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• W2104820453 abstract "HomeCirculationVol. 113, No. 11Life and Death of Cardiac Stem Cells Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBLife and Death of Cardiac Stem CellsA Paradigm Shift in Cardiac Biology Piero Anversa, MD, Jan Kajstura, PhD, Annarosa Leri, MD and Roberto Bolli, MD Piero AnversaPiero Anversa From the Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, (P.A., J.K., A.L.); and the Institute of Molecular Cardiology, University of Louisville, Louisville, Ky (R.B.). Search for more papers by this author , Jan KajsturaJan Kajstura From the Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, (P.A., J.K., A.L.); and the Institute of Molecular Cardiology, University of Louisville, Louisville, Ky (R.B.). Search for more papers by this author , Annarosa LeriAnnarosa Leri From the Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, (P.A., J.K., A.L.); and the Institute of Molecular Cardiology, University of Louisville, Louisville, Ky (R.B.). Search for more papers by this author and Roberto BolliRoberto Bolli From the Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, (P.A., J.K., A.L.); and the Institute of Molecular Cardiology, University of Louisville, Louisville, Ky (R.B.). Search for more papers by this author Originally published21 Mar 2006https://doi.org/10.1161/CIRCULATIONAHA.105.595181Circulation. 2006;113:1451–1463The recognition that myocyte mitosis occurs in the fetal, neonatal, adult, and hypertrophied heart and that a pool of primitive, undifferentiated cells is present in the myocardium has put forward a different view of the biology of the heart. The new paradigm suggests that myocyte formation is preserved during postnatal life, in adulthood or senescence, pointing to a remarkable growth reserve of the heart throughout the course of life of the organism. This article reviews a large body of novel information, which has been obtained in the last 2 decades, in favor of the notion that the mammalian heart has the inherent ability to continuously replace its parenchymal cells and that this unexpected characteristic has important implications in understanding myocardial homeostasis, cardiac aging, and tissue repair.The Heart Is a Self-Renewing OrganThe paradigm that the heart is a postmitotic organ incapable of regenerating parenchymal cells was established in the 1970s, and this dogma has profoundly conditioned basic and clinical research in cardiology for the last 3 decades. On the basis of this paradigm, cardiomyocytes undergo cellular hypertrophy1,2 but cannot be replaced either by entry into the cell cycle of a subpopulation of nonterminally differentiated myocytes or by activation of a pool of primitive cells that become committed to the myocyte lineage. The only response of cardiomyocytes to stress is hypertrophy and/or death. Therefore, a tremendous effort was made to identify the molecular mechanisms of myocyte hypertrophy and their genetic control. A sophisticated knowledge of various signaling pathways has been achieved, and our understanding of the biology of hypertrophic myocyte growth has advanced markedly.3 An array of new technologies has been introduced that has led to a scientific revolution in terms of questions, approaches, and interpretation of experimental results. Despite this enormous progress in our understanding of basic mechanisms of hypertrophy, however, very little has been translated into clinical interventions that interfere with the dramatic impact of ischemic myocardial injury and the devastating evolution of postinfarction heart failure.4Recently, an established notion of cardiac biology has been questioned. The general belief that during prenatal life cardiac progenitor cells undergo progressive lineage commitment and differentiation,5 which results in an irreversible loss of developmental options in adulthood, may not be valid.6 Similarly, the traditional view of the heart as an organ incapable of regeneration has been challenged. Myocyte replication, karyokinesis, cytokinesis, and foci of spontaneous myocardial regeneration have been documented in the human heart.7,8 These observations, together with the recognition that cell division, telomerase activity, telomeric shortening, and