CSps preserves systolic function, attenuates remodeling, decreases scar size and increases viable myocardium in a porcine model of ischemic cardiomyopathy. The 3D microtissues engraft efficiently in preclinical models of heart failure, as expected from prior work indicating their complex multi-layer nature combining cardiac progenitors, supporting cells and derivatives into the cardiomyocyte and endothelial lineages. Analysis of the MRI data continues. We have developed standard operating procedures for cardiosphere manufacturing and release criteria, product and freezing/thawing stability testing have been completed for the 3D microtissue development candidate. We have identified two candidate potency assays for future development. The disease team will evaluate the results of the safety study (immunology, histology, and markers of ischemic injury) and complete the pivotal pig study in Q1 2012. With data in hand, full efforts will be placed on preparation of the IND for Q2 2012 submission.

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Autologous cardiac-derived cells for advanced ischemic ...

This project aims to demonstrate both safety and efficacy of a heart-derived cell product in patients who have experienced a heart attack either recently or in the past by conducting a mid-stage (Phase II) clinical trial. The cell product is manufactured using heart tissue obtained from a healthy donor and can be used in most other individuals. Its effect is thought to be long-lasting (months-years) although it is expected to be cleared from the body relatively quickly (weeks-months). Treatment is administered during a single brief procedure, requiring a local anesthetic and insertion of a tube (or catheter) into the heart. The overriding goal for the product is to prevent patients who have had a heart attack from deteriorating over time and developing heart failure, a condition which is defined by the hearts inability to pump blood efficiently and one which affects millions of Americans. At the outset of the project, a Phase I trial was underway. The Phase II trial was initiated at the beginning of the current reporting period, and all subjects enrolled in Phase I completed follow up during the current reporting period. Fourteen patients were treated with the heart-derived cell product as part of Phase I. The safety endpoint for the trial was pre-defined and took into consideration the following: inflammation in the heart accompanied by an immune response, death due to abnormal heart rhythms, sudden death, repeat heart attack, treatment for symptoms of heart failure, need for a heart assist device, and need for a heart transplant. Both an independent Data and Safety Monitoring Board (DSMB) and CIRM agreed that Phase I met its safety endpoint. Preliminary efficacy data from Phase I collected during the current reporting period showed evidence of improvements in scar size, a measure of damage in the heart, and ejection fraction, a measure of the hearts ability to pump blood. At the end of the current reporting period, Phase II is still enrolling subjects and clinical trial sites are still being brought on for participation in the trial. Meanwhile, the manufacturing processes established continue to be employed to create cell products for use in Phase II. Manufacturing data and trial status updates were also provided to the Food and Drug Administration (FDA) as part of standard annual reporting.

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Allogeneic Cardiac-Derived Stem Cells for Patients ...

As their name suggests, embryonic stem cells (ESCs) are stem cells that are derived from embryos. If we wanted to be more scientific, we would say that ESCs are pluripotent stem cells derived from a blastocyst, an embryo in a very early stage (4-5 days of age).A blastocyst is consisted of 50-150 cells. ESCs measure approximately 14m in diameter.

The use of human embryonic stem cells is highly controversial, as their extraction requires the destruction of a human embryo, raising a great number of ethical issues. The main one is whether a blastocyst can be considered a living person or not. Check our article, Stem Cell Controversy for more info on this topic

Embryonic Stem cell propertiesThere are two important attributes that distinguish stem cells from any other typical cell:

Embryonic stem cells are pluripotent, having the capacity to differentiate and develop into almost all kinds of cells belonging to thethree primary germ layers:

As for self-renewal, ES cells have the capacity to replicate indefinitely. In other words they have the ability, under the proper conditions, to produce infinite numbers of daughter cells just from one or a few father cells.

Human Embryonic Stem Cell Extraction And CultureFirst the inner cell mass (ICM) of the blastocyst is separated from the trophectoderm. Then the cells of the ICM are placed on aplastic laboratory culture dish that contains a nutrient broth called the "culture medium".Typically the inner surface of the dish is coated with what is called a "feeder layer", consisting of reprogrammed embryonic mouse skin cells that don't divide. These mouse cells lay in the bottom of the dish and act as a support for the hESCs. The feeder layer not only provides support, but it also releases all the needed nutrients for thehESCs to grow and replicate. Recently, scientists have devised new ways for culturing hESCs without the need of a mouse feeder cell, a really important advance as there is always the danger of viruses being transmitted from the mouse cells to the human embryonic stem cells.

