Review Article | Published:

Therapeutic approaches for cardiac regeneration and repair

Nature Reviews Cardiology (2018) | Download Citation


Ischaemic heart disease is a leading cause of death worldwide. Injury to the heart is followed by loss of the damaged cardiomyocytes, which are replaced with fibrotic scar tissue. Depletion of cardiomyocytes results in decreased cardiac contraction, which leads to pathological cardiac dilatation, additional cardiomyocyte loss, and mechanical dysfunction, culminating in heart failure. This sequential reaction is defined as cardiac remodelling. Many therapies have focused on preventing the progressive process of cardiac remodelling to heart failure. However, after patients have developed end-stage heart failure, intervention is limited to heart transplantation. One of the main reasons for the dramatic injurious effect of cardiomyocyte loss is that the adult human heart has minimal regenerative capacity. In the past 2 decades, several strategies to repair the injured heart and improve heart function have been pursued, including cellular and noncellular therapies. In this Review, we discuss current therapeutic approaches for cardiac repair and regeneration, describing outcomes, limitations, and future prospects of preclinical and clinical trials of heart regeneration. Substantial progress has been made towards understanding the cellular and molecular mechanisms regulating heart regeneration, offering the potential to control cardiac remodelling and redirect the adult heart to a regenerative state.

Key points

  • Preclinical outcomes of cardiac regenerative therapy approaches have not translated effectively to clinical trials.

  • Transplantation of induced pluripotent stem cell-derived cardiomyocytes for cardiac repair has encountered problems related to safety and low engraftment rates.

  • Cell-free-based approaches for heart repair and regeneration involve cardioprotective secretory factors or direct reprogramming of resident cardiac fibroblasts to cardiomyocyte-like cells.

  • Endogenous cardiomyocyte proliferation can be evoked by modulating cell cycle regulators, the Hippo signalling pathway, and the cardiac microenvironment.

  • Genome editing can correct underlying mutations causing heart disease in animals and offers a state-of-the-art therapeutic approach for cardiac repair.

  • The therapeutic potential of cardiac regeneration approaches can be improved by optimizing the delivery method of the therapeutic factors.

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  1. 1.

    Roth, G. A. et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J. Am. Coll. Cardiol. 70, 1–25 (2017).

  2. 2.

    Cohn, J. N., Ferrari, R. & Sharpe, N. Cardiac remodeling — concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J. Am. Coll. Cardiol. 35, 569–582 (2000).

  3. 3.

    Sacks, C. A., Jarcho, J. A. & Curfman, G. D. Paradigm shifts in heart-failure therapy — a timeline. N. Engl. J. Med. 371, 989–991 (2014).

  4. 4.

    Packer, M. et al. Effect of carvedilol on survival in severe chronic heart failure. N. Engl. J. Med. 344, 1651–1658 (2001).

  5. 5.

    The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N. Engl. J. Med. 325, 293–302 (1991).

  6. 6.

    Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med. 341, 709–717 (1999).

  7. 7.

    McMurray, J. J. et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 371, 993–1004 (2014).

  8. 8.

    Rose, E. A. et al. Long-term use of a left ventricular assist device for end-stage heart failure. N. Engl. J. Med. 345, 1435–1443 (2001).

  9. 9.

    Bristow, M. R. et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N. Engl. J. Med. 350, 2140–2150 (2004).

  10. 10.

    Yacoub, M. Cardiac donation after circulatory death: a time to reflect. Lancet 385, 2554–2556 (2015).

  11. 11.

    Behfar, A., Crespo-Diaz, R., Terzic, A. & Gersh, B. J. Cell therapy for cardiac repair — lessons from clinical trials. Nat. Rev. Cardiol. 11, 232–246 (2014).

  12. 12.

    Menasche, P. et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117, 1189–1200 (2008).

  13. 13.

    Meyer, G. P. et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 113, 1287–1294 (2006).

  14. 14.

    Hare, J. M. et al. Comparison of allogeneic versus autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308, 2369–2379 (2012).

  15. 15.

    Beltrami, A. P. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776 (2003).