apoptosis occur in myocytes with aging and cardiac failure,7,9,10 suggest that in the adult heart, a class of parenchymal cells proliferates, undergoes telomere attrition, reaches terminal differentiation, and possibly experiences replicative senescence and ultimately, cell death.If adult, fully differentiated myocytes (≈25 000 μm3 in volume) were to retain the ability to divide, cells in mitosis before cytokinesis would be expected to be ≈50 000 μm3 to give rise to 2 daughter cells, each ≈25 000 μm3. Surprisingly, human myocytes in mitosis vary in size from <1000 μm3 to at most 5000 μm3, indicating that a different mechanism of myocyte formation is operative in the adult heart.8,10–12 The replicating cardiomyocytes resemble small amplifying cells that have originated by activation of progenitor cells. These observations, together with the demonstration of male cells in female hearts transplanted in male recipients,13 were the critical findings that led to the identification and characterization of stem cells in the adult myocardium. The presence of male cells in the female heart raised the possibility that these cells either were the progeny of primitive cells of the recipient’s bone marrow, which homed to the heart through the systemic circulation, or represented the product of stemlike cells that had migrated to the allograft from cardiac remnants.14 The discovery of cardiac stem cells (CSCs)6,15–20 distinct from hematopoietic stem cells (HSCs) and minimal spontaneous engraftment of HSCs into the heart argue against a significant role of the bone marrow in the turnover of cardiac cells.21,22The recognition that a pool of primitive cells resides in the myocardium and that these cells form myocytes, smooth muscle cells (SMCs), and endothelial cells (ECs)8,15,16,23 has provided a different perspective concerning the biology of the heart and mechanisms of myocardial homeostasis and tissue repair. The new paradigm implies that myocytes are no longer considered unusual cells that are created only during embryonic and fetal development so that their total number in the heart is established at birth and no further growth occurs postnatally, in adulthood, or during senescence.2,24 This paradigm refutes the belief that all cardiomyocytes have the same age and that the age of these cells corresponds to the age of the organ and organism. Similarly, this paradigm suggests that the turnover and growth of vascular SMCs and ECs may be regulated by differentiation of CSCs more than by the ability of these mature cells to reenter the cell cycle and divide.Thus, a new conceptual framework of the heart has emerged. The heart is now viewed as a self-renewing organ in which myocyte regeneration occurs throughout the organism lifespan (Figure 1). Myocytes are the progeny of resident CSCs stored in niches. The niches control the turnover of myocardial cells and the growth, migration, and commitment of primitive cells that leave the niches to replace old, dying cells in the myocardium.25 Regeneration implies that dead cells are replaced by newly formed cells that differentiate and organize in a complex pattern, restoring the original structure of the lost tissue. In adulthood, this process occurs in its completeness during physiological cell turnover, in the absence of injury. It is unknown why damage interferes with the recapitulation of cell turnover and restitutio ad integrum of the organ. A plausible hypothesis is that inflammation at the site of injury opposes the orderly reconstitution and spatial arrangement of myocytes and coronary vessels.26 However, CSCs can be coaxed in vivo to home to the damaged area and promote the formation of parenchymal cells and vascular structures, resulting in recovery of ventricular performance.23,25Download figureDownload PowerPointFigure 1. New paradigm of the heart. A, Cardiac niches contain stem cells, which, after activation, give rise to myocytes and vascular structures. B through E, Dividing myocytes (α-sarcomeric actin, red) in fetal (B), neonatal (C), adult (D), and hypertrophied (E) rat heart. Mitotic myocytes (arrows) are shown in inserts. Bright blue denotes Ki67. Scale bars=10 μm; for methods, see references.7,8,11,12Phenotype of CSCsInvestigators in several laboratories concur with