Isolation and expansion of adult cardiac stem cells from human and murine heart. Methods for isolating functionally competent CSCs and mechanisms proving that their activation can reverse cardiac dysfunction were later published by the same group.5,6 It was this pioneering work and the ability to adequately expand CSCs ex vivo that formed the basis for the first randomized clinical trial of CSC implant in patients with ischemic heart disease (SCIPIO trial).7 Phase I of the trial demonstrated a sound safety profile and potential for efficacy in improving ventricular function. They divide to replace worn-out or damaged cells, and to become new stem cells. Paracrine mechanisms in adult stem cell signaling and therapy. Because of poor engraftment and safety concerns regarding mesenchymal stem cell (MSC) therapy, MSC-derived exosomes have emerged as an alternative cell-free therapy for myocardial infarction (MI). 910-923. Later, rigorous protocol standardization and the use of key signaling factors such as bone morphogenetic protein 4 (BMP4) and Activin A enabled conversion of hESCs to CMs with >90% efficiency.39 Consequently, the formation of 3D aggregates, a labor-intensive process, has now been largely replaced by differentiation in monolayer cultures, which are more amenable to scale-up and automation.40, The discovery of induced pluripotent stem cell (iPSC) technology,41 based partly on principles highlighted by early somatic cell nuclear transfer experiments,42 has meant that mature somatic cells such as skin fibroblasts and peripheral blood mononuclear cells can be reprogrammed with relative ease to acquire an ESC-like phenotype. Sun et al. Immunogenicity of pluripotent stem cells and their derivatives. In this field of research, for years we have actively explored innovative biotherapies for cardiac repair. Timeline of important discoveries contributing to the field of stem cell cardiac differentiation and characterization (purple and green boxes), including the key Top 100 Circulation Research articles discussed in this review (red boxes). Cardiac stem cell research: Regulation and practice in the UK and Germany. The American Heart Association is qualified 501(c)(3) tax-exempt DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world. 2 This strategy was inspired by an early mouse study claiming that injection of adult bone marrow‐derived stem cells improved cardiac function after acute MI through the trans‐differentiation of the injected cells into cardiomyocytes. A goal of cardiac stem cell research is to foster the engraftment of new, beating cardiac myocytes into the ischemic region of the heart after a myocardial infarction. Stem cells are biological cells found in all multicellular organisms which have the remarkable potential to develop into many different cell types in the body during early life and growth. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. Preexisting cardiomyocytes (green: GFP+) in the injure borderzone dedifferentiate and proliferate to regenerate the resected apex over a period of 30 days. Myoblast transplantation for heart failure. Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB), Journal of the American Heart Association (JAHA), Customer Service and Ordering Information, Basic, Translational, and Clinical Research. The subsequent discovery that adult hearts contained cells that expressed the haematological stem cell marker c-Kit led to a large body of literature, mostly from Piero Aversa’s laboratory, which advanced the premise that cardiac c-Kit+ cells were clonogenic, multipotent, and capable of self-renewal (i.e. Historic landmarks in the field of cardiac stem cell biology. Multinucleation (DNA replication with karyokinesis but no cytokinesis), polyploidization (DNA replication without karyokinesis or cytokinesis), fusion of nonmyocytes with cardiac myocytes, or DNA repair can all be associated with DNA synthesis and/or reexpression of cell cycle proteins but does not necessarily represent true cardiac myocyte division. Combination of Cardiac Progenitor Cells From the Right Atrium and Left Ventricle Exhibits Synergistic Paracrine Effects In Vitro. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Scientists are also looking into the potential for This isolation technique later became feasible for human hearts and was used to test the therapeutic efficacy of cardiosphere-derived cells in the CADUCEUS trial.9 The phase I trial demonstrated a good safety profile and potential for reducing scar size and regional function compared with controls. E-mail. The concept of “classic” is inextricably linked to time—a classic is something that maintains its value regardless of its age. In 2003, He et al46 were among the first to perform similar characterizations of hESC-CMs. Potential sources of new cardiomyocytes in the adult heart. However, the diffusion of exosomes out of the infarcted heart following injection and the low productivity limit the potential of clinical applications. View 0 peer reviews of Cardiac Stem Cell Treatment in Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Studies on Publons COVID-19 : add an open review or score for a COVID-19 paper now to ensure the latest research gets the extra scrutiny it needs. Tissue engineering of a differentiated cardiac muscle construct. See this image and copyright information in PMC. Indian Heart J. Regenerated cardiomyocytes are derived from preexisting cardiomyocytes not progenitor cells. These characteristics make iPSCs ideal cellular models to provide a renewable source of CMs for basic research, pharmacological testing, and cell therapy (Figure 2).43. More recently, Dey et al10 performed detailed characterization of multiple stem cell populations and concluded that c-kit+ CSCs represent the most primitive population of multipotent cardiac progenitors when compared with bone marrow–derived c-kit+ populations, and that cardiosphere-derived cells are more closely related to bone marrow stem cells in terms of their gene and protein expression profiles. In addition, rigorous experimental optimization enabled them to identify internal and external solutions for patch-clamp electrophysiological analysis to confirm that CM populations comprised ventricular, atrial, and nodal subtypes and exhibited most basic cardiac-specific ionic currents (L-type, ICa, INa, Ito, IK, IK1, IK, ATP, IK, Ach, and If). Research is ongoing into the potential use of stem cells for heart health. Our researchers are isolating exosomes from specialized human cardiac-derived stem cells and finding that they have the same beneficial effects as other types of stem cells. An ALDH + stem cell population, the cardiac atrial appendage stem cells (CASCs), was isolated from human atrial appendages. The cell sources used in cell transplantation for research associated with MI include autologous marrow mononuclear cells (MNCs), mesenchymal stem cells (MSCs), skeletal myoblasts (SMs), cardiac progenitor/stem cells (CPCs/CSCs), bone marrow mononuclear cells, human embryonic stem cell-derived cardiomyocytes (hESC-CMs), and human induced pluripotent stem cell-derived … Figure 1. Timing of bone marrow cell delivery has minimal effects on cell viability and cardiac recovery after myocardial infarction, Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy, Imaging: guiding the clinical translation of cardiac stem cell therapy. Timeline of important discoveries contributing to the field of stem cell cardiac differentiation and characterization (purple and green boxes), including the key Top 100 Circulation Research articles discussed in this review (red boxes). These results sound dramatic, but are they an indication that we're getting close to perfecting this therapy? Cardiac stem-cell genetic research being conducted by Weill Cornell Medical College, NY Presbyterian Hospital and NY Stem. Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Soliman et al. Growth of engineered human myocardium with mechanical loading and vascular coculture. Over the past two decades, adult stem cell transplantation has been extensively evaluated as a therapeutic approach for cardiac repair. Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays. This interest stems from the relatively impaired angiogenesis seen in patients with ischemic heart disease as well as from findings that patients with coronary artery disease have reduced number and migratory activity of angiogenic precursors.22 It has also been observed that CD34+ cell injection ameliorates cardiac recovery in human patients with myocardial infarction by improving perfusion and by paracrine effects rather than CM differentiation.23 In one of the largest cell therapy trials to date, Losordo et al24 demonstrated that patients with refractory angina who received intramyocardial injections of CD34+ cells experienced significant improvements in angina frequency and exercise tolerance. This is a critical step toward developing more rational strategies to fight against cardiovascular disease. They represent an attractive source of stem cells because they are relatively abundant, accessible, and autologous, and their mechanisms of action for any observed improvement in cardiac function can be potentially delineated. Intramyocardial, autologous CD34+ cell therapy for refractory angina. These techniques are not limited to cardiac cells, or even to stem cells for that mater.” “This