Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity.  |  Differentiation of cells into cardiac myocytes that are both mechanically and electrically coupled to the healthy cardiac myocytes is one way to achieve this goal. Immunogenicity of pluripotent stem cells and their derivatives. Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Figure 1. In 2002, Xu et al38 were among the first to optimize cardiac differentiation protocols for hESCs by using DNA demethylating agent 5-azacytidine and enrichment with Percoll separation gradients to obtain ≤70% pure CM populations (Table). This is a critical step toward developing more rational strategies to fight against cardiovascular disease. 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). Our group focusses on the study of multipotent cardiac progenitor cells (CPC) isolated from adult heart, although precise understanding of cardiac precursor and stem cell biology is still lacking. Patient-specific stem cells and cardiovascular drug discovery. Clipboard, Search History, and several other advanced features are temporarily unavailable. An ALDH + stem cell population, the cardiac atrial appendage stem cells (CASCs), was isolated from human atrial appendages. HHS 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). Cardiomyocytes differentiated in vitro from embryonic stem cells developmentally express cardiac-specific genes and ionic currents. 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. Significantly, evidence of MNC mobilization after myocardial infarction in mice has supported that bone marrow cells play a role in myocardial healing after injury.11,12 Randomized human clinical studies of injected MNCs demonstrated a modest increase in left ventricular ejection fraction and a decrease in the New York Heart Association (NYHA) functional classification system.13 Patients with ischemic cardiomyopathy receiving MNCs also demonstrated a significant reduction in natriuretic peptide levels.14 Notably, infusion of MNCs with higher colony-forming capacity was associated with lower mortality, raising awareness of the notion that cell viability and quality have significant impacts on therapeutic effect. 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. 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). 2017 Jan 20;120(2):400-406. doi: 10.1161/CIRCRESAHA.116.309710. Establishment in culture of pluripotential cells from mouse embryos. 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. In vitro uses of human pluripotent stem cell-derived cardiomyocytes. J.C. Wu is a consultant for Merck and Novartis and is a cofounder of Stem Cell Theranostics. organization. Cardiac stem cell research: Regulation and practice in the UK and Germany. Contact Us, Correspondence to Joseph C. Wu, MD, PhD, 265 Campus Drive, Room G1120B, Stanford, CA 94305. 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. 10 breakthroughs in stem cell research Stem cells could help cure heart failure. Indeed, stem cell–based therapies have the potential to transform the treatment and prognosis of HF, for they aim at eliminating the underlying cause of 2015 Oct;95(4):1189-204. doi: 10.1152/physrev.00021.2014. 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. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. In a new study, scientists at Okayama University isolated cardiac stem cells and assessed their potential use as regenerative therapy in young patients with cardiac defects. 25 Membrane fusion is dependent on signaling mechanisms involving paxillin-induced focal adhesions and recycling of integrins as demonstrated between macrophages and myoblasts. Research is ongoing into the potential use of stem cells for heart health. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. The worldwide environment of cardiovascular disease: Prevalence, diagnosis, therapy, and policy issuesa report from the American College of Cardiology. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Cardiac stem cells (CSCs) show potential as a cellular therapeutic approach to blunt tissue damage and facilitate reparative and regenerative processes after myocardial infarction. 2007 Jul-Aug;50(1):31-48. doi: 10.1016/j.pcad.2007.03.005. 910-923. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Assays for CM characterization, such as assessment for cross striations, ultrastructure, and chronotropic drug response, were established decades ago for primary rodent myocytes and published in a highly cited Circulation Research article by Simpson and Savion in 1982.44 In 1994, Maltsev et al45 were able to apply the same assays for extensive characterization of mESC-CMs. Transplantation of pluripotent stem cell-derived cardiac cells have demonstrated substantial benefits to cardiac function in animal models of heart disease, from mice to monkeys. 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. 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 team not only showed the effectiveness of the cells in replenishing damaged … The recognition that the adult heart possesses a stem cell compartment that can regenerate myocytes and coronary vessels has raised the unique possibility to rebuild dead myocardium after infarction, to repopulate the hypertrophic decompensated heart with new better functioning myocytes and vascular structures, and, perhaps, to reverse ventricular dilation and wall thinning. Upcoming knowledge from clinical research points in the direction of bone marrow stem cell/immune progenitor cell senescence by epigenetic and somatic mutations is the potential cause. They divide to replace worn-out or damaged cells, and to become new stem cells. Schematic diagram of genetic lineage tracing strategy used in zebrafish to identify the source of new cardiac myocytes in the regenerated heart. 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. 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. Please enable it to take advantage of the complete set of features! Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Growth of engineered human myocardium with mechanical loading and vascular coculture. In 2003, He et al46 were among the first to perform similar characterizations of hESC-CMs. December 2012; Innovation The European Journal of Social Science Research 25(4) DOI: 10.1080/13511610.2012.723881. Epub 2012 Oct 6. going research on cardiac stem cells (CSCs) and their innate ability to restore differentiated, functional car-diac tissue have kindled unprecedented interest in re-cent years. Front Cell Dev Biol. 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. The most successful and widely acknowledged use of PSCs-CMs has, to date, been in disease modeling. A major hurdle, however, is their closer resemblance to fetal rather than adult CMs.71 Combination of increasingly efficient CM generation protocols40 and next-generation sequencing technology,72 as well as other high-throughput screening assays, such as single-cell PCR,73 can lead to identification of molecular markers to further enhance CM maturation. 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. E-mail. Cell transplantation to prevent heart failure: a comparison of cell types. 