Human Cardiac Stem Cells

Abstract

HomeCirculationVol. 120, No. 25Human Cardiac Stem Cells Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHuman Cardiac Stem CellsThe Heart of a Truth Annarosa Leri Annarosa LeriAnnarosa Leri From the Departments of Anesthesia and Medicine and the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Search for more papers by this author Originally published7 Dec 2009https://doi.org/10.1161/CIRCULATIONAHA.109.911107Circulation. 2009;120:2515–2518Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: December 7, 2009: Previous Version 1 The view of the heart as a static organ implies that myocyte death and formation play a negligible role in cardiac homeostasis. Although stem cells have been unexpectedly identified in several organs, including the brain, kidney, lung, and skeletal muscle, the search for a cardiac stem cell (CSC) has been perceived as a futile effort, given the acknowledged lack of regenerative potential of the myocardium. Nevertheless, in the past several years, the demonstration of myocyte renewal in the normal and diseased heart has revealed a new, dynamic, and lively picture of this organ. Components of the cell cycle machinery and markers of cell replication have been detected in cardiomyocytes. The demonstration that karyokinesis and cytokinesis involve cells expressing contractile proteins has provided evidence that cardiomyocyte division occurs in the adult heart.1 More recently, pulse-chase assays with thymidine analogs,2 lineage tracing protocols,3 and 14C birth dating of cells4 have shown the existence of myocyte turnover, a process that has been found to differ in magnitude according to the methods used for its documentation and quantification.Article see p 2559Over the years, the heart has provided us with the evidence that solves the critical problem of the origin of cardiomyocytes. At this moment in time, paraphrasing Eugenio Montale, we could say that the human heart is “on the verge of betraying [its] final secret offering the opportunity to uncover…the still point of the world, the link that won't hold, the thread to untangle that will finally lead to the heart of a truth.”5 Newly generated myocytes may derive from division of preexisting parenchymal cells or from activation and differentiation of resident CSCs. Discriminating between these two possibilities is not an easy task. Fate-mapping strategies, which are commonly used to track the origin of cells and their destiny, would represent the ideal retrospective assay for the analysis of cardiomyocyte turnover, inasmuch as the expression of the fluorescent label can be placed under the control of promoter of genes coding for contractile proteins.3 This protocol provides information at the level of populations of cells that share the reporter gene, but it fails to demonstrate in vivo the self-renewal, clonogenicity, and multipotentiality of single progenitor cells. This inherent limitation makes it impossible to establish the identity of the ancestors of replicating myocytes.6An alternative retrospective protocol is based on the stable integration of proviral integrants in the genome of the infected cells. The insertion site of the viral genome is inherited by the entire population derived from the parental cell. Clonal tracking of individual mouse and human c-kit-positive CSCs has documented that these cells possess the fundamental properties of stem cells in vivo under physiological conditions and after injury. By this approach, the existence of a direct link between human CSCs (hCSCs) and their committed myocyte progeny has been demonstrated.7 Still, the controversy concerning myocyte regeneration in the adult heart by endogenous progenitor cells has not been resolved, and whether hCSCs can be implemented therapeutically is questioned frequently.The study by Itzhaki-Alfia and colleagues8 published in this issue of Circulation deals with these fundamental questions and documents that the human heart contains a pool of cells capable of creating myocytes in vitro and regenerating myocardium in vivo. Successful collection of hCSCs was obtained from all myocardial specimens independently of age, sex, and type and duration of disease, which indicates that a stem cell compartment is present in the decompensated heart. Accordingly, functionally competent hCSCs may be isolated from myocardial samples and, after their expansion, administered back to the patient. Two Phase I clinical trials, testing the safety of c-kit-positive allographic hCSCs9 and cardiospheres,10 are in progress.The recognition that a stem cell compartment exists in the adult human heart answers only in part the question of whether these cells retain the capacity to divide and differentiate throughout life or whether the multiple variables that affect human beings, including age, diseases, and the interrelated effects of genes, environment, and probabilistic changes, interfere with the growth of hCSCs, limiting their therapeutic efficacy. The accumulation of senescent poorly contracting cardiomyocytes in the old heart poses the question of whether aging uniformly affects the hCSC compartment or whether a stem cell subset maintains its youth during the entire lifespan of the organ. Pathological states of ischemic and nonischemic origin, together with the duration and severity of disease, may have profound implications on the availability and function of hCSCs. The geographic distribution of hCSCs may not be uniform within the myocardium, and cells may accumulate preferentially in specific anatomic regions, possibly interfering with cell acquisition. Sex may represent another important determinant of hCSC growth and lineage commitment. These issues have been addressed carefully in the elegant study by Itzhaki-Alfia and collaborators.8Surgical specimens and endomyocardial biopsy specimens were obtained from the myocardium of the 4 cardiac chambers. Expansion of the dissociated cells favored the survival and proliferation of c-kit-positive cells, which, at early passages, accounted for 4% to 24% of the unfractionated pool—a value that is much higher than the frequency of lineage-negative c-kit-positive hCSCs found in situ.11 These human cells were negative for hematopoietic markers, excluding their bone marrow origin and mast cell contamination. A fraction of c-kit-positive cells showed various degrees of cardiomyocyte commitment and expressed transcription factors such as GATA4 and sarcomeric proteins. In addition, cardiac cells gave rise to other mesodermal lineages, including adipocytes and osteoblasts. This differentiation potential is consistent with the mesenchymal ancestry of the heart. The nonpermissive environment of the myocardium conceals and suppresses the formation of noncardiac cells in vivo; this phenomenon occurs only under specific culture conditions.12 The restriction in developmental options of hCSCs was confirmed here in vivo after myocardial infarction.8Nearly 7% of c-kit-negative cells displayed the Isl1 transcription factor in vitro. This finding is at variance with previous reports that indicated that Isl1-positive cells are present exclusively in the human fetal heart, sharply decreasing after midgestation and becoming undetectable at birth.13 The expression of Isl1 in cultured cardiac cells corresponds to the onset of myocyte commitment, inasmuch as Isl1, together with GATA-4, is a transcriptional activator of the myocyte transcription factor MEF2C.14 It is important to note that the upregulation of Isl1 in vitro does not imply that similar cells are present in situ in the human myocardium. Isl1-positive cells are myocyte precursors and lack the properties of stem cells. Their absence in the normal and failing human heart excludes any potential therapeutic use of this forming cardiomyocyte subset (Figure 1). Download figureDownload PowerPointFigure 1. Isl1 in the myocardium. Isl1-positive cells (red, arrows) are illustrated in the neural crest of a 13-day-old rat embryo at low (A) and higher (B) magnification. Isl1-positive cells are not found in the adult normal rat heart (C) and in the failing human heart (D), which have c-kit-positive (green) cardiac stem cells. Myocytes are stained by α-sarcomeric actin (α-sarc actin, red). Vimentin, white; nuclei are labeled by 4′,6-diamidino-2-phenylindole, blue.An important aspect of the study by Itzhaki-Alfia et al8 involves the recognition that the distribution of hCSCs in different anatomic regions of the heart conditions their number and functional behavior. The right atrium is the richest source of c-kit-positive cells, and these hCSCs are endowed with superior growth and differentiation potential. This finding has great clinical implications and is in harmony with the nonuniform localization of cardiac progenitors in the hearts of animals and humans.2,9,11 Clusters of hCSCs organized in structures with the architectural organization of niches are more abundant in the atria and apex,2 which are protected areas, exposed to low levels of hemodynamic stress. On the basis of the data collected by Itzhaki-Alfia and colleagues,8 it can be retrospectively inferred that the environment of the right atrial niches has the ability to maintain adult hCSCs in an undifferentiated state, preventing