is the latest in a chain of scientific discoveries that have come out of our lab here at Mass General and the Harvard Stem Cell Institute that have been a collaboration of physicians, scientists, and bioengineers,” Chien said. New clinical trials are underway to validate the efficacy of these therapies. Biomolecules. ... Oxford and Cambridge cardiac stem cells. Some studies show only modest or no improvement in heart function, but others have s… Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Extensive progress has been made in the field of cardiac stem cell biology to promote heart tissue repair by introduction of exogenous stem cells, such as MSCs, MNCs, adipose-derived stem cells, CD34+ cells, c-kit+ CSCs, and cardiosphere-derived cells, as evidenced by recent early phase clinical trials shown to reduce infarct size in patients (Table). Oettgen P. Cardiac stem cell therapy: need for optimization of efficacy and safety monitoring. Here, we present a general, critical overview of our experience in using mesenchymal stem cells, derived from cardiac adipose tissue and umbilical cord blood, in a variety of cell therapy and tissue engineering approaches. Pathologic assessment plays a crucial role in cardiac stem cell and gene therapy research by allowing researchers to evaluate the safety and effectiveness of such therapies in cardiac tissues. For this technology to be fully applied in the clinic, a greater understanding of the following issues that have plagued the field must be reached: (1) the potential consequences of depleting endogenous cardiac fibroblasts to replenish CMs; (2) the ability to transfect bystander cells such as smooth muscle and endothelial cells with cardiac transcription factors; and (3) the challenge of triggering immune response against the host cells transfected with viral versus nonviral vectors. Many protocols have been developed during the years to maximize the yield and efficiency of pluripotent ESC differentiation to CMs.37 One of the most used methods has been the formation of 3D aggregates named embryoid bodies, within which cardiac differentiation occurs. Novel microRNA prosurvival cocktail for improving engraftment and function of cardiac progenitor cell transplantation. In addition, experimental drugs have been used for in vitro amelioration of diseased phenotypes in human iPSC models of cardiovascular diseases48 and prediction of cytotoxic drug-induced side effects.49,50 Accumulated evidence suggests that PSC-CMs can offer the pharmaceutical industry a valuable physiologically relevant tool for validation of novel drug candidates and identification of potential cardiotoxic effects in early drug development stages, thereby easing the huge associated economic and patient care burdens.51,52. Background- Cardiac stem cells (CSCs) delivered to the infarcted heart generate a large number of small fetal-neonatal cardiomyocytes that fail to acquire the differentiated phenotype. After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. Schematic diagram of…, Strategies to regenerate adult heart after injury. December 2012; Innovation The European Journal of Social Science Research 25(4) DOI: 10.1080/13511610.2012.723881. That's based partly on recent animal studies in which scientists at both institutions isolated stem cells from the injured animals’ hearts and infused them back into the hearts of those same animals. By Jennifer Couzin-Frankel Oct. 16, 2018 , 5:50 PM. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Copyright © 2015 the American Physiological Society. 10 breakthroughs in stem cell research Stem cells could help cure heart failure. The difficulty is that the heart cells made with stem cells resemble the heart cells of an infant, rather than adult heart cells. The adult heart was previously thought to be a post mitotic organ without any regenerative capability. Advantages and disadvantages of the various cell sources used for cardiac regeneration studies, with examples of clinical trials in which cells were used for cardiac regeneration or, in parentheses, other conditions. In mice models, our research shows that exosomes produce the same post-surgery benefits, such as decreasing scar size, increasing healthy heart tissue and reducing levels of chemicals that lead to inflammation. Animal models are widely used as surrogates for studying human disease, both in order to recapitulate the complex clinical course of human heart failure and to generate in vitro tools for studying specific aspects of tissue dysfunction.2 Although useful insights have been gained, experimental findings from animal models have not always extrapolated to human disease presentation because of considerable species