  16. 16.

    Mummery, C. L. et al. Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. Circ. Res. 111, 344–358 (2012).

  17. 17.

    Ieda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).

  18. 18.

    Song, K. et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599–604 (2012).

  19. 19.

    Xin, M. et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl Acad. Sci. USA 110, 13839–13844 (2013).

  20. 20.

    Gourdie, R. G., Dimmeler, S. & Kohl, P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat. Rev. Drug Discov. 15, 620–638 (2016).

  21. 21.

    Xin, M., Olson, E. N. & Bassel-Duby, R. Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat. Rev. Mol. Cell Biol. 14, 529–541 (2013).

  22. 22.

    Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011).

  23. 23.

    Forte, E., Furtado, M. & Rosenthal, N. The interstitium in cardiac repair: role of the immune–stromal cell interplay. Nat. Rev. Cardiol. (in the press).

  24. 24.

    Cao, J. & Poss, K. D. The epicardium as a hub for heart regeneration. Nat. Rev. Cardiol. (in the press).

  25. 25.

    Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002).

  26. 26.

    Porrello, E. R. & Olson, E. N. A neonatal blueprint for cardiac regeneration. Stem Cell Res. 13, 556–570 (2014).

  27. 27.

    Soonpaa, M. H., Kim, K. K., Pajak, L., Franklin, M. & Field, L. J. Cardiomyocyte DNA synthesis and binucleation during murine development. Am. J. Physiol. 271, H2183–H2189 (1996).

  28. 28.

    Haubner, B. J. et al. Functional recovery of a human neonatal heart after severe myocardial infarction. Circ. Res. 118, 216–221 (2016).

  29. 29.

    Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

  30. 30.

    Laflamme, M. A. & Murry, C. E. Heart regeneration. Nature 473, 326–335 (2011).

  31. 31.

    Marelli, D., Desrosiers, C., el-Alfy, M., Kao, R. L. & Chiu, R. C. Cell transplantation for myocardial repair: an experimental approach. Cell Transplant. 1, 383–390 (1992).

  32. 32.

    Taylor, D. A. et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat. Med. 4, 929–933 (1998).

  33. 33.

    Al Attar, N. et al. Long-term (1 year) functional and histological results of autologous skeletal muscle cells transplantation in rat. Cardiovasc. Res. 58, 142–148 (2003).

  34. 34.

    Durrani, S., Konoplyannikov, M., Ashraf, M. & Haider, K. H. Skeletal myoblasts for cardiac repair. Regen Med. 5, 919–932 (2010).

  35. 35.

    Povsic, T. J. et al. A double-blind, randomized, controlled, multicenter study to assess the safety and cardiovascular effects of skeletal myoblast implantation by catheter delivery in patients with chronic heart failure after myocardial infarction. Am. Heart J. 162, 654–662.e1 (2011).

  36. 36.

    Fouts, K., Fernandes, B., Mal, N., Liu, J. & Laurita, K. R. Electrophysiological consequence of skeletal myoblast transplantation in normal and infarcted canine myocardium. Heart Rhythm 3, 452–461 (2006).

  37. 37.

    Sanganalmath, S. K. & Bolli, R. Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ. Res. 113, 810–834 (2013).

  38. 38.

    Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).

  39. 39.

    Jackson, K. A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001).

  40. 40.

    Schachinger, V. et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N. Engl. J. Med. 355, 1210–1221 (2006).

  41. 41.

    Traverse, J. H. et al. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA 308, 2380–2389 (2012).

  42. 42.

    Perin, E. C. et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA 307, 1717–1726 (2012).

  43. 43.

    Surder, D. et al. Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function. Circulation 127, 1968–1979 (2013).

  44. 44.

    Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).

  45. 45.

    Planat-Benard, V. et al. Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ. Res. 94, 223–229 (2004).

  46. 46.

    Antonitsis, P., Ioannidou-Papagiannaki, E., Kaidoglou, A. & Papakonstantinou, C. In vitro cardiomyogenic differentiation of adult human bone marrow mesenchymal stem cells. The role of 5-azacytidine. Interact. Cardiovasc. Thorac. Surg. 6, 593–597 (2007).