1-800-242-8721 CMs indicate cardiomyocytes; ESC, embryonic stem cell; and iPSC, induced pluripotent stem cell. eCollection 2020. 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. iPSCs retain the same capacity for high-efficiency cardiac differentiation as ESCs, with the added advantages of avoiding ethical debates related to use of human embryos and enabling autologous transplantation of CMs without the need for immunosuppression. https://doi.org/10.1161/CIRCRESAHA.113.302895, National Center The stem cells formed new heart muscle and blood vessel cells. Short-term immunosuppression promotes engraftment of embryonic and induced pluripotent stem cells. 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. Oettgen P. Cardiac stem cell therapy: need for optimization of efficacy and safety monitoring. However, the diffusion of exosomes out of the infarcted heart following injection and the low productivity limit the potential of clinical applications. A better understanding of the developmental changes in cardiac microenvironments occurring during heart maturation will be informative regarding the loss of adult regenerative potential. Paracrine mechanisms in adult stem cell signaling and therapy. Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. 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. 2020 Jun 9;8:321. doi: 10.3389/fcell.2020.00321. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Focusing on short coupled torsades de pointes, this research may lead to ground breaking discoveries in sudden cardiac arrest, sudden death and ventricular tachycardia. NIH 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. In this field of research, for years we have actively explored innovative biotherapies for cardiac repair. Combination of Cardiac Progenitor Cells From the Right Atrium and Left Ventricle Exhibits Synergistic Paracrine Effects In Vitro. Differentiation of rat myocytes in single cell cultures with and without proliferating nonmyocardial cells. Cardiogenic differentiation and transdifferentiation of progenitor cells. Myoblast transplantation for heart failure. For instance, recent reports have demonstrated that cardiac progenitor cells (CPCs), which are capable of differentiating into all three cardiovascular cell types, are present during normal fetal development and can be isolated from pluripotent stem cells. Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ Res. Over the past two decades, adult stem cell transplantation has been extensively evaluated as a therapeutic approach for cardiac repair. iPSCs are ideal cellular models for providing a renewable source of cardiomyocytes for in vitro disease modeling, pharmacological testing, and therapeutic applications in regenerative medicine. Heart disease, whether inherited or acquired, is the leading cause of mortality in men and women worldwide, accounting for 17.3 million deaths per year.1 The urgent need to improve existing therapies has driven researchers to seek a better understanding of the diverse but inter-related mechanistic origins of heart development and failure, with the ultimate goals of identifying novel pharmacological treatments and cell-based engineering approaches to replace damaged heart tissue. 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. Circulation. 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. 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. ... 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. Huang G, Garikipati VNS, Zhou Y, Benedict C, Houser SR, Koch WJ, Kishore R. Cells. 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. 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. Molecular imaging of bone marrow mononuclear cell homing and engraftment in ischemic myocardium. The use of PSC-CMs has also expanded to in vivo applications, with transplantation shown to improve cardiac function in rat and guinea pig models of acute myocardial infarction.59,60 Effective strategies to deplete potential tumorigenic cells,61,62 induce immunotolerance,63,64 and enhance cell survival65 are being sought. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiovascular progenitor cells (CPCs), a type of heart cell, are called building blocks because they’re used to form the heart during fetal development. Local Info Based on immunophenotype and in vitro differentiation studies, we suggest that CASCs … Extracellular matrix promotes highly efficient cardiac differentiation of human pluripotent stem cells: the matrix sandwich method. Cardiac stem-cell genetic research being conducted by Weill Cornell Medical College, NY Presbyterian Hospital and NY Stem. 7272 Greenville Ave. Biomolecules. In addition, we have developed new technologies that enable disease modeling and drug screening using human pluripotent stem cell-derived cardiomyocytes and cardiac organoids (Voges et al, Development, 2017; Mills et al, PNAS, 2017; Mills et al, Cell Stem Cell (In Press)). Stem Cell and Cardiac Regeneration- Latest research - Heart 2021 (Japan) Stroke - Heart Congress 2021 (Spain) Structural Heart Disease Interventions - Cardiologists 2021 (UK) The Cardiovascular Impact of COVID-19 - Heart Summit 2021 (UAE) The coronary care unit - Circulatory Health 2021 (Vietnam) Effect of Triptolide on Temporal Expression of Cell Cycle Regulators During Cardiac Hypertrophy. Novel microRNA prosurvival cocktail for improving engraftment and function of cardiac progenitor cell transplantation. In 2002, researcher Chunhui Xu and team at Emory University School of Medicine in Atlanta found that human embryonic stem cells can be made to form heart muscle cells. 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. Customer Service Thus, an important consideration in selecting the articles to be highlighted is that they have stood the test of time, which is the most reliable indicator of the value of scientific work. However, the interaction of CSCs with postmitotic myocytes results in … Some studies show only modest or no improvement in heart function, but others have s… Front Pharmacol. 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. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Before cardiac stem cells can become an approved treatment to regenerate damaged hearts, scientists must do larger clinical trials. In a new study, scientists at Okayama University isolated cardiac stem cells and assessed their potential use as regenerative therapy in young patients with cardiac defects. 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. Cardiac Progenitor Cells A population of resident cardiac stem cells, known as cardiogenic progenitor cells (CPCs), has been identified in the heart. 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. Cardiac Regeneration and Stem Cells Physiol Rev. In fact, says Brinker, the new cells have a pre-determined cardiac fate. 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. 2013 Aug 20;167(4):1141-6. doi: 10.1016/j.ijcard.2012.09.051. use prohibited. At the same time, hESCs and iPSCs are progressively being used to reliably generate de novo CMs. Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation | Tianxiao (TX) Han 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. 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