their depletion with aging and disease. Cell dynamics within the niches is tightly regulated; although new cardiomyocytes are continuously formed, the number of hCSCs within the niches remains constant in the heart in a steady state. According to the work by Itzhaki-Alfia and colleagues, the myocardial niche maintains a significant level of developmental plasticity in the diseased heart.8 Niches in the senescent failing organ retain the ability to sense cell injury in the tissue of residence, and they respond to these needs by increasing the number of dividing hCSCs. Although prolonged pathological states alter the niche microenvironment and/or progenitor cells, a class of hCSCs was collected from all myocardial samples, which points to a previously unappreciated growth reserve of the human heart. It defeats common thinking and projects a novel perspective for the management of the decompensated human heart.As reported by Itzhaki-Alfia and colleagues,8 myocardial samples obtained from female donors produced a larger number of hCSCs. These observations support speculation that the lower incidence of heart failure in women may depend on a greater or more efficient pool of hCSCs that may be present at birth and persist throughout life. This difference between the sexes may enhance cardiac cell turnover in adulthood and senescence, delaying the onset of the aging myopathy. Similarly, the adult female heart is more effective at sustaining pathological loads than is the male heart; the cardiomyocyte compartment in females is composed of younger, better-functioning cells because hCSCs may more efficiently replace old dying myocytes with new differentiated progeny.15,16 Although only 4 cases of end-stage heart failure were studied, the left ventricle was still the richest anatomic source of hCSCs.8 This is a critical and novel finding. It is difficult to envision how the cause of heart failure and the unpredictable path of the disease influence the hCSC compartment and its distribution. Ischemic heart disease and hypertension are the major causes of congestive heart failure; in both cases, prolonged overload on the myocardium may result in activation and proliferation of hCSCs located at the border zone of the necrotic or scarred infarct or scattered throughout the myocardium of the hypertensive heart. This possibility has been shown to be valid in animals17 and humans,11,18 which suggests that progenitor cells initiate an intense, albeit inadequate, regenerative response to counteract cell death and restore cardiac muscle mass.The study by Itzhaki-Alfia and collaborators8 emphasizes once more the critical role of hCSCs in the modulation of myocardial homeostasis and regeneration after injury. Different classes of stem and progenitor cells have been characterized in the embryonic, fetal, postnatal, and adult hearts, but whether they represent distinct categories of undifferentiated cells with diverse functional behavior is currently unknown. Various surface antigens and transcription factors have been used to identify these cells and their distribution in several anatomic regions of the heart (Figure 2). Although these findings have begun to untangle “the thread […] that will finally lead to the heart of a truth,” a heated controversy over myocyte regeneration persists.19 This scenario does not differ from the debate that in the early 1970s questioned the existence of hematopoietic stem cells, which were considered elusive and enigmatic. As discussed in Lancet,20 over the years, however, “the fierce controversies about the details of blood cell development…have quite died down. The textbooks no longer begin with descriptions and illustrations of rival theories; instead there seems general agreement on the existence of a stem cell which can give rise to all varieties of hemopoietic cells…. One of the reasons for its neglect is that most of the work has been done on rodents or birds…. Perhaps, experimental hematologists should now devote more of their resources to the direct study of human disease.” We should probably follow this suggestion. Download figureDownload PowerPointFigure 2. Cardiac progenitor cell classes. This scheme illustrates the classes of stem and progenitor cells described so far in the heart: c-kit-, Sca-1-, Isl-1- and Musashi-1-positive cells, side population, cardiospheres, and epicardial progenitors.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Source of FundingDr Leri is supported by grants from the National Institutes of Health.DisclosuresNone.FootnotesCorrespondence to Annarosa Leri, MD, Departments of Anesthesia and Medicine, and Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail [email protected] References 1 Leri A, Kajstura J, Anversa P. Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev. 2005; 85: 1373–1416.CrossrefMedlineGoogle Scholar2 Urbanek K, Cesselli D, Rota M, Nascimbene A, DeAngelis A, Hosoda T, Bearzi C, Boni A, Bolli R, Kajstura J, Anversa P, Leri A. Stem cell niches in the adult mouse heart. Proc Natl Acad Sci U S A. 2006; 103: 9226–9231.CrossrefMedlineGoogle Scholar3 Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med. 2007; 13: 970–974.CrossrefMedlineGoogle Scholar4 Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J. Evidence for cardiomyocyte renewal in humans. Science. 2009; 324: 98–102.CrossrefMedlineGoogle Scholar5 Montale E. Collected Poems 1920–1954. New York: Farrar, Straus and Giroux, 1998: 8–9.Google Scholar6 Suh H, Consiglio A, Ray J, Sawai T, D'Amour KA, Gage FH. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+-neural stem cells in the adult hippocampus. Cell Stem Cell. 2007; 1: 515–528.CrossrefMedlineGoogle Scholar7 Hosoda T, D'Amario D, Cabral-Da-Silva MC, Zheng H, Padin-Iruegas ME, Ogorek B, Ferreira-Martins J, Yasuzawa-Amano S, Amano K, Ide-Iwata N, Cheng W, Rota M, Urbanek K, Kajstura J, Anversa P, Leri A. Clonality of mouse and human cardiomyogenesis in vivo. Proc Natl Acad Sci U S A. 2009; 106: 17169–17174.CrossrefMedlineGoogle Scholar8 Itzhaki-Alfia Ayelet, Leor J, Raanani E, Sternik L, Spiegelstein D, Netser S, Holbova R, Pevsner-Fischer M, Lavee J, Barbash IM. Patient characteristics and cell source determine the number of isolated human cardiac progenitor cells. Circulation. 2009; 120: 2559–2566.LinkGoogle Scholar9 Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, Yasuzawa-Amano S, Trofimova I, Siggins RW, LeCapitaine N, Cascapera S, Beltrami AP, D'Alessandro DA, Zias E, Quaini F, Urbanek K, Michler RE, Bolli R, Kajstura J, Leri A, Anversa P. Human cardiac stem cells. Proc Natl Acad Sci U S A. 2007; 104: 14068–14073.CrossrefMedlineGoogle Scholar10 Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, Giacomello A, Abraham MR, Marbán E. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007; 115: 896–908.LinkGoogle Scholar11 Urbanek K, Torella D, Sheikh F, De Angelis A, Nurzynska D, Silvestri F, Beltrami CA, Bussani R, Beltrami AP, Quaini F, Bolli R, Leri A, Kajstura J, Anversa P. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci U S A. 2005; 102: 8692–8697.CrossrefMedlineGoogle Scholar12 Beltrami AP, Cesselli D, Bergamin N, Marcon P, Rigo S, Puppato E, D'Aurizio F, Verardo R, Piazza S, Pignatelli A, Poz A, Baccarani U, Damiani D, Fanin R, Mariuzzi L, Finato N, Masolini P, Burelli S, Belluzzi O, Schneider C, Beltrami CA. Multipotent cells can be generated in vitro from several adult human organs. Blood. 2007; 110: 3438–3446.CrossrefMedlineGoogle Scholar13 Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR. Human ISL 1-heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature. 2009; 460: 113–117.CrossrefMedlineGoogle Scholar14 Dodou E, Verzi MP, Anderson JP, Xu SM, Balck BL. Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development. 2004; 131: 3931–3942.CrossrefMedlineGoogle Scholar15 Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, Colussi C, Di Meglio F, Nadal-Ginard B, Frustaci A, Leri A, Maseri A, Anversa P. Senescence and death of primitive cells and myocytes leads to premature cardiac aging and heart failure. Circ Res. 2003; 93: 604–613.LinkGoogle Scholar16 Gonzalez A, Rota M, Nurzynska D, Misao Y, Tillmanns J, Ojaimi C, Padin-Iruegas ME, Müller P, Esposito G, Bearzi C, Vitale S, Dawn B, Sanganalmath SK, Baker M, Hintze TH, Bolli R, Urbanek K, Hosoda T, Anversa P, Kajstura J, Leri A. Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res. 2008; 102: 597–606.LinkGoogle Scholar17 Boni A, Urbanek K, Nascimbene A, Hosoda T, Zheng H, Delucchi F, Amano K, Gonzalez A, Vitale S, Ojaimi C, Rizzi R, Bolli R, Yutzey KE, Rota M, Kajstura J, Anversa P, Leri A. Notch1 regulates the fate of cardiac progenitor cells. Proc Natl Acad Sci U S A. 2008; 105: 15529–15534.CrossrefMedlineGoogle Scholar18 Urbanek K, Torella D, Sheikh F, De Angelis A, Nurzynska D, Silvestri F, Beltrami CA, Bussani R, Beltrami AP, Quaini F, Bolli R, Leri A, Kajstura J, Anversa P. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci U S A. 2003; 100: 10440–10445.CrossrefMedlineGoogle Scholar19 Parmacek MS, Epstein JA. Cardiomyocyte renewal. N Engl J Med. 2009; 361: 86–88.CrossrefMedlineGoogle Scholar20 Haemopoiesis. Lancet. 