  47. 47.

    Li, X. et al. Bone marrow mesenchymal stem cells differentiate into functional cardiac phenotypes by cardiac microenvironment. J. Mol. Cell Cardiol. 42, 295–303 (2007).

  48. 48.

    Quevedo, H. C. et al. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc. Natl Acad. Sci. USA 106, 14022–14027 (2009).

  49. 49.

    Amado, L. C. et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc. Natl Acad. Sci. USA 102, 11474–11479 (2005).

  50. 50.

    Mathiasen, A. B. et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial). Eur. Heart J. 36, 1744–1753 (2015).

  51. 51.

    Dixon, J. A. et al. Mesenchymal cell transplantation and myocardial remodeling after myocardial infarction. Circulation 120, S220–229 (2009).

  52. 52.

    Silva, G. V. et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 111, 150–156 (2005).

  53. 53.

    Messina, E. et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ. Res. 95, 911–921 (2004).

  54. 54.

    Oh, H. et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl Acad. Sci. USA 100, 12313–12318 (2003).

  55. 55.

    Laugwitz, K. L. et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005).

  56. 56.

    Johnston, P. V. et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 120, 1075–1083 (2009).

  57. 57.

    Bolli, R. et al. Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 128, 122–131 (2013).

  58. 58.

    Leong, Y. Y., Ng, W. H., Ellison-Hughes, G. M. & Tan, J. J. Cardiac stem cells for myocardial regeneration: they are not alone. Front. Cardiovasc. Med. 4, 47 (2017).

  59. 59.

    Bolli, R. et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378, 1847–1857 (2011).

  60. 60.

    Chugh, A. R. et al. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation 126, S54–64 (2012).

  61. 61.

    Ellison, G. M. et al. Adult c-kit(pos) cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell 154, 827–842 (2013).

  62. 62.

    van Berlo, J. H. et al. c-Kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509, 337–341 (2014).

  63. 63.

    The Lancet, E. Expression of concern: the SCIPIO trial. Lancet 383, 1279 (2014).

  64. 64.

    Makkar, R. R. et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379, 895–904 (2012).

  65. 65.

    Murry, C. E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).

  66. 66.

    Mummery, C. et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107, 2733–2740 (2003).

  67. 67.

    Qiao, H. et al. Long-term improvement in postinfarct left ventricular global and regional contractile function is mediated by embryonic stem cell-derived cardiomyocytes. Circ. Cardiovasc. Imag. 4, 33–41 (2011).

  68. 68.

    Shiba, Y. et al. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489, 322–325 (2012).

  69. 69.

    Chong, J. J. et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510, 273–277 (2014).

  70. 70.

    US National Library of Medicine. (2014).

  71. 71.

    Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

  72. 72.

    Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

  73. 73.

    Kawamura, M. et al. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation 126, S29–S37 (2012).

  74. 74.

    Shiba, Y. et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538, 388–391 (2016).

  75. 75.

    Miura, K. et al. Variation in the safety of induced pluripotent stem cell lines. Nat. Biotechnol. 27, 743–745 (2009).

  76. 76.

    Sougawa, N. et al. Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy. Sci. Rep. 8, 3726 (2018).

  77. 77.

    Tohyama, S. et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 12, 127–137 (2013).

  78. 78.

    Tohyama, S. et al. Efficient large-scale 2D culture system for human induced pluripotent stem cells and differentiated cardiomyocytes. Stem Cell Rep. 9, 1406–1414 (2017).

  79. 79.

    Chow, A. et al. Human induced pluripotent stem cell-derived cardiomyocyte encapsulating bioactive hydrogels improve rat heart function post myocardial infarction. Stem Cell Rep. 9, 1415–1422 (2017).

  80. 80.

    Kawamura, M. et al. Enhanced therapeutic effects of human iPS cell derived-cardiomyocyte by combined cell-sheets with omental flap technique in porcine ischemic cardiomyopathy model. Sci. Rep. 7, 8824 (2017).