It should be noted that the process described above isn't always successful, and many times the cells fail to replicate and/or survive. If on the other hand, the hESCs do manage to survive and multiply enough so that the dish is "full", they have to be removed and plated into several dishes. This replating and subculturing process can be done again and again for many months. This way we can get millions and millions of hESCs from the handful ones we had at the beginning.

At any stage of the process, a batch of hESCs can be frozen for future use or to be sent somewhere else for further culturing and experimentation.

How are human embryonic stem cells induced to differentiate ?There are various options for researchers to choose from, if they decide to differentiate the cultured cells.

The easiest one, is to simply allow the cells to replicate until the disc is "full". Once the disc is full, they start to clump together forming embryoid bodies(rounded collections of cells ). These embryoid bodies contain all kinds of cells including muscle, nerve, blood and heart cells. As said before, although this is easiest method to induce differentiation, it is the most inefficient and unpredictable as well.

In order to induce differentiation to a specific type of cell, researchers have to change the environment of the dish by employingone of the ways below:

Human Embryonic Stem Cells, potential usesMany researchers believe that studying hESCs is crucial for fully understanding the complex events happening during the fetal development. This knowledge would also include all the complex mechanisms that trigger undifferentiated stem cells to develop into tissues and organs. A deeper understanding of all these mechanisms would in return give scientists a deeper understanding of what sometimes goes wrong and as a result tumours,birth defects and other genetic conditions occur, thus helping them to come up with effective treatments.

Several new studies also address the fact that human embryonicstem cells can be used as models for human genetic disorders that currently have no reliable model system. Two examples are the Fragile-X syndromeandCystic fibrosis.

As of now, there has been only one human clinical trial ,involving embryonic stem cells, with the officialapproval of the U.S. Food and Drug Administration (FDA).The trial started on January 23, 2009, and involved the transplantation ofoligodendrocytes (a cell type of the brain and spinal cord) derived from human embryonic stem cells. During phase I of the trial, 8 to 10paraplegics with fresh spinal cord injuries (two weeks or less) were supposed to participate.

In August 2009,the trial wasput on hold, due to concerns made by the FDA, regarding a small number of microscopic cysts found in several treated rat models. InJuly 30, 2010 the hold was lifted and researchers enrolled the first patient and administered him with the stem cell therapy.

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Embryonic Stem Cells | Stem Cells Freak

To meet the industry needs and to benefit students and research scholars, Nitte University has set up the a centre for stem cell research at K S Hedge Medical Academy (Kshema).

The Nitte University Centre for Stem Cell Research and Regenerative Medicine (NUCSReM), has been established to further advance the understanding of stem cell biology and to facilitate clinical application of stem cells to treat patients with various ailments, says N Vinaya Hegde, chancellor, Nitte University.

Gianvito Martino, the head of the Neurosciences division at the Institute of San Raffaele in Milan in a speech at Multiple Sclerosis Week, which took place from May 23-31, warned against trips of hope to clinics that promise effective treatments using stem cells.

According to Martino, who coordinated a Consensus Conference on last Tuesday in London on the neurodegenerative disease, where the guidelines for pre-clinical studies and clinical treatments with stem cells were defined, hundreds of Italian patients each year go on these trips due to cures that are promised. In the best-case scenario, these patients return in the Read More

Scientists have claimed they would serve the worlds first test tube hamburger this October.

A team, led by Prof Mark Post of Maastricht University in the Netherlands, says it has already grown artificial meat in the laboratory, and now aims to create a hamburger, identical to a real stuff, by generating strips of meat from stem cells.

The finished product is expected to cost nearly 220,000 pounds, The Daily Telegraph reported.

Prof Post said his team has successfully replicated the process with cow cells and calf serum, bringing the first artificial burger a step closer.