the notion that the heart contains a compartment of undifferentiated cells with the characteristics of stem cells.6,8,15–20,23,25,27 However, the actual number of CSCs remains controversial. Reports in mice,17,25 rats,15 dogs,23 and humans8 indicate that there is 1 stem cell per ≈8000 to 20 000 myocytes, or ≈32 000 to 80 000 cardiac cells. Some investigators have reported that primitive cells represent 2% of all cells, ie, 2 per ≈25 myocytes, or ≈100 cardiac cells.16,18 This high value may reflect the contribution of endothelial progenitors.19,27 Discrepancy also exists in the identification of the stem cell antigens c-kit and Sca-1 on cardiac primitive cells. The presence of Sca-1 has been reported,16–19,25,27 whereas c-kit has been detected in 4 studies15,17,25,27 and found to be absent in another.16 c-kit–positive cells are an established component of the canine23 and human7,8,13,20 heart, and their activation leads to formation of new myocardium (Figure 2). The regenerative potential of c-kit–positive and Sca-1–positive cells after infarction15 or ischemia/reperfusion injury16,28 differs significantly; a robust regenerative response occurs with c-kit–positive cells,15,28 whereas little engraftment and repair take place with Sca-1–positive cells.16 Whether the modality of administration of cells, the animal model, and the properties of the injected cells are responsible for the different outcome is presently unclear. Download figureDownload PowerPointFigure 2. Primitive cells and myocardial regeneration. A, Cluster of c-kit–positive CSCs (green) in human heart. B and C, Arrowheads in B delineate new myocytes (myosin, red), and the rectangle delimits the area at higher magnification in C. Ki67 (yellow) labels developing myocytes, 1 of which is in mitosis (arrow). Arrowheads indicate c-kit–positive cells. Scale bars=10 μm; for methods, see Urbanek et al.8 B and C are reproduced with permission from Urbanek et al.7 Abbreviations are as defined in text.The developing and adult heart typically contain a CSC pool that has the ability to efflux the Hoechst 33342 dye.6,16,18,19,29 Similar cells, which express an ATP-binding cassette transporter, have been identified in other organs and termed side-population (SP) cells.19,30 The classic member of this family is a P-glycoprotein that confers to the cells multidrug resistance by extruding anticancer drugs and rhodamine 123. These putative CSCs are 93% Sca-1–positive and appear to represent a subset, 1 per ≈10 000 cells, of the 2% Sca-1–positive cells in the mouse heart.16 According to a different study, however, SP cells comprise 2% of all cells (2 per ≈100 cardiac cells).18 Cardiac SP cells appear to express CD31 and form hematopoietic colonies in vitro.18 The presence of CD31, common to bone marrow SP cells,21,30 together with the peculiar growth behavior of these cells in vitro, raises questions concerning their actual origin and suggests possible colonization to the heart from the hematopoietic system.Recently, a novel Sca-1–positive, Hoechst 33342 dye–low, and CD31-negative cardiac SP cell has been identified.19,29 The modest expression of c-kit in these cells was attributed to methodological limitations inherent in the enzymatic cleavage of this receptor during digestion of the myocardium and cell isolation.19 There is 1 SP cell per ≈30 000 cardiac cells in the mouse heart. CD31-negative cardiac SP cells acquire the myocyte lineage, reach the adult phenotype through a process mediated by cellular coupling with differentiated cardiomyocytes, and contract in vitro.19 These results strengthen the notion of a functional role for resident SP cells in the heart.The Isl1 transcription factor is associated with the commitment to the myocyte lineage of cardiac cells that have lost their undifferentiated stem cell state. Isl1 and GATA4 are transcriptional coactivators of the myocyte transcription factor MEF2C.31 Homozygous deletion of Isl1 alters development of the mouse heart, affecting the atria, right ventricle, and outflow tract,32,33 and Isl1-positive cells may have implications for myocyte replacement in the newborn.34Together, these observations are consistent with the notion that the heart possesses an intrinsic capacity for regeneration, but whether differences