Mammalian Heart Regeneration
Authors: Stefanie A. Doppler, Marcus-Andre Deutsch, Vahid Serpooshan, Guang Li, Elda Dzilic, Rüdiger Lange, Markus Krane, Sean M. Wu
Journal: Circulation Research (2017)

HomeCirculation ResearchVol. 120, No. 4Mammalian Heart Regeneration Free AccessDiscussionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessDiscussionPDF/EPUBMammalian Heart RegenerationThe Race to the Finish Line Stefanie A. Doppler, Marcus-Andre Deutsch, Vahid Serpooshan, Guang Li, Elda Dzilic, Rüdiger Lange, Markus Krane and Sean M. Wu Stefanie A. DopplerStefanie A. Doppler From the Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Germany (S.A.D., M.-A.D., E.D., R.L., M.K.); Stanford Cardiovascular Institute (V.S., G.L., E.D., S.M.W.), Institute for Stem Cell and Regenerative Medicine (S.M.W.), and Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.-A.D., M.K.). , Marcus-Andre DeutschMarcus-Andre Deutsch From the Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Germany (S.A.D., M.-A.D., E.D., R.L., M.K.); Stanford Cardiovascular Institute (V.S., G.L., E.D., S.M.W.), Institute for Stem Cell and Regenerative Medicine (S.M.W.), and Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.-A.D., M.K.). , Vahid SerpooshanVahid Serpooshan From the Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Germany (S.A.D., M.-A.D., E.D., R.L., M.K.); Stanford Cardiovascular Institute (V.S., G.L., E.D., S.M.W.), Institute for Stem Cell and Regenerative Medicine (S.M.W.), and Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.-A.D., M.K.). , Guang LiGuang Li From the Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Germany (S.A.D., M.-A.D., E.D., R.L., M.K.); Stanford Cardiovascular Institute (V.S., G.L., E.D., S.M.W.), Institute for Stem Cell and Regenerative Medicine (S.M.W.), and Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.-A.D., M.K.). , Elda DzilicElda Dzilic From the Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Germany (S.A.D., M.-A.D., E.D., R.L., M.K.); Stanford Cardiovascular Institute (V.S., G.L., E.D., S.M.W.), Institute for Stem Cell and Regenerative Medicine (S.M.W.), and Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.-A.D., M.K.). , Rüdiger LangeRüdiger Lange From the Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Germany (S.A.D., M.-A.D., E.D., R.L., M.K.); Stanford Cardiovascular Institute (V.S., G.L., E.D., S.M.W.), Institute for Stem Cell and Regenerative Medicine (S.M.W.), and Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.-A.D., M.K.). , Markus KraneMarkus Krane From the Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Germany (S.A.D., M.-A.D., E.D., R.L., M.K.); Stanford Cardiovascular Institute (V.S., G.L., E.D., S.M.W.), Institute for Stem Cell and Regenerative Medicine (S.M.W.), and Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.-A.D., M.K.). and Sean M. WuSean M. Wu From the Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Germany (S.A.D., M.-A.D., E.D., R.L., M.K.); Stanford Cardiovascular Institute (V.S., G.L., E.D., S.M.W.), Institute for Stem Cell and Regenerative Medicine (S.M.W.), and Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.-A.D., M.K.). Originally published17 Feb 2017https://doi.org/10.1161/CIRCRESAHA.116.310051Circulation Research. 2017;120:630–632A long-standing goal of cardiovascular scientists is to repair damaged hearts after myocardial infarction by overcoming the limited regenerative capacity of the adult mammalian heart. Many new strategies are being actively investigated for generating functional cardiomyocytes or progenitor cells. The race is on for the first demonstration of durable therapeutic heart repair in human.The classical paradigm that the adult mammalian heart is a postmitotic, terminally differentiated organ has been actively debated. Data from 14C dating studies have demonstrated a limited self-renewal capacity of the adult mammalian heart that declines with age.1 These repair processes are, however, insufficient to compensate for extensive cell loss occurring after acute or chronic cardiac injury. Therefore, investigators in cardiovascular regenerative medicine have actively explored different approaches to replace the postinfarct scar tissue with contractile muscle cells. Despite these efforts, a central question for the field of cardiac regenerative medicine remains: what strategy will take us to the finish line in this race to achieve complete heart regeneration? In this Viewpoint article, we comment on recent experimental and clinical approaches to regenerate the failing heart and highlight the urgent need to clarify the biology of cardiomyocyte (CM) development, growth, and maturation.Mechanisms of Endogenous RegenerationThe mammalian heart harbors multiple cell types that may be targeted in regenerative strategies. Conceptually, the most direct approach is to stimulate pre-existing CMs to re-enter the cell cycle. Alternatively, resident cardiomyogenic stem/progenitor cell populations have been described to differentiate directly into CMs. Although there are advantages and disadvantages to each approach, it is clear that both strategies have demonstrated early promises that require further improvement and independent validation in nonrodent models.Induction of Cardiomyocyte DivisionNeonatal HeartThe regenerative capacity of the neonatal mammalian heart seems to be greater than that of adult heart because of the presence of a short window of CM proliferative competence.2 Immediately after birth, the neonatal mouse heart harbors some regenerative potential, although