  81. 81.

    Chen, T. S. et al. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 38, 215–224 (2010).

  82. 82.

    Gassmann, M. et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 390–394 (1995).

  83. 83.

    Bersell, K., Arab, S., Haring, B. & Kuhn, B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138, 257–270 (2009).

  84. 84.

    D’Uva, G. et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat. Cell Biol. 17, 627–638 (2015).

  85. 85.

    Gao, R. et al. A Phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J. Am. Coll. Cardiol. 55, 1907–1914 (2010).

  86. 86.

    Reuter, S., Soonpaa, M. H., Firulli, A. B., Chang, A. N. & Field, L. J. Recombinant neuregulin 1 does not activate cardiomyocyte DNA synthesis in normal or infarcted adult mice. PLoS ONE 9, e115871 (2014).

  87. 87.

    Harada, K. et al. Vascular endothelial growth factor administration in chronic myocardial ischemia. Am. J. Physiol. 270, H1791–H1802 (1996).

  88. 88.

    Gyongyosi, M. et al. NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation 112, I157–165 (2005).

  89. 89.

    House, S. L. et al. Cardiac-specific overexpression of fibroblast growth factor-2 protects against myocardial dysfunction and infarction in a murine model of low-flow ischemia. Circulation 108, 3140–3148 (2003).

  90. 90.

    Simons, M. et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 105, 788–793 (2002).

  91. 91.

    Garbayo, E. et al. Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion. Sci. Rep. 6, 25932 (2016).

  92. 92.

    Zangi, L. et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat. Biotechnol. 31, 898–907 (2013).

  93. 93.

    Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

  94. 94.

    Liu, N. & Olson, E. N. MicroRNA regulatory networks in cardiovascular development. Dev. Cell 18, 510–525 (2010).

  95. 95.

    van Rooij, E. & Olson, E. N. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat. Rev. Drug Discov. 11, 860–872 (2012).

  96. 96.

    Porrello, E. R. et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc. Natl Acad. Sci. USA 110, 187–192 (2013).

  97. 97.

    Eulalio, A. et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature 492, 376–381 (2012).

  98. 98.

    Chen, J. et al. mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. Circ. Res. 112, 1557–1566 (2013).

  99. 99.

    Tian, Y. et al. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci. Transl Med. 7, 279ra38 (2015).

  100. 100.

    Liu, X. et al. miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell Metab. 21, 584–595 (2015).

  101. 101.

    Aurora, A. B. et al. MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca(2)(+) overload and cell death. J. Clin. Invest. 122, 1222–1232 (2012).

  102. 102.

    Wang, L. L. et al. Sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischaemic injury. Nat. Biomed. Engineer. 1, 983–992 (2017).

  103. 103.

    Colombo, M., Raposo, G. & Thery, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014).

  104. 104.

    Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

  105. 105.

    Sluijter, J. P., Verhage, V., Deddens, J. C., van den Akker, F. & Doevendans, P. A. Microvesicles and exosomes for intracardiac communication. Cardiovasc. Res. 102, 302–311 (2014).

  106. 106.

    Chen, L. et al. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem. Biophys. Res. Commun. 431, 566–571 (2013).

  107. 107.

    Ibrahim, A. G., Cheng, K. & Marban, E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep. 2, 606–619 (2014).

  108. 108.

    Barile, L. et al. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc. Res. 103, 530–541 (2014).

  109. 109.

    Gallet, R. et al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur. Heart J. 38, 201–211 (2017).

  110. 110.

    Arslan, F. et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 10, 301–312 (2013).

  111. 111.

    Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).

  112. 112.

    Kaufmann, K. B., Buning, H., Galy, A., Schambach, A. & Grez, M. Gene therapy on the move. EMBO Mol. Med. 5, 1642–1661 (2013).

  113. 113.

    Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400–409 (2016).

  114. 114.

    Sadahiro, T., Yamanaka, S. & Ieda, M. Direct cardiac reprogramming: progress and challenges in basic biology and clinical applications. Circ. Res. 116, 1378–1391 (2015).

