Human Embryonic Stem Cells vs Human Induced Pluripotent Stem Cells for Cardiac Repair

Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) have the capacity to differentiate into any specialized cell type, including cardiomyocytes. Therefore, hESC-derived and hiPSC-derived cardiomyocytes (hESC-CMs and hiPSC-CMs, respectively) offer great potential for cardiac regenerative medicine. Unlike some organs, the heart has a limited ability to regenerate, and dysfunction resulting from significant cardiomyocyte loss under pathophysiological conditions, such as myocardial infarction (MI), can lead to heart failure. Unfortunately, for patients with end-stage heart failure, heart transplantation remains the main alternative, and it is insufficient, mainly because of the limited availability of donor organs. Although left ventricular assist devices are progressively entering clinical practice as a bridge to transplantation and even as an optional therapy, cell replacement therapy presents a plausible alternative to donor organ transplantation. During the past decade, multiple candidate cells were proposed for cardiac regeneration, and their mechanisms of action in the myocardium have been explored. The purpose of this article is to critically review the comprehensive research involving the use of hESCs and hiPSCs in MI models and to discuss current controversies, unresolved issues, challenges, and future directions.     

The Rejuvenation of Aged Stem Cells for Cardiac Repair

Rejuvenation is one of the greatest challenges of modern science. Aging affects every tissue and organ in the body, leading to a deterioration of normal function and inhibition of repair mechanisms. Cell therapy has received much attention for its potential to regenerate organs, but in the context of cardiac repair, the initial clinical trials in aged patients did not replicate the dramatic benefits recorded in preclinical studies with young animals. The benefits of autologous cell therapy are reduced in the elderly, the largest target group for regenerative medicine. Adult stem cell functionality decreases with age which impairs tissue regeneration. In this review we discuss the age-related changes in stem cell function, with particular attention to stem cell therapy in heart disease. We also focus on possible mechanisms of adult stem cell aging and targets for rejuvenation strategies to reverse the aging process. We provide useful insights on how to apply this knowledge to advance cellular therapies for heart disease.     

Stem Cells and Cardiac Repair: A Critical Analysis

Utilizing stem cells to repair the damaged heart has seen an intense amount of activity over the last 5 years or so. There are currently multiple clinical studies in progress to test the efficacy of various different cell therapy approaches for the repair of damaged myocardium that were only just beginning to be tested in preclinical animal studies a few years earlier. This rapid transition from preclinical to clinical testing is striking and is not typical of the customary timeframe for the progress of a therapy from bench-to-bedside. Doubtless, there will be many more trials to follow in the upcoming years. With the plethora of trials and cell alternatives, there has come not only great enthusiasm for the potential of the therapy, but also great confusion about what has been achieved. Cell therapy has the potential to do what no drug can: regenerate and replace damaged tissue with healthy tissue. Drugs may be effective at slowing the progression of heart failure, but none can stop or reverse the process. However, tissue repair is not a simple process, although the idea on its surface is quite simple. Understanding cells, the signals that they respond to, and the keys to appropriate survival and tissue formation are orders of magnitude more complicated than understanding the pathways targeted by most drugs. Drugs and their metabolites can be monitored, quantified, and their effects correlated to circulating levels in the body. Not so for most cell therapies. It is quite difficult to measure cell survival except through ex vivo techniques like histological analysis of the target organ. This makes the emphasis on preclinical research all the more important because it is only in the animal studies that research has the opportunity to readily harvest the target tissues and perform the detailed analyses of what has happened with the cells. This need for detailed and usually time-intensive research in animal studies stands in contrast to the rapidity with which therapies have progressed to the clinic. It is now becoming clear through a number of notable examples that progress to the clinic may have occurred too quickly, before adequate testing and independent verification of results could be completed (Check, Nature 446:485–486, 2007; Chien, J Clin Investig 116:1838–1840, 2006; Giles, Nature 442:344–347, 2006). Broad reproducibility and transfer of results from one lab to another has been and always will be essential for the successful application of any cell therapy. So, what is the prognosis for cell therapy to repair heart damage? Will there be an approved cell therapy, or multiple ones, or will it require combinations of more than one cell type to be successful? These are questions often asked. The answers are difficult to know and even more difficult to predict because there are so many variables associated with cell-based therapies. There is much about the biology of cell systems that we still do not understand. Much of the pluripotency or transdifferentiation phenomena (see below) being observed go against accepted and well-tested principles for cell development and fate choice, and has caused a reevaluation of long-accepted theories. Clearly, new pathways for tissue repair and regeneration have been uncovered, but will these new pathways be sufficient to effect significant tissue repair and regeneration? Despite the false starts so far, there is the strong likelihood one or possibly multiple cell therapies will succeed. Clearly, important information has been gained, which should better guide the field to achieving success. When there is the successful verification in patients of a cell therapy, there will be an explosion of technological advances around the approach(es) that succeed. Whatever cells get approved accompanying them will be: more effective delivery methods; growth and storage methods; combination therapies, mixes of cells or cells + gene therapies; combinations with biomaterials and technologies for immune protection, allowing allografting. There are many parallel paths of technology development waiting to be brought together once there is an effective cellular approach. The coming years will no doubt bring some exciting developments.     

