Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Induced regeneration—the progress and promise of direct reprogramming for heart repair

Abstract

Regeneration of cardiac tissue has the potential to transform cardiovascular medicine. Recent advances in stem cell biology and direct reprogramming, or transdifferentiation, have produced powerful new tools to advance this goal. In this Review we examine key developments in the generation of new cardiomyocytes in vitro as well as the exciting progress that has been made toward in vivo reprogramming of cardiac tissue. We also address controversies and hurdles that challenge the field.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Therapeutic approaches to regenerate cardiac tissue.
Figure 2: Development of cardiac muscle.
Figure 3: Defining cardiomyocyte identity.

Similar content being viewed by others

References

  1. Murry, C.E., Reinecke, H. & Pabon, L.M. Regeneration gaps: observations on stem cells and cardiac repair. J. Am. Coll. Cardiol. 47, 1777–1785 (2006).

    Article  PubMed  Google Scholar 

  2. Go, A.S. et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127, e6–e245 (2013).

    PubMed  Google Scholar 

  3. 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–S64 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Doetschman, T.C., Eistetter, H., Katz, M., Schmidt, W. & Kemler, R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morphol. 87, 27–45 (1985).

    CAS  PubMed  Google Scholar 

  8. Kattman, S.J. et al. Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8, 228–240 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Willems, E. et al. Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell–derived mesoderm. Circ. Res. 109, 360–364 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Burridge, P.W. et al. A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS ONE 6, e18293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Elliott, D.A. et al. NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat. Methods 8, 1037–1040 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Zhang, Q. et al. Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals. Cell Res. 21, 579–587 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Uosaki, H. et al. Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface expression. PLoS ONE 6, e23657 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hudson, J., Titmarsh, D., Hidalgo, A., Wolvetang, E. & Cooper-White, J. Primitive cardiac cells from human embryonic stem cells. Stem Cells Dev. 21, 1513–1523 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Burridge, P.W., Keller, G., Gold, J.D. & Wu, J.C. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell 10, 16–28 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dubois, N.C. et al. SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nat. Biotechnol. 29, 1011–1018 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Segers, V.F. & Lee, R.T. Biomaterials to enhance stem cell function in the heart. Circ. Res. 109, 910–922 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Vunjak-Novakovic, G., Lui, K.O., Tandon, N. & Chien, K.R. Bioengineering heart muscle: a paradigm for regenerative medicine. Annu. Rev. Biomed. Eng. 13, 245–267 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Masuda, S., Shimizu, T., Yamato, M. & Okano, T. Cell sheet engineering for heart tissue repair. Adv. Drug Deliv. Rev. 60, 277–285 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Li, R.K. et al. Survival and function of bioengineered cardiac grafts. Circulation 100, II63–II69 (1999).

    CAS  PubMed  Google Scholar 

  23. Kofidis, T. et al. Injectable bioartificial myocardial tissue for large-scale intramural cell transfer and functional recovery of injured heart muscle. J. Thorac. Cardiovasc. Surg. 128, 571–578 (2004).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Staerk, J. et al. Reprogramming of human peripheral blood cells to induced pluripotent stem cells. Cell Stem Cell 7, 20–24 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Loh, Y.H. et al. Reprogramming of T cells from human peripheral blood. Cell Stem Cell 7, 15–19 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Seki, T. et al. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7, 11–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Zhou, T. et al. Generation of induced pluripotent stem cells from urine. J. Am. Soc. Nephrol. 22, 1221–1228 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Reiter, J.F. et al. Gata5 is required for the development of the heart and endoderm in zebrafish. Genes Dev. 13, 2983–2995 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Latinkić, B.V., Kotecha, S. & Mohun, T.J. Induction of cardiomyocytes by GATA4 in Xenopus ectodermal explants. Development 130, 3865–3876 (2003).

    Article  PubMed  CAS  Google Scholar 

  31. David, R. et al. MesP1 drives vertebrate cardiovascular differentiation through Dkk-1–mediated blockade of Wnt-signalling. Nat. Cell Biol. 10, 338–345 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Bondue, A. et al. Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell 3, 69–84 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Lindsley, R.C. et al. Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ESCs. Cell Stem Cell 3, 55–68 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Takeuchi, J.K. & Bruneau, B.G. Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459, 708–711 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Davis, R.L., Weintraub, H. & Lassar, A.B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).