  115. 115.

    Nam, Y. J. et al. Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors. Development 141, 4267–4278 (2014).

  116. 116.

    Zhou, H., Dickson, M. E., Kim, M. S., Bassel-Duby, R. & Olson, E. N. Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes. Proc. Natl Acad. Sci. USA 112, 11864–11869 (2015).

  117. 117.

    Muraoka, N. et al. MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J. 33, 1565–1581 (2014).

  118. 118.

    Yamakawa, H. et al. Fibroblast growth factors and vascular endothelial growth factor promote cardiac reprogramming under defined conditions. Stem Cell Rep. 5, 1128–1142 (2015).

  119. 119.

    Abad, M. et al. Notch inhibition enhances cardiac reprogramming by increasing MEF2C transcriptional activity. Stem Cell Rep. 8, 548–560 (2017).

  120. 120.

    Mohamed, T. M. et al. Chemical enhancement of in vitro and in vivo direct cardiac reprogramming. Circulation 135, 978–995 (2017).

  121. 121.

    Zhao, Y. et al. High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat. Commun. 6, 8243 (2015).

  122. 122.

    Jayawardena, T. M. et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ. Res. 110, 1465–1473 (2012).

  123. 123.

    Zhou, H. et al. ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression. Genes Dev. 31, 1770–1783 (2017).

  124. 124.

    Zhou, Y. et al. Bmi1 is a key epigenetic barrier to direct cardiac reprogramming. Cell Stem Cell 18, 382–395 (2016).

  125. 125.

    Liu, Z. et al. Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte. Nature 551, 100–104 (2017).

  126. 126.

    Lalit, P. A. et al. Lineage reprogramming of fibroblasts into proliferative induced cardiac progenitor cells by defined factors. Cell Stem Cell 18, 354–367 (2016).

  127. 127.

    Islas, J. F. et al. Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. Proc. Natl Acad. Sci. USA 109, 13016–13021 (2012).

  128. 128.

    Fu, J. D. et al. Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Rep. 1, 235–247 (2013).

  129. 129.

    Nam, Y. J. et al. Reprogramming of human fibroblasts toward a cardiac fate. Proc. Natl Acad. Sci. USA 110, 5588–5593 (2013).

  130. 130.

    Wada, R. et al. Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc. Natl Acad. Sci. USA 110, 12667–12672 (2013).

  131. 131.

    Cao, N. et al. Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science 352, 1216–1220 (2016).

  132. 132.

    Yang, N., Ng, Y. H., Pang, Z. P., Sudhof, T. C. & Wernig, M. Induced neuronal cells: how to make and define a neuron. Cell Stem Cell 9, 517–525 (2011).

  133. 133.

    Pang, Z. P. et al. Induction of human neuronal cells by defined transcription factors. Nature 476, 220–223 (2011).

  134. 134.

    Zhou, J. X. & Huang, S. Understanding gene circuits at cell-fate branch points for rational cell reprogramming. Trends Genet. 27, 55–62 (2011).

  135. 135.

    Qian, L. et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485, 593–598 (2012).

  136. 136.

    Inagawa, K. et al. Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. Circ. Res. 111, 1147–1156 (2012).

  137. 137.

    Nam, Y. J., Song, K. & Olson, E. N. Heart repair by cardiac reprogramming. Nat. Med. 19, 413–415 (2013).

  138. 138.

    Miyamoto, K. et al. Direct in vivo reprogramming with Sendai virus vectors improves cardiac function after myocardial infarction. Cell Stem Cell 22, 91–103.e5 (2018).

  139. 139.

    Li, H. O. et al. A cytoplasmic RNA vector derived from nontransmissible Sendai virus with efficient gene transfer and expression. J. Virol. 74, 6564–6569 (2000).

  140. 140.

    Pasumarthi, K. B., Nakajima, H., Nakajima, H. O., Soonpaa, M. H. & Field, L. J. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ. Res. 96, 110–118 (2005).

  141. 141.