in the expression of surface antigens reflect CSC subclasses, which are functionally distinct, is difficult to ascertain. A direct comparison among stem cell phenotypes would require transplantation studies in which single CSCs are delivered to the chemically ablated or irradiated organ. To date, no information is available concerning the repopulating ability of individual CSCs in the depleted heart. Stem cell depletion is complex in solid organs, and currently, there are no protocols available to eliminate resident CSCs in the absence of extensive parenchymal damage and myocardial scarring.26 So far, only limited characterization of the in vitro properties of CSCs has been performed. However, these data do not answer the question whether the expression of 1 stem cell antigen versus another carries a greater or reduced regeneration potential for the diseased heart.Classification of CSCs and Their ProgenyInformation obtained so far on the phenotype of adult CSCs is incomplete. The nomenclature is imprecise, and frequently, cells with distinct growth behaviors are defined by the same terminology. Some comments may be helpful. CSCs are undifferentiated, lineage-negative cells that possess a high growth potential.6,15–20,23,25 At the single-cell level, CSCs are self-renewing, clonogenic,15,19,23 and capable of differentiating in mature progenies in vitro15–17,19,23 and in vivo.8,15,16,23,25 Stem cells divide rarely, whereas the committed, amplifying cells are the actual group of replicating cells. Stem cells in the bone marrow, some areas of the brain, skeletal muscle, and heart share in different proportions the stem cell–related antigens c-kit, MDR1, and Sca-1.8,23,25We propose a classification of cardiac immature cells into 4 classes: CSCs, progenitors, precursors, and amplifying cells. These cell types can be viewed as subsequent steps in the progressive evolution from a more primitive to a more differentiated phenotype (Figure 3). The first 3 cell types express c-kit, MDR1, and Sca-1, whereas the last type no longer expresses these antigens. This relatively simple terminology defines the fundamental characteristics of CSCs and the classes of cells generated by their lineage commitment. Download figureDownload PowerPointFigure 3. Hierarchy of CSC growth and differentiation. A, Asymmetrical division of a CSC into a daughter CSC and a daughter cardiac progenitor (CPg). CPg gives rise to myocyte progenitor (MPg) and precursor (MPr), EC progenitor (EPg) and precursor (EPr), and SMC progenitor (SMPg) and precursor (SMPr). Precursors become transient amplifying cells, which divide and differentiate into mature myocytes, ECs, and SMCs. CSCs are lineage-negative cells that express only c-kit, MDR1, or Sca-1. Progenitors express stem cell antigens and transcription factors of cardiac cells but do not exhibit specific cytoplasmic proteins. Precursors possess stem cell antigens, transcription factors, and membrane and cytoplasmic proteins typical of myocytes, ECs, and SMCs. Amplifying cells have nuclear, cytoplasmic, and membrane proteins of cardiac cell lineages but are negative for stem cell antigens. TGFβ indicates transforming growth factor β receptor; other abbreviations are as defined in text. B, Colocalization of c-kit, MDR1, and Sca-1 in CSCs. Areas corresponding to cells positive for 1 antigen only were enlarged 3 times. C and D, Clones derived from a single Sca-1–like-positive cell (C, yellow) and a single c-kit–positive cell (D, green). Scale bars=100 μm. Reproduced with permission from Linke et al.23The recognition of lineage-negative CSCs and their progenies is technically demanding and complex in the rat,15 mouse,6,16–19,25 dog,23 and human8 heart. These cell categories can be identified in isolated cardiac cell preparations or in sections of atrial and ventricular myocardium. In both cases, this is accomplished by utilizing several mixtures of antibodies directly labeled by fluorochromes to avoid cross-reactivity and nonspecific staining.8,23 With histological approaches, major screening with cocktails of fluorescein-conjugated antibodies may be followed by immunostaining with indirect labeling; this approach requires the use of secondary antibodies. Additionally, it is necessary to achieve the level of