In October we are going to provide a Read More

Studies begun by Harvard Stem Cell Institute (HSCI) scientists eight years ago have led to a report published today that may be amount to a major step in developing treatments for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs disease.

The findings by Kevin Eggan, a professor in Harvards Department of Stem Cell and Regenerative Biology (HSCRB), and colleagues also has produced functionally identical results in human motor neurons in a laboratory dish and in a mouse model of the disease, demonstrating that modeling the human disease with customized stem cells in the laboratory could relatively soon eliminate some Read More

Frank LaFerla, left, Mathew Blurton-Jones and colleagues found that neural stem cells could be a potential treatment for advanced Alzheimer's disease

UC Irvine scientists have shown for the first time that neural stem cells can rescue memory in mice with advanced Alzheimers disease, raising hopes of a potential treatment for the leading cause of elderly dementia that afflicts 5.3 million people in the U.S.

Mice genetically engineered to have Alzheimers performed markedly better on memory tests a month after mouse neural stem cells were injected into their brains. The stem cells secreted a protein that created more neural connections, improving Read More

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"Latest Stem Cells News" - news from the world about stem ...

Stem cells (magenta with green nuclei) encapsulated in nanogel (yellow) for heart repair. Credit: MolGraphics.com

Cardiac stem cell therapy is a promising treatment for damaged hearts. However, researchers are still working on two major issues with the therapy how to keep the stem cells in place and how to prevent rejection when the stem cells are not from the patients own body. A new approach from NC State researcher Ke Cheng and a team of international collaborators may solve both of these problems.

The heart is a powerful muscle. Thats great if youre running a marathon, but if youre trying to inject stem cells into the heart with the hopes that theyll stay put, its a problem. One of the major drawbacks of cardiac stem cell therapy is simply that the cells do not stick to the injured heart tissue.

Enter a thermosensitive nanogel that is liquid at room temperature but becomes a thick, sticky gel as it warms. Cheng, associate professor of molecular biomedical sciences at NC States College of Veterinary Medicine and associate professor in the NC State/UNC Joint Department of Biomedical Engineering, partnered with chemical engineers from the University of Adelaide and cardiac specialists from the University of Zhengzhou and UNC-Chapel Hill to test the nanogel as a delivery mechanism for cardiac stem cells.

The nanogel, poly(N-isopropylacrylamine-co-acrylic acid), or P(NIPAM-AA) for short, had another property that made it appealing for use: in its thickened state it had porous openings large enough for a stem cells healing factors to escape, but not large enough for immune cells to enter. And it could be adjusted to slowly degrade over time, giving stem cells enough time to repair a damaged heart before dissolving away.

Autologous stem cells grown from a patients own cells are ideal to use in therapies, but that isnt always practical, Cheng says. For one thing, growing the cells takes time, which a patient may not have. For another, the heart cells themselves may be affected by disease, so stem cells taken from that source would not be useful.

Thats why were working on allogeneic stem cell therapies, but whenever you introduce cells from an outside source into the body, the immune system will attack them. The nanogel delivery method keeps the cells in place, protects them from the bodys immune response, and allows the regenerative factors released by the stem cells to reach the heart.

Cheng and his collaborators tested the nanogel delivery system in mice and pigs with hearts damaged by a heart attack. Without the nanogel, only about one percent of injected stem cells stayed in the heart. With the gel, up to 15 percent of the stem cells stayed put. They also found that in both animal models heart function improved three to four weeks after treatment. Mice showed a greater improvement than pigs, but in both models heart function was maintained and did not decrease.

We are pleased with these results, Cheng says. The nanogel is a safe, cost-effective way to deliver the cells directly to the affected area, and the large animal (pig) data is promising, which may lead to a human clinical trial in the future.

Chengs work appears in the journal ACS Nano, and was supported by the NIH and by NC States Chancellors Faculty Excellence Program and Chancellors Innovation Fund.

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Stuck on You: Nanogel Capsule Helps Cardiac Stem Cells ...