    Chaudhry, H. W. et al. Cyclin A2 mediates cardiomyocyte mitosis in the postmitotic myocardium. J. Biol. Chem. 279, 35858–35866 (2004).

  142. 142.

    Mohamed, T. M. A. et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell 173, 104–116.e12 (2018).

  143. 143.

    Mahmoud, A. I. et al. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497, 249–253 (2013).

  144. 144.

    Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).

  145. 145.

    Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011).

  146. 146.

    Heallen, T. et al. Hippo signaling impedes adult heart regeneration. Development 140, 4683–4690 (2013).

  147. 147.

    Tao, G. et al. Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 534, 119–123 (2016).

  148. 148.

    Leach, J. P. et al. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 550, 260–264 (2017).

  149. 149.

    Tallquist, M. D. & Molkentin, J. D. Redefining the identity of cardiac fibroblasts. Nat. Rev. Cardiol. 14, 484–491 (2017).

  150. 150.

    Weber, K. T., Sun, Y., Bhattacharya, S. K., Ahokas, R. A. & Gerling, I. C. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat. Rev. Cardiol. 10, 15–26 (2013).

  151. 151.

    Moon, J. et al. Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist. Proc. Natl Acad. Sci. USA 114, 1649–1654 (2017).

  152. 152.

    Cittadini, A. et al. Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure. Cardiovasc. Res. 58, 555–564 (2003).

  153. 153.

    Duan, J. et al. Wnt1/betacatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J. 31, 429–442 (2012).

  154. 154.

    Kanemitsu, H. et al. Chymase inhibition prevents cardiac fibrosis and dysfunction after myocardial infarction in rats. Hypertens. Res. 29, 57–64 (2006).

  155. 155.

    Sassoli, C. et al. Relaxin prevents cardiac fibroblast-myofibroblast transition via notch-1-mediated inhibition of TGF-beta/Smad3 signaling. PLoS ONE 8, e63896 (2013).

  156. 156.

    Samuel, C. S. et al. Relaxin remodels fibrotic healing following myocardial infarction. Lab. Invest. 91, 675–690 (2011).

  157. 157.

    Chablais, F. & Jazwinska, A. The regenerative capacity of the zebrafish heart is dependent on TGFbeta signaling. Development 139, 1921–1930 (2012).

  158. 158.

    Pitt, B. et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial — the Losartan Heart Failure Survival Study ELITE II. Lancet 355, 1582–1587 (2000).

  159. 159.

    Ikeuchi, M. et al. Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovasc. Res. 64, 526–535 (2004).

  160. 160.

    Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

  161. 161.

    Zhou, B. et al. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J. Clin. Invest. 121, 1894–1904 (2011).

  162. 162.

    Mollmann, H. et al. Bone marrow-derived cells contribute to infarct remodelling. Cardiovasc. Res. 71, 661–671 (2006).

  163. 163.

    Kramann, R. et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16, 51–66 (2015).

  164. 164.

    Zhang, H. et al. Pigment epithelium-derived factor attenuates myocardial fibrosis via inhibiting Endothelial-to-Mesenchymal Transition in rats with acute myocardial infarction. Sci. Rep. 7, 41932 (2017).

  165. 165.

    Kanisicak, O. et al. Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat. Commun. 7, 12260 (2016).

  166. 166.

    Bassat, E. et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547, 179–184 (2017).

  167. 167.

    Puente, B. N. et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157, 565–579 (2014).

  168. 168.

    Nakada, Y. et al. Hypoxia induces heart regeneration in adult mice. Nature 541, 222–227 (2017).

  169. 169.

    Piquereau, J. et al. Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell? Front. Physiol. 4, 102 (2013).

  170. 170.

    Canseco, D. C. et al. Human ventricular unloading induces cardiomyocyte proliferation. J. Am. Coll. Cardiol. 65, 892–900 (2015).

  171. 171.

    Quaife-Ryan, G. A. et al. Multicellular transcriptional analysis of mammalian heart regeneration. Circulation 136, 1123–1139 (2017).

  172. 172.

    Aurora, A. B. et al. Macrophages are required for neonatal heart regeneration. J. Clin. Invest. 124, 1382–1392 (2014).