ongoing debate remains about the exact degree of regeneration. Neonatal regeneration in the human heart has been suggested by newborn children with acute myocardial infarction.3 However, whether this recovery involves CM regeneration versus ventricular unloading and early revascularization requires further validation. With regard to the signaling pathways that might activate neonatal CM division, it has been reported that Meis1 and neuregulin-1 play important roles.2,4 The finding of extensive CM proliferation seen in Hippo pathway knockout animals raises exciting prospect for future therapies.5Adult HeartDuring physiological homeostasis in human, the number of new adult CMs generated is estimated to be ≈1% per year.1 This rate declines with age but likely increases after injury. D'Uva et al6 recently reported the induction of binucleated CM proliferation by constitutive activation of the ERBB2 receptor. Interestingly, this approach results in cardiac hypertrophy and CM proliferation in the neonatal heart and CM dedifferentiation, proliferation, and redifferentiation in the adult heart.Recruitment of Endogenous Stem/Progenitor CellsThe role of endogenous stem/progenitor cells to mediate heart repair or regeneration has garnered intense interest among cardiovascular investigators. This coincided with the rising interest in stem cell biology in general in the past 2 decades and the hope that this alternative approach may be more efficient in generating new CMs in the diseased heart than trying to force a mitotically inactive adult CM to re-enter the cell cycle.Resident Cardiac Stem CellMany different cell populations within the adult heart expressing markers such as Sca-1, c-Kit, Hoechst dye exclusion (ie, side population), or PDGFRα have been studied for their cardiomyogenic potential.7 In most cases, these cells were shown to turn on sarcomeric protein genes under in vitro culturing conditions, and their identity as a stem/progenitor cell for CMs has been proposed based on these data. Given the limited cell engraftment/survival after transplantation, it has been challenging to assess the degree of their differentiation into functional CMs in vivo. Recent lineage-tracing data have raised the possibility that few c-Kit–expressing cells give rise to adult CMs in the murine heart.8 Intriguingly, a large number of c-Kit+ cells in the adult heart may represent endothelial cells, and a rare number of these may undergo CM conversion.9Circulating Stem/Progenitor CellThe bone marrow, spleen, and the liver can serve as reservoir for hematopoietic stem or progenitor cells that respond and migrate to the site of myocardial injury via circulation. Although these cells seem to provide important cytokines/growth factors for cardiac repair, they do not become CMs by direct differentiation.10 Recently, Wu et al11 used a murine parabiosis model to show that a small number of circulating cells adopted cardiovascular cell fate via cell fusion, whereas an even smaller (<0.1%) number of cells result from transdifferentiation. It seems that cell fusion as a strategy for generating new proliferative cardiomyocytes would require a significant increase in efficiency to be effective for repairing the ≈1 billion lost cardiomyocytes after a large infarction.Transplantation of Exogenous CellsA wealth of basic and clinical studies in the past 2 decades has examined the consequences of autologous cell transplantation to regenerate the damaged heart. Although many issues have been explored, it remains unclear whether there is an optimal cell type that can regenerate the damaged heart after transplantation. Given the space constraint, we refer the readers to other excellent review article on this topic and instead focus our discussion to studies involving transplantation of pluripotent stem cell–derived CMs as a potential strategy for remuscularizing post-MI hearts.Pluripotent Stem Cell–Derived Cardiac CellsMouse and human embryonic stem cells (ESCs) have demonstrated remarkable capacity to differentiate into multiple key cardiac cell types in the body. However, the use of human ESCs (hESCs) for research or clinical purposes has raised ethical concerns. The establishment of induced pluripotent stem cells (iPSCs) by somatic reprogramming circumvented many of these ethical challenges. Although iPSCs have proven to be a robust alternative to ESCs, questions about their risk of teratoma formation remain. Furthermore, hiPSC-derived CMs are fetal-like and immature so may not fully recapitulate the adult mature CM physiology required for proper function. Nevertheless, there has been significant progress in the transplantation of human ESC- or iPSC-derived cardiac cells by either direct injection or a cardiac patch.By Direct InjectionWith regard to transplantation of hESC-derived CMs (hESC-CMs), a series of studies in rodents followed by large animal models have led to the first demonstration of hESC-CMs transplantation into a nonhuman primate model.12 These GCaMP-labeled hESC-CMs (≈109 cells) were intramyocardially injected into infarcted macaque hearts. The investigators showed that a fraction of the injected CMs integrated into the host myocardium by histological assessment and were electrically coupled to the native rhythm. Interestingly, there was an increased incidence of nonfatal ventricular arrhythmias during the first 2 to 4 weeks after transplantation. Further studies will be needed to reduce the frequency of ventricular arrhythmia and assess whether the engrafted cells contribute to cardiac