New Jersey's Premier Heart Transplant Program

The Barnabas Health Heart Failure and Transplant program is the most experienced and comprehensive center in New Jersey. It has been at the forefront of highly specialized care for more than twenty years. Our cardiac surgeons and heart specialists' expertise has made RWJBarnabas Health a regional and national training center for physicians, nurses and emergency services technicians.

Dr. Joseph Clemente, host of MHC-TV, interviews Mark J. Zucker, M.D., J.D., Director, Heart Failure Treatment and Transplant Program at Newark Beth Israel Medical Center. They discuss getting a heart transplant, other treatments such as the Left Ventricular Assist Device (LVAD), and about stem cell research ongoing today.

Learn about CardioMEMS, a new treatment for heart failure

Barnabas Health Heart Centers Earn Recognition from American Heart Association in Heart Failure Treatment

The Barnabas Health Heart Centers provide progressive heart failure management that optimizes the patient's transition to home and empowers them to improve their heart health. Advanced practice nurses contact patients within days of discharge and facilitate daily medical monitoring, education, and counseling. Patient-centered programs bring together all the medical resources necessary to combat heart failure and the reduction in hospital readmission rates has been significant. Heart failure clinics are based at all Barnabas Health hospitals.

Clinical trials provide patients with access for breakthrough medications, devices, and therapies, while being continually monitored and evaluated. Our participation in new cardiac stem cell research for patients with refractory angina and chronic myocardial ischemia may someday help the heart heal itself. Improved technology has made positive outcomes with ECMO more likely both at our center and nationally, and has resulted in increased referrals for this critical care.

The Newark Beth Israel Medical Center heart transplant program is one of the top ten heart transplant centers in the United States with survival rates that consistently meet or exceed national benchmarks. The center is at the forefront of improving the quality of life for transplant candidates and recipients, as well as increasing access to transplant. Our unique work in establishing successful protocols for discontinuing steroid medications for immunosuppression is improving the medical management and survival rates for transplant recipients worldwide. Noninvasive gene expression testing offers an alternative technique for assessing immunosuppression and predicting rejection. The center is also part of groundbreaking research that is exploring innovating methods for preserving donor organs for transplant.

Implantable VADs are placed for myocardial recovery, bridge to transplant, and destination therapy. Because the VAD program is totally integrated with heart failure and transplant services, patients are thoroughly and continually evaluated for all treatment options. The heart transplant center's experience has made it a principal site for clinical research trials of the latest generation of mechanical assist devices and a regional VAD transplantation training site. With virtually all FDA-approved and investigational implantable devices available, patients receive the device that meets their individual needs.

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Heart Failure and Transplant Program New Jersey

Nov. 14, 2011 -- The first use of heart stem cells in humans looks like a major breakthrough for people suffering heart failure after heart attacks.

It's early -- results are in for only the first 16 patients -- but the results already are drawing praise from experts not easily impressed by first reports.

"This is a groundbreaking study of extreme importance," Joshua Hare, MD, director of the University of Miami's Interdisciplinary Stem Cell Institute, tells WebMD via email. Hare was not involved in the study.

"The reported benefits are of an unexpected magnitude," writes Gerd Heusch, MD, PhD, chair of the Institute of Pathophysiology at the University of Essen, Germany, in an editorial in the Nov. 14 online issue of The Lancet.

Study researcher John H. Loughran, MD, of the University of Louisville, Ky., could barely contain his excitement in an interview with WebMD.

"The improvement we have seen in patients is quite encouraging," he says. "Michael Jones, our first patient, could barely walk 30 feet [before treatment]. I saw him this morning. He says he plays basketball with his granddaughter, works on his farm, and gets on the treadmill for 30 minutes three times a week. It is stories like that that makes these results really encouraging."

The breakthrough comes just as researchers were becoming discouraged by studies in which bone-marrow stem cells failed to heal damaged hearts.

Instead of getting stem cells from the bone marrow, the new technique harvests stem cells taken from the patients' own hearts during bypass surgery. Just 1 gram of heart tissue -- about 3.5 hundredths of an ounce -- is taken.

Using a technique invented by Brigham & Women's Hospital researchers Piero Anversa, MD, and colleagues, heart stem cells are taken from the tissue and grown in the lab. These adult stem cells already are committed to becoming heart cells, but they can transform into any of the three different kinds of heart tissues.