C-Kit~+心脏干细胞在心肌修复中的作用

终末期冠心病是因大量心肌细胞丧失功能而致不可逆转性损害,以心力衰竭为主要表现的临床综合征。自发现C-Kit~+心脏干细胞可分化为心肌细胞后,移植C-Kit~+心脏干细胞促进心肌的修复便成为基础和临床研究的热点之一。尽管还有诸多问题尚待解决,但这为终末期心肌修复的研究带来新的方向。现就C-Kit受体及配体、C-Kit~+心脏干细胞及其在心肌修复中的作用、局限性做一综述。     

Mesenchymal Stem Cells and Cardiac Repair: Principles and Practice

Mesenchymal stem cells (MSCs) are cluster of differentiation 34 (CD34)–CD45-negative nonhematopoietic progenitors derived typically from the stromal fraction of the bone marrow. These stem cells display multipotent properties with a demonstrable differentiation capacity along multiple mesodermal lineages. In the setting of myocardial injury, preclinical studies indicate benefit of both autologous and allogeneic transplantation in line with a recognized immunotolerant profile. Initial clinical experience supports the value of mesenchymal stem-cell-based therapy in ischemic cardiomyopathy. Experience is however limited to naïve mesenchymal stem cells, with efforts underway to identify optimal means of enhancing the cardiogenic potential of transplanted cells through guided cardiopoiesis with the ultimate aim of achieving standardized therapy of the ischemic myocardium.     

Resident Cardiac Stem Cells and Their Role in Stem Cell Therapies for Myocardial Repair

Despite advances in treatment, heart failure remains one of the top killers in Canada. This recognition motivated a new research focus to harness the fundamental repair properties of the human heart. Since then, cardiac stem cells (CSCs) have emerged as a promising cell candidate to regenerate damaged hearts. The rationale of this approach is simple with ex vivo amplification of CSCs from clinical-grade biopsies, followed by delivery to areas of injury, where they engraft and regenerate the heart. In this review we will summarize recent advances and discuss future developments in CSC-mediated cardiac repair to treat the growing number of Canadians living with and dying from heart failure.     

Imaging Cardiac Stem Cell Therapy: Translations to Human Clinical Studies

Stem cell therapy promises to open exciting new options in the treatment of cardiovascular diseases. Although feasible and clinically safe, the in vivo behavior and integration of stem cell transplants still remain largely unknown. Thus, the development of innovative non-invasive imaging techniques capable of effectively tracking such therapy in vivo is vital for a more in-depth investigation into future clinical applications. Such imaging modalities will not only generate further insight into the mechanisms behind stem cell-based therapy, but also address some major concerns associated with translational cardiovascular stem cell therapy. In the present review, we summarize the principles underlying three major stem cell tracking methods: (1) radioactive labeling for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, (2) iron particle labeling for magnetic resonance imaging (MRI), and (3) reporter gene labeling for bioluminescence, fluorescence, MRI, SPECT, and PET imaging. We then discuss recent clinical studies that have utilized these modalities to gain biological insights into stem cell fate.     