variation.3 Here, we describe prominent routes taken toward the goal of cardiac regeneration by focusing on key contributing articles published by Circulation Research in the 60 years since its establishment. Integrating human pluripotent stem cells into drug development. Due to space limitations, we are unable to include all of the important papers relevant to cardiac stem cell biology; we apologize to the investigators who have made significant contributions to this field. Circulation. In cardiac stem cell treatments, stem cells are taken from a patient’s bone marrow or fat tissue in a sterile surgical procedure and injected via a catheter-wire into infarcted or poorly contracting muscular segments of the heart’s main pumping chamber, the left ventricle (LV). The use of pluripotent stem cell–derived cardiomyocytes (PSC-CMs), which include both hESC-CMs and iPSC-CMs, for downstream applications requires that their properties be physiologically analogous to human CMs in vivo. Despite their immature fetal phenotype, extensive pharmacological validation confirms their potential use in drug evaluation.47 Clinically relevant drugs (eg, adrenergic receptor blockers, calcium channel blockers) have been shown to exert chronotropic and inotropic effects on PSC-CMs. Strategies to regenerate adult heart after injury. Schematic diagram of genetic lineage tracing strategy used in zebrafish to identify the source of new cardiac myocytes in the regenerated heart. In a subsequent publication, the group identified that CD34+ cells secrete exosomes that might account for some of the improved phenotypes.25 The benefit of CD34+ cells was also shown for nonischemic cardiomyopathy, when intracoronary injections resulted in a small, but significant, improvement in ventricular function and survival.26 More importantly, this study demonstrated that higher intramyocardial homing was associated with better cell therapy response, providing support to previous observations regarding MNCs that cell delivery method and quality play significant roles in their therapeutic efficacy. The discovery of induced pluripotency technologies, which likewise led to the Nobel Prize in 2012 for Sir John Gurdon and Shinya Yamanaka, allowed the generation of patient-specific iPSC-CMs for studying human disease models of familial hypertrophic cardiomyopathy,53 familial dilated cardiomyopathy,54 long QT syndrome,55 Timothy syndrome,56 arrhythmogenic right ventricular dysplasia,57 and others47 (Figure 2). An important potential application of human stem cells, through a more complete understanding of the genetic and molecular controls of cell division and differentiation, is the generation of cells and tissues that could be used for cell-based therapies. Figure 2. In vitro uses of human pluripotent stem cell-derived cardiomyocytes. The team not only showed the effectiveness of the cells in replenishing damaged … Regenerative medicine and stem cell research have tremendous potential to revolutionize the treatment of cardiac disease. By looking back at the illustrious past of Circulation Research, we hope to promote a deeper appreciation of the contributions of this journal to the advancement of knowledge. Cardiac stem cells (CSCs) show potential as a cellular therapeutic approach to blunt tissue damage and facilitate reparative and regenerative processes after myocardial infarction. Cardiomyocytes differentiated in vitro from embryonic stem cells developmentally express cardiac-specific genes and ionic currents. Cardiac Stem Cells. Based on immunophenotype and in vitro differentiation studies, we suggest that CASCs … \"This is a field where, depending on which investigator you ask, you can get incredibly different answers,\" says Dr. Richard Lee, professor of medicine at Harvard Medical School and a leading expert on stem cell therapy.\"The field is young. Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. McQuaig R, Dixit P, Yamauchi A, Van Hout I, Papannarao JB, Bunton R, Parry D, Davis P, Katare R. Cell Transplant. 