resolution afforded by confocal microscopy.35 Contrary to common belief,2,36–38 confocal microscopy is the only method that permits quantitative measurement of the frequency and distribution of CSC classes in the myocardium.26,39 Fluorescence-activated cell sorting analysis is extremely efficient in separating cells in specific categories according to the expression of 1 or more surface epitopes,40,41 but the distinction between lineage-negative and committed cells requires the analysis of nuclear and cytoplasmic proteins. This can only be obtained by fixation of cells to make them permeable for the detection of intracellular components.42,43 Similar problems exist with immunolabeling. With either protocol, cell viability is lost, precluding further study.Although stem cells have been known for quite some time, the importance of stem cell antigens in the growth and differentiation potential of these cells remains poorly understood.44–46 These limitations are not restricted to the heart and CSCs but also apply to stem cells in other organs, including the bone marrow. As indicated earlier, c-kit, MDR1, and Sca-1 are present not only on the surface of primitive cells but also in cells undergoing lineage differentiation, complicating recognition of the actual primitive cells in the population. Similarly, the detection of these antigens in cells collected by enzymatic digestion of the myocardium is highly dependent on the isolation protocol, which inevitably affects the yield, properties, and purity of the preparation, as well as the integrity of surface antigens. For this reason, some of the differences encountered in the characterization of CSCs and various subsets may be accounted for by technical difficulties inherent in the separation and collection of these cells from a solid organ.19To gain insights into the functional implications that different CSC surface antigens may have in myocardial growth in large mammals, CSCs were isolated and characterized in the dog heart.23 Consistent with results in the mouse,25 rat,15 and human8 heart, canine CSCs expressing 3 surface antigens constitute the prevailing population, (≈60%); those expressing 2 antigens, the second most frequent fraction (≈25%); and those expressing 1 antigen, the least represented component (≈15%). CSCs with 1 epitope were equally distributed, nearly 5% for each surface antigen. The size of clones and subclones varies when CSCs express different epitopes (Figure 3).Clones from c-kit–positive CSCs are 2.3-fold, 5.9-fold, and 7.6-fold larger than MDR1-, Sca-1–like-, and c-kit/MDR1/Sca-1–like-positive clones, respectively.23 When the same number of clonogenic cells, ≈100, from each of these clones is driven to growth and differentiation, the magnitude of the population of committed cells differs, depending on whether it develops from c-kit–, MDR1-, Sca-1–like-, or c-kit/MDR1/Sca-1–like-positive clonogenic cells. Over a period of 4 weeks, 1.05×106, 3.9×105, 2.4×105, and 1.6×105 differentiated cardiac cells are formed from c-kit–, MDR1-, Sca-1–like-, and c-kit/MDR1/Sca-1–like-positive clonogenic cells, respectively.23 Therefore, the ability of c-kit–positive cells to generate cardiac cell lineages is greater than that of MDR1-, Sca-1–like-, and c-kit/MDR1/Sca-1–like-positive cells. Clonogenic MDR1-positive cells produce more myocardial cells than do Sca-1–like- and c-kit/MDR1/Sca-1–like-positive cells. Although there is no appreciable difference in the relative proportion of myocytes formed by each clonogenic CSC class (myocytes, ≈50%; SMCs, ≈40%; and ECs, ≈10%), the aggregate number of myocytes, SMCs, and ECs created by the c-kit–positive cells is several-fold larger than that obtained from other CSC categories.23Understanding the relation between stem cell antigens and growth characteristics of CSCs has important implications in the future implementation of CSC therapy in patients. A critical question that needs to be addressed is whether human c-kit–positive CSCs, followed by MDR1-positive cells, constitute the more powerful CSC classes for acute regeneration of myocytes and coronary vessels in the damaged heart. Sca-1–like- and c-kit/MDR1/Sca-1–like-positive CSCs may be less relevant for emergency need and may be implicated in the formation of coronary