骨髓来源细胞向肺内迁移分化的实验研究

目的：观察骨髓来源细胞能否向肺内迁移及其特点。方法：野生型（257BL／6J雌性小鼠作为受体接受10Gy的射线照射后,经尾静脉植入同等背景的转增强型绿色荧光蛋白（EGFP）基因的C57BL／6J雄性小鼠（绿鼠）骨髓细胞1×10^7个／只。移植受体稳定1年后检测肺组织中EGFP的表达。结果：野生型小鼠肺组织中EGFP的表达率为0,绿鼠各组织中EGFP的表达率为100％。骨髓移植受体鼠肺组织有广泛的EGFP阳性细胞分布,主要分布在肺间质中,在支气管上皮、肺泡上皮中也有EGFP阳性细胞存在,表达率为100％,与野生型相比差异有显著性（P〈0．01）。结论：受放射线照射后的C57BL／6J小鼠,接受同种异基因小鼠骨髓来源细胞能向肺内迁移并分化为肺的组织细胞。     

Sca-1~+心肌干细胞的研究进展

干细胞抗原1(Sca-1)是干细胞的一种重要表面标记物,体内许多干细胞都表达Sca-1。同样,心肌干细胞也表达Sca-1。目前研究发现,Sca-1+心肌干细胞能够分化为心肌细胞,对心肌梗死后心室重构与心肌再生具有明显作用,能够促进心脏的修复。因此,Sca-1+心肌干细胞有可能使心肌梗死的临床治疗取得实质性的进展。现综述了Sca-1+心肌干细胞的来源、分化、作用等方面。     

In Vivo Imaging and Monitoring of Transplanted Stem Cells: Clinical Applications

Regenerative medicine using stem cells has appeared as a potential therapeutic alternative for coronary artery disease, and stem cell clinical studies are currently on their way. However, initial results of these studies have provided mixed information, in part because of the inability to correlate organ functional information with the presence/absence of transplanted stem cells. Recent advances in molecular biology and imaging have allowed the successful noninvasive monitoring of transplanted stem cells in the living subject. In this article, different imaging strategies (direct labeling, indirect labeling with reporter genes) to study the viability and biology of stem cells are discussed. In addition, the limitations of each approach and imaging modality (eg, single photon emission computed tomography, positron emission tomography, and MRI) and their requirements for clinical use are addressed. Use of these strategies will be critical as the different regenerative therapies are being tested for clinical use.     

Stem Cells

In this issue, ‘Pancreatology and the Web’ focuses on stem cell research, one of the 21st century's most exciting areas of science. Stem cell research has been advancing our knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Although still in its infancy, this field also offers a revolutionary way to repair diseased and damaged body tissues by replacing them with healthy new cells, thereby promising the possibility of cell-based therapies to treat disease, known as regenerative or reparative medicine. Stem cells are unspecialized cells that retain the ability to renew themselves through cell division and can differentiate into a diverse range of specialized cell types, such as the insulin-producing cells of the pancreas. In addition, another emerging field is specific to cancer stem cells, which are a subset of the bulk tumor responsible for initiating and maintaining the disease. Therefore, with the exciting progress in thefield, these websites were chosen to direct you toward more information about stem cells, whether this applies to your area of research or you wish to have a better knowledge base of the field in general.     

CD34+ Stem Cells: Promising Roles in Cardiac Repair and Regeneration

Cell therapy has received significant attention as a novel therapeutic approach to restore cardiac function after injury. CD34-positive (CD34⁺) stem cells have been investigated for their ability to promote angiogenesis and contribute to the prevention of remodelling after infarct. However, there are significant differences between murine and human CD34⁺ cells; understanding these differences might benefit the therapeutic use of these cells. Herein we discuss the function of the CD34 cell and highlight the similarities and differences between murine and human CD34 cell function, which might explain some of the differences between the animal and human evolutions. We also summarize the studies that report the application of murine and human CD34⁺ cells in preclinical studies and clinical trials and current limitations with the application of cell therapy for cardiac repair. Finally, to overcome these limitations we discuss the application of novel humanized rodent models that can bridge the gap between preclinical and clinical studies as well as rejuvenation strategies for improving the quality of old CD34⁺ cells for future clinical trials of autologous cell transplantation.