2007 Apr;87(2):521-44. doi: 10.1152/physrev.00032.2006. Taken together, these advances in adult and PSC biology during the past decades may herald a new area of cardiovascular regenerative and personalized medicine in upcoming years. Two American Heart Association (AHA) journals, Circulation and Circulation Research, have retracted 13 papers from the now defunct laboratory of cardiac stem cell researcher Piero Anversa, MD. Retract cardiac stem cell papers, Harvard Medical School says. The Elusive Progenitor Cell in Cardiac Regeneration: Slip Slidin' Away. They’re also investigating the effect of stem cell-derived cardiac cells on repairing damaged hearts and their potential to treat heart muscle diseases. Mouse CMs generated by direct transdifferentiation are positive for CM-specific sarcomeric markers and exhibit electrophysiological and gene expression profiles similar to those of fetal CMs, although this was disputed by other investigators.33 In vitro transdifferentiation toward CM-like cells was also reported for human fibroblasts, albeit by more time-consuming and less efficient protocols that generated mostly partially reprogrammed CMs.34 Current efforts in this research area focus on optimizing transdifferentiation efficiency and CM maturation, further characterizing derived CMs, and validating that in vitro and in vivo transdifferentiation occur in the absence of experimental artifacts, which can include incomplete silencing of transgene expression from Cre-lox systems, cell fusion events, and the possibility of retrovirus transfecting not only dividing fibroblasts but also nondividing CMs in vivo. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. The Hippo Pathway in Cardiac Regeneration and Homeostasis: New Perspectives for Cell-Free Therapy in the Injured Heart. Historic landmarks in the field of cardiac stem cell biology. The isolation by Evans and Kaufman of mouse embryonic stem cells (mESCs) in 198135 and the generation of human embryonic stem cells (hESCs) by Thomson in 199836 allowed new opportunities for in vitro generation of CMs. The exact mechanistic and functional outcome implications of such differences are not yet known but may aid ongoing clinical trials in understanding the biology of these promising cell populations. Molecular imaging of bone marrow mononuclear cell homing and engraftment in ischemic myocardium. Beyond the potential ability of these models to reveal insights into pathological disease mechanisms, they also offer unique opportunities to explore promising new genetic therapies58 and to identify loci or pathways related to predisposition toward cardiac disorders, thus enabling refinement of phenotype-to-genotype correlations to improve risk stratification and disease management. That could take three or four years, Bolli says. Transcriptional and functional profiling of human embryonic stem cell-derived cardiomyocytes. Dissecting the molecular relationship among various cardiogenic progenitor cells. Heart development in mammals is followed by a postnatal decline in cell proliferation and cell renewal from stem cell populations. cardiac stem cell research Researchers are using stem cells in two important ways to improve cardiac health.... Second, stem cells offer ways to replace damaged heart tissue. ... 1 , W Robb MacLellan 1 Affiliation 1 Center for Cardiovascular Biology, Institute for Stem Cell Research and Division of Cardiology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington. Human CD34+ cells in experimental myocardial infarction: long-term survival, sustained functional improvement, and mechanism of action. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. 7. Overview of high throughput sequencing technologies to elucidate molecular pathways in cardiovascular diseases. López E, Marinaro F, de Pedro MLÁ, Sánchez-Margallo FM, Gómez-Serrano M, Ponath V, Pogge von Strandmann E, Jorge I, Vázquez J, Fernández-Pereira LM, Crisóstomo V, Álvarez V, Casado JG. Moreover, not only is modification of tissue repair mechanisms the consequence of stem cell mutations and DNA-pathology, but these may also form the cause of disease mechanisms and progression. Please enable it to take advantage of the complete set of features! Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Research shows that pluripotent stem cell-derived cardiomyocytes can form beating human heart muscle cells that both release the necessary signals and replace muscle lost to heart attack. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Dallas, TX 75231 Endogenous cardiac stem cells were first discovered in 2003 by Bernardo Nadal-Ginard, Piero Anversa and colleagues in the adult rat heart and since then have been identified and isolated from mouse, dog, porcine and human hearts. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. Mesenchymal stem cells and their potential as cardiac therapeutics. Cardiac regeneration strategies and de novo generation of cardiomyocytes have long been significant areas of research interest in cardiovascular medicine. Cross-striations, ultrastructure, and chronotropic response to isoproterenol. Schematic diagram depicting strategies, outlined in…, NLM Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation steps. Are underway to validate the efficacy of these therapies the low productivity the. 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