arterioles, capillary structures, and myocytes to compensate for a defective growth in the other stem cell populations. Alternatively, these latter 2 classes may be prevalently involved in the low physiological turnover of cardiac cells. These possibilities are not mutually exclusive.CSCs and Cell TurnoverResearchers from 8 laboratories have shown that stem cells are present in the adult heart of small and large mammals, including humans.6–8,13,15–20,23,25,27,29 Despite these findings, the shift in paradigm from the heart as a postmitotic organ to a self-renewing organ has not yet occurred. At best, the heart is now viewed as an organ capable of some but severely limited regeneration.1,2,18,47 On the basis of this premise, strategies aimed at reversing the terminally differentiated state of myocytes have been proposed as an alternative intervention for the cellular repopulation of the diseased heart.48 In this section, we discuss the reasons for the unwillingness to lay to rest the old dogma and adopt a novel biological perspective of the heart. The new paradigm sees the heart as a highly dynamic organ in which old, poorly functioning myocytes and vascular SMCs and ECs are continuously replaced by activation and commitment of resident CSCs. The recognition of the mechanisms that regulate the physiological turnover of cardiac cells may offer a unique, unprecedented approach for cardiac repair. Potentiation of this naturally occurring process may become the most efficient and successful form of tissue reconstitution for the failing heart. In this scenario, exogenous expansion of autologous CSCs,15,16,20 bone marrow progenitor cells,35,49–53 and skeletal myoblasts54 for subsequent myocardial implantation55,56 would be seen as a secondary model of cell therapy and not as the primary method of choice. Similarly, the use of genetically manipulated, nonmalignant, nonimmunogenic embryonic stem cells57,58 would be envisioned only in extreme cases. Currently, embryonic stem cells are immunogenic59 and tumorigenic,60–62 precluding their clinical relevance in the near future.26The reluctance to accept a reassessment of cardiac biology and pathology has its foundation on 4 major questions: (1) Are CSCs responsible for myocardial homeostasis and therefore, for an effective physiological replacement of dying cardiac cells, including cardiomyocytes? (2) Is the CSC pool activated after injury, and if so, does this lead to a relevant increase in the number of myocytes and coronary vessels? (3) If properly activated, are CSCs able to translocate to areas of damage, grow, and differentiate, thereby restoring the lost myocardium? (4) Assuming that the heart has a powerful growth reserve dictated by the CSC compartment, do aging and chronic heart failure reduce the pool of functionally competent CSCs, and if so, is this defect important in the development of end-stage failure? The answers to these questions will provide a framework for a cardiac paradigm that does not ignore the discovery of CSCs and their role in the life and death of the heart.Cardiac homeostasis is regulated by the balance between old, senescent cardiac cells undergoing apoptosis/necrosis and the formation of new cells through the commitment of CSCs. CSCs are clustered in the atria and apex but are also present throughout the ventricular myocardium.25 An equivalent loss and generation of cardiomyocytes, vascular SMCs, and ECs would be expected to occur in the entire heart to preserve its equilibrium, before aging effects become apparent.10,63,64 Because of the conviction that myocytes cannot be replaced1,2 and that “adult” SMCs and ECs reenter the cell cycle and divide,65,66 independently from lineage specification of primitive cells, the possible function of CSCs in myocardial cell turnover has only been recently explored.Information obtained so far is incomplete but strongly supports the notion that the heart contains a pool of replicating, lineage-negative CSCs, together with myocyte, SMC, and EC progenitors and precursors, and highly proliferating amplifying cells. The retroviral tagging of undifferentiated cells in vivo or in vitro before their intramyocardial injection has demonstrated that developing and mature cells are the progeny of activated CSCs.15,25,28 