function in the long term.Via Engineered Cardiac PatchTo overcome the challenges associated with cell survival after transplantation, investigators have explored the creation of bioengineered tissues using cells or soluble factors. A recent study demonstrated the delivery of human ESC-derived cardiac cells in cardiac patches into ischemic cardiomyopathy patients.13 Although not designed as an efficacy study, the reported improvement of left ventricular ejection fraction from 26% to 36% by echocardiography is encouraging. Importantly, no arrhythmia, teratoma formation, or immunosuppression-related events were observed. Many issues on the use of bioengineered patches will need to be resolved. These includes the need for a well-developed vascular network for cell survival, electrically synchronizing the transplanted cells with the native myocardium, and, ideally, a less invasive way to introduce these patches so that the number of patients eligible to receive this treatment is not limited to the ones who are undergoing an open-chest surgery. We anticipate that new engineering breakthroughs such as 3-dimensional bioprinting, decellularized cardiac matrix, or novel nanoparticles will help to move the field forward.Direct Reprogramming StrategiesDistinct from the reprogramming of adult somatic cells into iPSCs, the direct reprogramming of one adult cell type into another, without passing through a pluripotent state, has been vigorously pursued in recent years. A theoretical advantage of this approach is the availability of a larger population of fibroblasts in a post-MI heart that can be targeted and the avoidance of teratoma risk.Conversion of Fibroblasts Into CardiomyocytesBy the overexpression of 3 cardiac transcription factors (Gata4, Mef2c, and Tbx5), Ieda et al14 reported the generation of induced CMs in vitro. This study was subsequently followed by studies reporting the conversion of cardiac fibroblasts into CMs in vivo. Additional follow-on studies have identified new transcription factors, microRNAs, and delivery methods to improve the efficiency of fibroblasts conversion to CMs; however, questions remain as to whether this method will be efficient enough to generate the large number of CMs needed for complete regeneration and whether the reprogramming methods in animal models would work as well in humans without using oncogenic viral vectors.Conversion of Fibroblasts Into Cardiac Progenitor CellsGiven the limited proliferation of differentiated CMs, it has become of interest to directly reprogram fibroblasts into cardiac progenitor cells (CPCs) that can proliferate and differentiate into all major cardiac lineages. Recently, Lalit et al15 reported the generation of tripotent CPCs by introducing Gata4, Nkx2.5, Tbx5, Mesp1, and Baf60c into fibroblasts via lentiviruses. The authors reported improvement in cardiac function after transplantation of these induced CPCs into infarcted mouse hearts. It remains to be determined whether the cardiac functional improvement is directly related to the generation of new CMs from induced CPCs or from an injection paracrine effect. Furthermore, it would be of interest to see whether this phenomenon holds true during in vivo induced CPC reprogramming.Summary and Future PerspectiveThe number and variety of promising approaches to address the failing heart via endogenous and exogenous stem cells and direct CM targeting clearly reflects the clinical need (Figure). Although it remains to be seen which treatment approach will result in the best outcome with the least toxicity, each of these strategies has demonstrated advantages and disadvantages in preclinical studies that warrant further investigation. Although currently it is unclear which of the various strategies described in this article will prevail, the cardiac regeneration race seems to be in full swing. We anticipate that a significantly greater understanding of the biology of CM development and differentiation will be necessary to achieve this worthwhile goal.Download figureDownload PowerPointFigure. Many promising strategies to repair and recover failing myocardium are actively being explored. These include stimulation of endogenous cells, delivery of exogenous cells, and the direct conversion of fibroblasts into CMs or cardiac progenitor cells (CPCs). CFs indicates cardiac fibroblasts; ECs, endothelial cells; iCPCs, induced cardiac progenitor cells; iECs, induced ECs; iPSCs, induced pluripotent stem cells; iSMCs, induced SMCs; MSCs, mesenchymal stem cells; and SMCs, smooth muscle cells.Sources of FundingThe authors are supported in part by the National Institutes of Health Pathway to Independence Award (1K99HL127295-01A1), Director's Pioneer Award (DP1 LM012179-02), the NHLBI Progenitor Cell Biology Consortium (U01 HL099776-7), American Heart Association Postdoctoral Fellowship (16POST31150010), and the Endowed Faculty Scholar Award of the Lucile Packard Foundation for Children and Child Health Research Institute at Stanford.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Sean M. Wu, MD, PhD, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Lokey Stem Cell Bldg, Room G1120A, 265 Campus Dr, Stanford, CA 94305. E-mail [email protected]; or Markus Krane, MD, Division of Experimental Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Lazarettstraße 36, Munich, Germany. E-mail [email protected]References1. 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. doi: 10.1126/science.1164680.CrossrefMedlineGoogle Scholar2. 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