It's the first time tissue-specific stem cells, other than bone-marrow cells, have been tested in humans, Hare says.

In the study, about a million of the cells were infused into each patient's heart with a catheter. Calculations suggest that each of these infused cells could generate 4 trillion new heart cells.

The study was designed to show whether the technique was safe. It was: No harmful effects have been seen. But to the researchers' surprise, the relatively small number of cells infused into patients had a major effect.

Of the 14 patients analyzed so far, heart function improved dramatically. And in the eight patients seen one year after treatment, improvement appears to have continued. Moreover, the scars on patients hearts -- areas of dead tissue killed during their heart attacks -- are healing.

And patients aren't just doing better on measures of heart function. Like Michael Jones, they report vastly improved quality of life and ability to perform daily tasks.

"Now this is an open-label trial, so patients know they are treated. This means we have to take what they say with a grain of salt," Loughran says. "But we see these patients not only are feeling better but doing more."

The only downside of this early success is that the ongoing study already has enrolled all 20 of the patients who will be treated. The experimental treatment simply will not be available to other patients in the near future. A larger, phase II study is planned.

"All the patients that call in to us, and there are quite a few interested, we encourage them to maintain close contact with their doctors," Loughran says. "Lifestyle changes and medical management are the most important things for them right now. We will be working very hard to get new trials under way."

The findings were reported at the American Heart Associations Scientific Sessions meeting in Orlando, Fla., and in the Nov. 14 online edition of The Lancet.

SOURCES:

John H. Loughran, MD, fellow in cardiovascular medicine, University of Louisville, Ky.

Joshua Hare, MD, director, Interdisciplinary Stem Cell Institute, University of Miami.

Bolli, R. The Lancet, published online Nov. 14, 2011.

Heusch, G. The Lancet, published online Nov. 14, 2011.

Traverse, J.H. Journal of the American Medical Association, published online Nov. 14, 2011.

Hare, J. Journal of the American Medical Association, published online Nov. 14, 2011.

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Stem Cells Repair Heart in First-Ever Study - webmd.com

Stem cells are found in the early embryo, the foetus, amniotic fluid, the placenta and umbilical cord blood. After birth and for the rest of life, stem cells continue to reside in many sites of the body, including skin, hair follicles, bone marrow and blood, brain and spinal cord, the lining of the nose, gut, lung, joint fluid, muscle, fat, and menstrual blood, to name a few.In the growing body, stem cells are responsible for generating new tissues, and once growth is complete, stem cells are responsible for repair and regeneration of damaged and ageing tissues. The question that intrigues medical researchers is whether you can harness the regenerative potential of stem cells and be able to grow new cells for treatments to replace diseased or damaged tissue in the body.

To find out more about how stem cells are used in research and in the development of new treatments download a copy of The Australian Stem Cell Handbook or visit Stem Cell Clinical Trials to find out more about the latest clinical research using stem cells.

Stem cells can be divided into two broad groups:tissue specific stem cells(also known as adult stem cells) andpluripotent stem cells(including embryonic stem cells and iPS cells).

To learn more about the different types of stem cells visit our frequently asked questions page.

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About Stem Cells

High levels of stem cell factor (SCF) are associated with reduced risk of mortality and cardiovascular events, according to a study published online Aug. 26 in theJournal of Internal Medicine.

(HealthDay News) -- High levels of stem cell factor (SCF) are associated with reduced risk of mortality and cardiovascular events, according to a study published online Aug. 26 in theJournal of Internal Medicine.

Harry Bjrkbacka, Ph.D., from Lund University in Sweden, and colleagues examined the correlation between circulating levels of SCF and risk for development of cardiovascular events and death. SCF was analyzed from plasma from 4,742 participants in the Malm Diet and Cancer Study; participants were followed for a mean of 19.2 years.

The researchers found that participants with high baseline levels of SCF had lower cardiovascular and all-cause mortality and reduced risk of heart failure, stroke, and myocardial infarction. There was a correlation for smoking, diabetes, and high alcohol consumption with lower levels of SCF. After adjustment for traditional cardiovascular risk factors, the highest versus the lowest SCF quartile remained independently associated with lower risk of cardiovascular (hazard ratio, 0.59; 95 percent confidence interval, 0.43 to 0.81) and all-cause mortality (hazard ratio, 0.68; 95 percent confidence interval, 0.57 to 0.81) and with lower risk of heart failure (hazard ratio, 0.5; 95 percent confidence interval, 0.31 to 0.8) and stroke (hazard ratio, 0.66; 95 percent confidence interval, 0.47 to 0.92) but not myocardial infarction (hazard ratio, 0.96; 95 percent confidence interval, 0.72 to 1.27).

"The findings provide clinical support for a protective role of SCF in maintaining cardiovascular integrity," the authors write.

The possibilities that stem cell therapies present in the prevention, regeneration, and treatment of many health conditions seem to be still untouched. If course, stem cell research is still ongoing and no one is complete stem cell expert yet, but maybe thats a good approach to take. I am not so sure I would be comfortable in this modern area of easily accessible information with a physician that still doesnt consider his or her self a student. Whether your doctor is 65 or 38 I hope they are still open to learning, stated Dr. Ronald Klatz, President of the A4M.

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Stem Cell Factor Tied to Reduced Risk of Cardiac Events, Death - Anti Aging News

TAMPA (FOX 13) - Repairing a damaged heart has become much more than opening clogged arteries in the Cardiac Catheterization Lab at Pepin Heart Hospital in Tampa.

Dr. Charles Lambert and his team are injecting stem cells directly into specific areas in the walls of damaged hearts.

"We know where viable tissue is, what part of the heart is contracting and has live cells there," he explains.

Finding that living tissue begins with creating a color-coded map of the heart identifying areas where blood flow is maximized.

"We go back after mapping with a needle that comes out of the catheter and we do roughly twenty injections in viable tissue area," Lambert says.

It's all part of an experimental clinical trial Shiela Allen hopes will help her failing heart recover. Less than two hours after welcoming her youngest grandchild into this world, her grandson drove her to the emergency room.

"I couldn't breathe," she recalled.

Sheila was shocked when doctors told her that her heart was pumping at less than half of what it should.

"Now that I look back, I can figure out I had all the symptoms but I was just putting it off because I'm busy, I'm old, I'm a little bit overweight," she admits.

Like many women, Sheila ignored warning signs like fatigue, coughing and shortness of breath - especially when lying down.

"The coughing was odd to me because I was not congested, I could not lay flat in bed so I was propped up on four or five pillows," she says.

Similar to a balloon filled with too much water, the cardiac muscle is overstretched, thin, and weak. So weak, it can only pump a fraction of the blood inside its chambers to the rest of the body. That causes fluid to back up into the lungs and other parts of the body like the legs.

For about a decade, cardiologists have tried using stem cells to strengthen the muscle with mixed results. This study is hoping a new twist, will make it more successful.

Along with using the heart map to direct the injections, the stem cells are also different. Instead of taking them from the patient, syringes like these are filled with stem cells from donors.

"These trial cells are taken from healthy volunteers that are actually medical students, not here in town, but actually up in the northeast," he explains.

Another key difference in the study is the product's maker, Mesoblast. It is allowing people like Sheila, who have heart failure from unknown causes, to also enter the study. The clinical trial using the younger cells is now in 50 centers across the world.

"They're preserved so when we randomize a patient we take it off the shelf, treat it, warm it, the cells are perfectly alive and healthy and then administer it to the patients," Lambert says.

Side effects in earlier studies included a drop in blood pressure, bleeding, and fluid accumulation around the heart.

"It was basically like I was having another heart catheterization," Sheila says her side effects were minimal. "Three days after the procedure I was on a plane going on a trip."

She's not sure if she got a placebo or the actual cells, but as she completes her cardiac rehabilitation therapy, she says she is feeling better, "I've had a little more energy I dont know if it's related to that."

Energy allowing her to spend time with her family, and watch her youngest grandchild grow.

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Damaged hearts being repaired with stem cells - FOX 13 News, Tampa Bay