A similar analysis could not be obtained in the human heart. All of these cell classes have been identified in the ventricular myocardium, however, suggesting that a similar growth behavior occurs in the human heart (Figure 4) and that it involves CSC multilineage commitment and differentiation.7,8,10–13 Myocytes, and SMCs and ECs in coronary vessels, die continuously, and the constant replacement of cells preserves the integrity of the tissue and the function of the organ. Whether cell death triggers regeneration or whether regeneration activates cell death is not known, but cellular aging with loss of replicating cells is invariably associated with initiation of the death pathway.67–69Download figureDownload PowerPointFigure 4. Regeneration of human myocardium. A and B, Small, developing myocytes (α-sarcomeric actin, red) are positive for telomerase (A, green) and MCM5 (A, white). MEF2C is also present in the nuclei (B, yellow), and connexin 43 is detected (B, green, arrowheads). C through E, Metaphase chromosomes (C), karyokinesis (D), and cytokinesis (E, arrows) are present in dividing myocytes. Ki67 in the chromosomes is apparent (C through E, yellow). Developing arteriole with SMCs (α-smooth muscle actin, red) contains erythrocytes (yellow). Dispersed SMCs are observed (F, arrows); GATA6 is present in SMC nuclei (white dots). Scale bars=10 μm. Reproduced with permission from Urbanek et al7 (C–E) and Urbanek et al8 (A, B, F).In recent work,7,8,10–13 the numbers of cycling and noncycling lineage-negative CSCs, myocyte progenitors/precursors, cycling amplifying myocytes, terminally differentiated nonaged myocytes, and senescent myocytes have been measured in the human heart. Similarly, the mitotic index and Ki67 and MCM5 labeling of myocyte nuclei have been obtained in humans.7,8,11,12 On the basis of the fact that mitosis is a rapid process,70 the duration of the cell cycle in forming myocytes has been estimated previously to be ≈25 hours.7,11,12 Additionally, the ratio of progenitors to precursors to amplifying cells to lineage-negative CSCs was determined8 to compute the number of transit generations from the uncommitted state to terminal differentiation, ie, ≈7 rounds of the cell cycle.71 Together, these data define the rate of turnover (death/formation) of the myocyte population. In the normal human heart, there are ≈5×109 parenchymal cells in the left ventricle inclusive of the interventricular septum,72,73 and ≈3×106 terminally differentiated myocytes are generated per day (Table) by commitment and growth of CSCs.7,8,11,12 This degree of myocyte formation ensures that the entire cell population of the heart is replaced approximately every 4.5 years. Thus, parenchymal cells cannot live, as is generally believed, as long as the organism, ≈80 years.74 The human heart replaces completely its myocyte population ≈18 times during the course of life, independently from cardiac diseases. Generation and Loss of Myocytes in the Normal and Infarcted Human HeartControlAcute InfarctsChronic InfarctsMean±SDReferencesMean±SDReferencesMean±SDReferences*P<0.05 vs control hearts.†P<0.05 vs acute infarcts.‡Not significantly different from 1.00.§Product of line 3 and line 4.∥Quotient of line 7 and line 6.¶Quotient of line 5 and line 8.CSCs, cells/mm33.7±0.57, 841±7*811±2*†8Cycling CSCs, %3.5±1.87, 833±6*7, 815±3*†7, 8Myocytes generated, cells · d−1 · mm−318±77, 81160±290*7, 8130±31*†7, 8Viable LV mass, g164±277, 8, 11, 12190±318, 12260±38*†8, 11Myocytes generated in LV, cells/d2.9±1.0×106§…220±42×106*§…34±6×106*†§…Myocytes in LV4.9±1.0×1097, 8, 11, 124.6±0.7×1098, 124.3±0.7×1098, 11Time to replace LV myocytes, d1668±740∥…21±6*∥…125±37*†∥…Myocytes lost in LV, cells/d2.9±0.9×10675, 76179±49×106*75, 7697±21×106*†75, 76Myocytes generated-to-lost ratio1.0±0.47‡¶…1.22±0.41‡¶…0.35±0.10¶…There is a remarkable balance between the formation and loss of myocytes physiologically (Table). It has been shown that in" @default.
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• W2104820453 title "Life and Death of Cardiac Stem Cells" @default.
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• W2104820453 doi "https://doi.org/10.1161/circulationaha.105.595181" @default.
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