1972; 299: 1056–1057.CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By John J, Ushakumary M, Chandrasekher S and Chenicheri S (2022) COVID-19 and acute myocardial injury: Stem cell driven tissue remodeling in COVID-19 infection Stem Cells and COVID-19, 10.1016/B978-0-323-89972-7.00001-5, (111-124), . Pavlyukova E, Kolosova M, Unasheva A and Karpov R (2018) Left ventricular untwist in healthy children and adolescents born full-term, Bulletin of Siberian Medicine, 10.20538/1682-0363-2018-4-110-121, 17:4, (110-121) Kandaswamy E and Zuo L (2018) Recent Advances in Treatment of Coronary Artery Disease: Role of Science and Technology, International Journal of Molecular Sciences, 10.3390/ijms19020424, 19:2, (424) Fujita A, Mikamo A, Hamano K and Hosoyama T (2018) Cardiac Stem and Progenitor Cells for Treating Heart Diseases Reference Module in Biomedical Sciences, 10.1016/B978-0-12-801238-3.65514-9, . Leite C, Almeida T, Lopes C and Dias da Silva V (2015) Multipotent stem cells of the heart—do they have therapeutic promise?, Frontiers in Physiology, 10.3389/fphys.2015.00123, 6 Crisostomo V, Casado J, Baez-Diaz C, Blazquez R and Sanchez-Margallo F (2015) Allogeneic cardiac stem cell administration for acute myocardial infarction, Expert Review of Cardiovascular Therapy, 10.1586/14779072.2015.1011621, 13:3, (285-299), Online publication date: 4-Mar-2015. Purvis N, Bahn A and Katare R (2015) The Role of MicroRNAs in Cardiac Stem Cells, Stem Cells International, 10.1155/2015/194894, 2015, (1-10), . Bernal A and Gálvez B (2013) The Potential of Stem Cells in the Treatment of Cardiovascular Diseases, Stem Cell Reviews and Reports, 10.1007/s12015-013-9461-4, 9:6, (814-832), Online publication date: 1-Dec-2013. Anversa P, Kajstura J, Rota M and Leri A (2013) Regenerating new heart with stem cells, Journal of Clinical Investigation, 10.1172/JCI63068, 123:1, (62-70), Online publication date: 2-Jan-2013. Wen Z, Mai Z, Zhang H, Chen Y, Geng D, Zhou S and Wang J (2012) Local activation of cardiac stem cells for post-myocardial infarction cardiac repair, Journal of Cellular and Molecular Medicine, 10.1111/j.1582-4934.2012.01589.x, 16:11, (2549-2563), Online publication date: 1-Nov-2012. Teng M, Zhao X and Huang Y (2012) Regenerating cardiac cells: insights from the bench and the clinic, Cell and Tissue Research, 10.1007/s00441-012-1484-7, 350:2, (189-197), Online publication date: 1-Nov-2012. Ye L, Zhang E, Xiong Q, Astle C, Zhang P, Li Q, From A, Harrison D, Zhang J and Qin G (2012) Aging Kit Mutant Mice Develop Cardiomyopathy, PLoS ONE, 10.1371/journal.pone.0033407, 7:3, (e33407) Ferreira-Martins J, Ogórek B, Cappetta D, Matsuda A, Signore S, D'Amario D, Kostyla J, Steadman E, Ide-Iwata N, Sanada F, Iaffaldano G, Ottolenghi S, Hosoda T, Leri A, Kajstura J, Anversa P and Rota M (2012) Cardiomyogenesis in the Developing Heart Is Regulated by C-Kit–Positive Cardiac Stem Cells, Circulation Research, 110:5, (701-715), Online publication date: 2-Mar-2012. Rupp S, Bauer J, Gerlach S, Fichtlscherer S, Zeiher A, Dimmeler S and Schranz D (2012) Pressure overload leads to an increase of cardiac resident stem cells, Basic Research in Cardiology, 10.1007/s00395-012-0252-x, 107:2, Online publication date: 1-Mar-2012. Leri A, Hosoda T, Kajstura J, Anversa P and Rota M (2011) Identification of a coronary stem cell in the human heart, Journal of Molecular Medicine, 10.1007/s00109-011-0769-8, 89:10, (947-959), Online publication date: 1-Oct-2011. Leri A, Kajstura J, Anversa P, Dimmeler S and Losordo D (2011) Role of Cardiac Stem Cells in Cardiac Pathophysiology: A Paradigm Shift in Human Myocardial Biology, Circulation Research, 109:8, (941-961), Online publication date: 30-Sep-2011. Kajstura J, Rota M, Hall S, Hosoda T, D'Amario D, Sanada F, Zheng H, Ogórek B, Rondon-Clavo C, Ferreira-Martins J, Matsuda A, Arranto C, Goichberg P, Giordano G, Haley K, Bardelli S, Rayatzadeh H, Liu X, Quaini F, Liao R, Leri A, Perrella M, Loscalzo J and Anversa P (2011) Evidence for Human Lung Stem Cells, New England Journal of Medicine, 10.1056/NEJMoa1101324, 364:19, (1795-1806), Online publication date: 12-May-2011. Li T, Cheng K, Malliaras K, Matsushita N, Sun B, Marbán L, Zhang Y and Marbán E (2010) Expansion of human cardiac stem cells in physiological oxygen improves cell production efficiency and potency for myocardial repair, Cardiovascular Research, 10.1093/cvr/cvq251, 89:1, (157-165), Online publication date: 1-Jan-2011., Online publication date: 1-Jan-2011. December 22, 2009Vol 120, Issue 25 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.109.911107PMID: 19996014 Originally publishedDecember 7, 2009 Keywordsregeneration, myocardialstem cellsEditorialsPDF download Advertisement SubjectsHeart FailureMyocardial Regeneration