  173. 173.

    Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

  174. 174.

    Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

  175. 175.

    Guiraud, S. et al. The pathogenesis and therapy of muscular dystrophies. Annu. Rev. Genom. Hum. Genet. 16, 281–308 (2015).

  176. 176.

    Long, C. et al. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345, 1184–1188 (2014).

  177. 177.

    Long, C. et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351, 400–403 (2016).

  178. 178.

    Tabebordbar, M. et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351, 407–411 (2016).

  179. 179.

    Nelson, C. E. et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351, 403–407 (2016).

  180. 180.

    Amoasii, L. et al. Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy. Sci. Transl Med. 9, eaan8081 (2017).

  181. 181.

    Kazuki, Y. et al. Complete genetic correction of ips cells from Duchenne muscular dystrophy. Mol. Ther. 18, 386–393 (2010).

  182. 182.

    Young, C. S. et al. A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell 18, 533–540 (2016).

  183. 183.

    Kyrychenko, V. et al. Functional correction of dystrophin actin binding domain mutations by genome editing. JCI Insight 2, e95918 (2017).

  184. 184.

    Zhang, Y. et al. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Sci. Adv. 3, e1602814 (2017).

  185. 185.

    Long, C. et al. Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing. Sci. Adv. 4, eaap9004 (2018).

  186. 186.

    Strong, A. & Musunuru, K. Genome editing in cardiovascular diseases. Nat. Rev. Cardiol. 14, 11–20 (2017).

  187. 187.

    McGinley, L. M. et al. Mesenchymal stem cell survival in the infarcted heart is enhanced by lentivirus vector-mediated heat shock protein 27 expression. Hum. Gene Ther. 24, 840–851 (2013).

  188. 188.

    Mohsin, S. et al. Human cardiac progenitor cells engineered with Pim-I kinase enhance myocardial repair. J. Am. Coll. Cardiol. 60, 1278–1287 (2012).

  189. 189.

    Yang, Y. G. & Sykes, M. Xenotransplantation: current status and a perspective on the future. Nat. Rev. Immunol. 7, 519–531 (2007).

  190. 190.

    Yang, L. et al. Genome-wide inactivation of porcine endogenous retroviruses (PERVs). Science 350, 1101–1104 (2015).

  191. 191.

    Qi, L. S. et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152, 1173–1183 (2013).

  192. 192.

    Gilbert, L. A. et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154, 442–451 (2013).

  193. 193.

    Black, J. B. et al. Targeted epigenetic remodeling of endogenous loci by CRISPR/Cas9-based transcriptional activators directly converts fibroblasts to neuronal cells. Cell Stem Cell 19, 406–414 (2016).

  194. 194.

    Chakraborty, S. et al. A CRISPR/Cas9-based system for reprogramming cell lineage specification. Stem Cell Rep. 3, 940–947 (2014).

  195. 195.

    Pascual-Gil, S., Garbayo, E., Diaz-Herraez, P., Prosper, F. & Blanco-Prieto, M. J. Heart regeneration after myocardial infarction using synthetic biomaterials. J. Control. Release 203, 23–38 (2015).

  196. 196.

    Oduk, Y. et al. VEGF nanoparticles repair heart after myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 314, H278–H284 (2018).

  197. 197.

    Seif-Naraghi, S. B. et al. Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction. Sci. Transl Med. 5, 173ra25 (2013).

  198. 198.

    Weinberger, F. et al. Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells. Sci. Transl Med. 8, 363ra148 (2016).

  199. 199.

    Zimmermann, W. H. et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat. Med. 12, 452–458 (2006).

  200. 200.

    Shudo, Y. et al. Novel regenerative therapy using cell-sheet covered with omentum flap delivers a huge number of cells in a porcine myocardial infarction model. J. Thorac. Cardiovasc. Surg. 142, 1188–1196 (2011).

  201. 201.

    Riegler, J. et al. Human engineered heart muscles engraft and survive long term in a rodent myocardial infarction model. Circ. Res. 117, 720–730 (2015).

  202. 202.

    Tokita, Y. et al. Repeated administrations of cardiac progenitor cells are markedly more effective than a single administration: a new paradigm in cell therapy. Circ. Res. 119, 635–651 (2016).

  203. 203.

    Milani-Nejad, N. & Janssen, P. M. Small and large animal models in cardiac contraction research: advantages and disadvantages. Pharmacol. Ther. 141, 235–249 (2014).

  204. 204.

    Chamuleau, S. A. J. et al. Translational research in cardiovascular repair: a call for a paradigm shift. Circ. Res. 122, 310–318 (2018).

  205. 205.

    Olson, E. N. Gene regulatory networks in the evolution and development of the heart. Science 313, 1922–1927 (2006).

  206. 206.

    Major, R. J. & Poss, K. D. Zebrafish heart regeneration as a model for cardiac tissue repair. Drug Discov. Today Dis. Models 4, 219–225 (2007).

  207. 207.

    Rosenthal, N. & Brown, S. The mouse ascending: perspectives for human-disease models. Nat. Cell Biol. 9, 993–999 (2007).

  208. 208.

    Gandolfi, F. et al. Large animal models for cardiac stem cell therapies. Theriogenology 75, 1416–1425 (2011).

  209. 209.

    Daadi, M. M., Barberi, T., Shi, Q. & Lanford, R. E. Nonhuman primate models in translational regenerative medicine. Stem Cells Dev. 23 (Suppl. 1), 83–87 (2014).

  210. 210.

    Chong, J. J. & Murry, C. E. Cardiac regeneration using pluripotent stem cells — progression to large animal models. Stem Cell Res. 13, 654–665 (2014).

  211. 211.

    Sayed, N., Liu, C. & Wu, J. C. Translation of human-induced pluripotent stem cells: from clinical trial in a dish to precision medicine. J. Am. Coll. Cardiol. 67, 2161–2176 (2016).

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The authors thank L. Amoasii and Y.-L. Min (University of Texas Southwestern Medical Center, USA) and S. Tohyama (Keio University School of Medicine, Japan) for constructive scientific discussions, J. Cabrera (University of Texas Southwestern Medical Center, USA) for assistance with figures, and A. McKenzie (University of Texas Southwestern Medical Center, USA) for help with editing. Work in the authors’ laboratory is supported by grants from the NIH (AR-067294, HL-130253, HD-087351, and HL-138426), Fondation Leducq Transatlantic Networks of Excellence in Cardiovascular Research, and the Robert A. Welch Foundation (grant 1–0025 to E.N.O.). H.H. is supported by the Uehara Memorial Foundation Postdoctoral Fellowship and the Kanae Foreign Study Grant.

Reviewer information

Nature Reviews Cardiology thanks T. Eschenhagen and the other, anonymous reviewers for their contribution to the peer review of this work.

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  1. Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Hisayuki Hashimoto
    • , Eric N. Olson
    •  & Rhonda Bassel-Duby
  2. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Hisayuki Hashimoto
    • , Eric N. Olson
    •  & Rhonda Bassel-Duby


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All authors researched the data for this article, discussed the content, wrote the manuscript, and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Eric N. Olson.


Left ventricular assist devices

(LVADs). Electromechanical devices to support circulation of a failing heart.

Cardiac resynchronization therapy

Therapy that uses an electromechanical device to resynchronize ventricular contraction in patients with heart failure.

Lineage tracing

A method to identify all progeny originating from a single cell.


A fusion protein containing Cre recombinase flanked at both ends with a mutated murine oestrogen receptor (Mer) ligand binding domain. MerCreMer generates an inducible Cre recombinase activation system that can gain access to the nuclear compartment only with exposure to tamoxifen.


Colloid gels composed of a network of hydrophilic polymer chains.

Paracrine effects

The effects on a cell that are induced by secreted factors from another cell.

Synthetic modified RNA

Chemically synthesized RNA with changes to the chemical composition that alter function or stability of the RNA.


Cell, tissue, or organ transplantation across different species.

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