    Article  CAS  PubMed  Google Scholar 

  36. Wang, Z., Wang, D.Z., Pipes, G.C. & Olson, E.N. Myocardin is a master regulator of smooth muscle gene expression. Proc. Natl. Acad. Sci. USA 100, 7129–7134 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J. & Melton, D.A. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627–632 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Feng, R. et al. PU.1 and C/EBPα/β convert fibroblasts into macrophage-like cells. Proc. Natl. Acad. Sci. USA 105, 6057–6062 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Addis, R.C. et al. Efficient conversion of astrocytes to functional midbrain dopaminergic neurons using a single polycistronic vector. PLoS ONE 6, e28719 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Caiazzo, M. et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476, 224–227 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Kim, J. et al. Direct reprogramming of mouse fibroblasts to neural progenitors. Proc. Natl. Acad. Sci. USA 108, 7838–7843 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huang, P. et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475, 386–389 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Sekiya, S. & Suzuki, A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475, 390–393 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Kelly, M.C., Chang, Q., Pan, A., Lin, X. & Chen, P. Atoh1 directs the formation of sensory mosaics and induces cell proliferation in the postnatal mammalian cochlea in vivo. J. Neurosci. 32, 6699–6710 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, Z. et al. Age-dependent in vivo conversion of mouse cochlear pillar and Deiters' cells to immature hair cells by Atoh1 ectopic expression. J. Neurosci. 32, 6600–6610 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Buganim, Y. et al. Direct reprogramming of fibroblasts into embryonic sertoli-like cells by defined factors. Cell Stem Cell 11, 373–386 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Blau, H.M. et al. Plasticity of the differentiated state. Science 230, 758–766 (1985).

    Article  CAS  PubMed  Google Scholar 

  49. Evans, S.M., Tai, L.J., Tan, V.P., Newton, C.B. & Chien, K.R. Heterokaryons of cardiac myocytes and fibroblasts reveal the lack of dominance of the cardiac muscle phenotype. Mol. Cell. Biol. 14, 4269–4279 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen, J.X. et al. Inefficient reprogramming of fibroblasts into cardiomyocytes using gata4, mef2c, and tbx5. Circ. Res. 111, 50–55 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Srivastava, D. & Ieda, M. Critical factors for cardiac reprogramming. Circ. Res. 111, 5–8 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Inagawa, K. & Ieda, M. Direct reprogramming of mouse fibroblasts into cardiac myocytes. J. Cardiovasc. Transl. Res. 6, 37–45 (2013).

    Article  PubMed  Google Scholar 

  54. Wang, B. et al. Reprogramming efficiency and quality of induced pluripotent stem cells (iPSCs) generated from muscle-derived fibroblasts of mdx mice at different ages. PLoS Curr. 3, RRN1274 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Protze, S. et al. A new approach to transcription factor screening for reprogramming of fibroblasts to cardiomyocyte-like cells. J. Mol. Cell. Cardiol. 53, 323–332 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Anokye-Danso, F. et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8, 376–388 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Kim, J. et al. Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 9, 413–419 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pfisterer, U. et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc. Natl. Acad. Sci. USA 108, 10343–10348 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. He, J.Q., Ma, Y., Lee, Y., Thomson, J.A. & Kamp, T.J. Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ. Res. 93, 32–39 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Otsuji, T.G. et al. Progressive maturation in contracting cardiomyocytes derived from human embryonic stem cells: qualitative effects on electrophysiological responses to drugs. Stem Cell Res. 4, 201–213 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. Mathison, M. et al. In vivo cardiac cellular reprogramming efficacy is enhanced by angiogenic preconditioning of the infarcted myocardium with vascular endothelial growth factor. J. Am. Heart. Assoc. 1, e005652 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Kim, T.K. et al. Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes. Proc. Natl. Acad. Sci. USA 108, 11918–11923 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Addis, R.C. et al. Optimization of direct fibroblast reprogramming to cardiomyocytes using calcium activity as a functional measure of success. J. Mol. Cell. Cardiol. 60, 97–106 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. DeHaan, R.L. & Gottlieb, S.H. The electrical activity of embryonic chick heart cells isolated in tissue culture singly or in interconnected cell sheets. J. Gen. Physiol. 52, 643–665 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Davies, M.P. et al. Developmental changes in ionic channel activity in the embryonic murine heart. Circ. Res. 78, 15–25 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Satin, J. et al. Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. J. Physiol. (Lond.) 559, 479–496 (2004).

    Article  CAS  Google Scholar 

  73. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chiu, L.L., Iyer, R.K., Reis, L.A., Nunes, S.S. & Radisic, M. Cardiac tissue engineering: current state and perspectives. Front. Biosci. 17, 1533–1550 (2012).

    Article  CAS  Google Scholar 

  76. Boudou, T. et al. A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. Tissue Eng. Part A 18, 910–919 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Efe, J.A. et al. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat. Cell Biol. 13, 215–222 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Christoforou, N. et al. Transcription factors MYOCD, SRF, Mesp1 and SMARCD3 enhance the cardio-inducing effect of GATA4, TBX5, and MEF2C during direct cellular reprogramming. PLoS One 8, e63577 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Bers, D.M. Cardiac excitation-contraction coupling. Nature 415, 198–205 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Tian, L. et al. Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators. Nat. Methods 6, 875–881 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tallini, Y.N. et al. Imaging cellular signals in the heart in vivo: cardiac expression of the high-signal Ca2+ indicator GCaMP2. Proc. Natl. Acad. Sci. USA 103, 4753–4758 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the American Heart Association Jon Holden DeHaan Cardiac Myogenesis Research Center, US National Institutes of Health grant NIH U01 HL100405 and the Spain Fund for Regenerative Medicine.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Russell C Addis or Jonathan A Epstein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Addis, R., Epstein, J. Induced regeneration—the progress and promise of direct reprogramming for heart repair. Nat Med 19, 829–836 (2013). https://doi.org/10.1038/nm.3225

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3225

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing