Dedifferentiation and the Heart

  • Xiaobing Fu
  • Andong Zhao
  • Tian Hu


Mending a broken heart is not only a thing people do when their feelings and sensibilities get hurt, but it is also the dream for generations of cardiologists. Heart disease, or cardiovascular diseases, constitutes one leading cause for current morbidity and mortality. Scientists and physicians could only modulate patients’ heart function or use supportive methods on heart disease. The ability of heart regeneration in lower vertebrate animals has got quite admiring looks from us human beings. Accordingly, the mechanisms of heart regeneration in animals and the barriers of that in humans have got intensive investigations. Nowadays, the centrosome has been found to be associated with cardiomyocyte proliferation. The dissolution of a centrosome would halt cardiomyocyte proliferation and bog down the cell cycle in G0/G1 phase. And relevant underlying mechanism has been intensively investigated, including the barrier of human cardiomyocyte proliferation, manipulation of reentering cell cycle, epigenetic regulation of cardiomyocyte regeneration, and other stem cells or progenitor cells in the heart. The author has compiled current researches and literatures on the heart regeneration model, cardiomyocyte dedifferentiation, and the cell cycle regulation of cardiomyocytes. New techniques and perspectives are also included in this review, such as small molecular regulator, miRNA, and epigenetic modulations.


Cardiovascular disease Regeneration Dedifferentiation Cardiomyocytes Cell cycle Cardiac progenitor cells 


  1. 1.
    Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367(9524):1747–57.CrossRefPubMedGoogle Scholar
  2. 2.
    Jessup M, Brozena S. Medical progress: heart failure. N Engl J Med. 2003;348(20):2007–18.CrossRefPubMedGoogle Scholar
  3. 3.
    Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30–41.CrossRefPubMedGoogle Scholar
  4. 4.
    Macmahon HE. Hyperplasia and regeneration of the myocardium in infants and in children. Am J Pathol. 1937;13(5):845–54.5.PubMedPubMedCentralGoogle Scholar
  5. 5.
    McMahon JT, Ratliff NB. Regeneration of adult human myocardium after acute heart transplant rejection. J Heart Transplant. 1990;9(5):554–67.PubMedGoogle Scholar
  6. 6.
    Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A. 1998;95(15):8801–5.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med. 2001;344(23):1750–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisen J. Evidence for cardiomyocyte renewal in humans. Science. 2009;324(5923):98–102.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kajstura J, Urbanek K, Perl S, Hosoda T, Zheng HQ, Ogorek B, Ferreira-Martins J, Goichberg P, Rondon-Clavo C, Sanada F, D’Amario D, Rota M, del Monte F, Orlic D, Tisdale J, Leri A, Anversa P. Cardiomyogenesis in the adult human heart. Circ Res. 2010;107(2):305–U307.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mollova M, Bersell K, Walsh S, Savla J, Das LT, Park SY, Silberstein LE, dos Remedios CG, Graham D, Colan S, Kuhn B. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Natl Acad Sci U S A. 2013;110(4):1446–51.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Tang Y, Nyengaard JR, Andersen JB, Baandrup U, Gundersen HJG. The application of stereological methods for estimating structural parameters in the human heart. Anat Rec (Hoboken). 2009;292(10):1630–47.CrossRefGoogle Scholar
  12. 12.
    Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science. 2002;298(5601):2188–90.CrossRefPubMedGoogle Scholar
  13. 13.
    Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, Evans T, MacRae CA, Stainier DYR, Poss KD. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010;464(7288):601–U162.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Jopling C, Sleep E, Raya M, Marti M, Raya A, Belmonte JCI. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010;464(7288):606–U168.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lepilina A, Coon AN, Kikuchi K, Holdway JE, Roberts RW, Burns CG, Poss KD. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell. 2006;127(3):607–19.CrossRefPubMedGoogle Scholar
  16. 16.
    Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ. Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Phys. 1996;271(5 Pt 2):H2183–9.Google Scholar
  17. 17.
    Soonpaa MH, Field LJ. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Phys. 1997;272(1 Pt 2):H220–6.Google Scholar
  18. 18.
    Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331(6020):1078–80.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sleep E, Boue S, Jopling C, Raya M, Raya A, Belmonte JCI. Transcriptomics approach to investigate zebrafish heart regeneration. J Cardiovasc Med. 2010;11(5):369–80.CrossRefGoogle Scholar
  20. 20.
    Lien CL, Schebesta M, Makino S, Weber GJ, Keating MT. Gene expression analysis of zebrafish heart regeneration. PLoS Biol. 2006;4(8):1386–96.CrossRefGoogle Scholar
  21. 21.
    Zhang YQ, Li TS, Lee ST, Wawrowsky KA, Cheng K, Galang G, Malliaras K, Abraham MR, Wang C, Marban E. Dedifferentiation and proliferation of mammalian cardiomyocytes. PLoS One. 2010;5(9):e12559.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Rucker-Martin C, Pecker F, Godreau D, Hatem SN. Dedifferentiation of atrial myocytes during atrial fibrillation: role of fibroblast proliferation in vitro. Cardiovasc Res. 2002;55(1):38–52.CrossRefPubMedGoogle Scholar
  23. 23.
    Dispersyn GD, Mesotten L, Meuris B, Maes A, Mortelmans L, Flameng W, Ramaekers F, Borgers M. Dissociation of cardiomyocyte apoptosis and dedifferentiation in infarct border zones. Eur Heart J. 2002;23(11):849–57.CrossRefPubMedGoogle Scholar
  24. 24.
    Ausma J, Thone F, Dispersyn GD, Flameng W, Vanoverschelde JL, Raemaekers FCS, Borgers M. Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant. Mol Cell Biochem. 1998;186(1-2):159–68.CrossRefPubMedGoogle Scholar
  25. 25.
    Driesen RB, Verheyen FK, Debie W, Blaauw E, Babiker FA, Cornelussen RNM, Ausma J, Lenders MH, Borgers M, Chaponnier C, Ramaekers FCS. Re-expression of alpha skeletal actin as a marker for dedifferentiation in cardiac pathologies. J Cell Mol Med. 2009;13(5):896–908.CrossRefPubMedGoogle Scholar
  26. 26.
    Hein S, Block T, Zimmermann R, Kostin S, Scheffold T, Kubin T, Klovekorn WP, Schaper J. Deposition of nonsarcomeric alpha-actinin in cardiomyocytes from patients with dilated cardiomyopathy or chronic pressure overload. Exp Clin Cardiol. 2009;14(3):E68–75.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Kubin T, Poling J, Kostin S, Gajawada P, Hein S, Rees W, Wietelmann A, Tanaka M, Lorchner H, Schimanski S, Szibor M, Warnecke H, Braun T. Oncostatin M is a major mediator of cardiomyocyte dedifferentiation and remodeling. Cell Stem Cell. 2011;9(5):420–32.CrossRefPubMedGoogle Scholar
  28. 28.
    Rumyantsev PP. Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. Int Rev Cytol. 1977;51:186–273.PubMedGoogle Scholar
  29. 29.
    Wills AA, Holdway JE, Major RJ, Poss KD. Regulated addition of new myocardial and epicardial cells fosters homeostatic cardiac growth and maintenance in adult zebrafish. Development. 2008;135(1):183–92.CrossRefPubMedGoogle Scholar
  30. 30.
    Li F, Wang X, Capasso JM, Gerdes AM. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol. 1996;28(8):1737–46.CrossRefPubMedGoogle Scholar
  31. 31.
    Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, Wu TD, Guerquin-Kern JL, Lechene CP, Lee RT. Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2013;493(7432):433–U186.CrossRefPubMedGoogle Scholar
  32. 32.
    Malliaras K, Zhang Y, Seinfeld J, Galang G, Tseliou E, Cheng K, Sun B, Aminzadeh M, Marban E. Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med. 2013;5(2):191–209.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Bersell K, Arab S, Haring B, Kuhn B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell. 2009;138(2):257–70.CrossRefPubMedGoogle Scholar
  34. 34.
    Olivetti G, Cigola E, Maestri R, Corradi D, Lagrasta C, Gambert SR, Anversa P. Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. J Mol Cell Cardiol. 1996;28(7):1463–77.CrossRefPubMedGoogle Scholar
  35. 35.
    Obaya AJ, Sedivy JM. Regulation of cyclin-Cdk activity in mammalian cells. Cell Mol Life Sci. 2002;59(1):126–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Pasumarthi KBS, Field LJ. Cardiomyocyte cell cycle regulation. Circ Res. 2002;90(10):1044–54.CrossRefPubMedGoogle Scholar
  37. 37.
    Brooks G, Poolman RA, McGill CJ, Li JM. Expression and activities of cyclins and cyclin-dependent kinases in developing rat ventricular myocytes. J Mol Cell Cardiol. 1997;29(8):2261–71.CrossRefPubMedGoogle Scholar
  38. 38.
    Brooks G, Poolman RA, Li JM. Arresting developments in the cardiac myocyte cell cycle: role of cyclin-dependent kinase inhibitors. Cardiovasc Res. 1998;39(2):301–11.CrossRefPubMedGoogle Scholar
  39. 39.
    Poolman RA, Brooks G. Expressions and activities of cell cycle regulatory molecules during the transition from myocyte hyperplasia to hypertrophy. J Mol Cell Cardiol. 1998;30(10):2121–35.CrossRefPubMedGoogle Scholar
  40. 40.
    Poolman RA, Gilchrist R, Brooks G. Cell cycle profiles and expressions of p21CIP1 AND P27KIP1 during myocyte development. Int J Cardiol. 1998;67(2):133–42.CrossRefPubMedGoogle Scholar
  41. 41.
    Sdek P, Zhao P, Wang YP, Huang CJ, Ko CY, Butler PC, Weiss JN, MacLellan WR. Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes. J Cell Biol. 2011;194(3):407–23.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wamstad JA, Alexander JM, Truty RM, Shrikumar A, Li FG, Eilertson KE, Ding HM, Wylie JN, Pico AR, Capra JA, Erwin G, Kattman SJ, Keller GM, Srivastava D, Levine SS, Pollard KS, Holloway AK, Boyer LA, Bruneau BG. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell. 2012;151(1):206–20.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Delgado-Olguin P, Huang Y, Li X, Christodoulou D, Seidman CE, Seidman JG, Tarakhovsky A, Bruneau BG. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet. 2012;44(3):343–U158.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Matkovich SJ, Edwards JR, Grossenheider TC, Strong CD, Dorn GW. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. Proc Natl Acad Sci U S A. 2014;111(33):12264–9.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Porrello ER, Johnson BA, Aurora AB, Simpson E, Nam YJ, Matkovich SJ, Dorn GW, van Rooij E, Olson EN. miR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ Res. 2011;109(6):670–U208.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Yin VP, Lepilina A, Smith A, Poss KD. Regulation of zebrafish heart regeneration by miR-133. Dev Biol. 2012;365(2):319–27.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wystub K, Besser J, Bachmann A, Boettger T, Braun T. miR-1/133a clusters cooperatively specify the cardiomyogenic lineage by adjustment of myocardin levels during embryonic heart development. PLoS Genet. 2013;9(9):e1003793.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wei YS, Peng SW, Wu M, Sachidanandam R, Tu ZD, Zhang SH, Falce C, Sobie EA, Lebeche D, Zhao Y. Multifaceted roles of miR-1s in repressing the fetal gene program in the heart. Cell Res. 2014;24(3):278–92.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Di Stefano V, Giacca M, Capogrossi MC, Crescenzi M, Martelli F. Knockdown of cyclin-dependent kinase inhibitors induces cardiomyocyte re-entry in the cell cycle. J Biol Chem. 2011;286(10):8644–54.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Soonpaa MH, Koh GY, Pajak L, Jing S, Wang H, Franklin MT, Kim KK, Field LJ. Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice. J Clin Invest. 1997;99(11):2644–54.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Pasumarthi KBS, Nakajima H, Nakajima HO, Soonpaa MH, Field LJ. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ Res. 2005;96(1):110–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Chaudhry HW, Dashoush NH, Tang HY, Zhang L, Wang XY, Wu EX, Wolgemuth DJ. Cyclin A2 mediates cardiomyocyte mitosis in the postmitotic myocardium. J Biol Chem. 2004;279(34):35858–66.CrossRefPubMedGoogle Scholar
  53. 53.
    Woo YJ, Panlilio CM, Cheng RK, Liao GP, Atluri P, Hsu VM, Cohen JE, Chaudhry HW. Therapeutic delivery of cyclin A2 induces myocardial regeneration and enhances cardiac function in ischemic heart failure. Circulation. 2006;114:I206–13.CrossRefPubMedGoogle Scholar
  54. 54.
    Agah R, Kirshenbaum LA, Abdellatif M, Truong LD, Chakraborty S, Michael LH, Schneider MD. Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo. J Clin Invest. 1997;100(11):2722–8.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ebelt H, Hufnagel N, Neuhaus P, Neuhaus H, Gajawada P, Simm A, Muller-Werdan U, Werdan K, Braun T. Divergent siblings – E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis. Circ Res. 2005;96(5):509–17.CrossRefPubMedGoogle Scholar
  56. 56.
    Ebelt H, Zhang Y, Kampke A, Xu J, Schlitt A, Buerke M, Muller-Werdan U, Werdan K, Braun T. E2F2 expression induces proliferation of terminally differentiated cardiomyocytes in vivo. Cardiovasc Res. 2008;80(2):219–26.CrossRefPubMedGoogle Scholar
  57. 57.
    MacLellan WR, Garcia A, Oh H, Frenkel P, Jordan MC, Roos KP, Schneider MD. Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb. Mol Cell Biol. 2005;25(6):2486–97.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Mahmoud AI, Kocabas F, Muralidhar SA, Kimura W, Koura AS, Thet S, Porrello ER, Sadek HA. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature. 2013;497(7448):249–53.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Kerkela R, Kockeritz L, MacAulay K, Zhou J, Doble BW, Beahm C, Greytak S, Woulfe K, Trivedi CM, Woodgett JR, Epstein JA, Force T, Huggins GS. Deletion of GSK-3 beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. J Clin Investig. 2008;118(11):3609–18.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Gao RL, Zhang J, Cheng LQ, Wu XS, Dong W, Yang XC, Li TC, Liu XF, Xu YB, Li XY, Zhou MD. 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. 2010;55(18):1907–14.CrossRefPubMedGoogle Scholar
  61. 61.
    Jabbour A, Hayward CS, Keogh AM, Kotlyar E, McCrohon JA, England JF, Amor R, Liu XF, Li XY, Zhou MD, Graham RM, Macdonald PS. Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur J Heart Fail. 2011;13(1):83–92.CrossRefPubMedGoogle Scholar
  62. 62.
    Engel FB, Schebesta M, Duong MT, Lu G, Ren SX, Madwed JB, Jiang HP, Wang Y, Keating MT. P38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 2005;19(10):1175–87.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Engel FB, Hsieh PC, Lee RT, Keating MT. FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc Natl Acad Sci U S A. 2006;103(42):15546–51.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, Martin JF. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011;332(6028):458–61.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Heallen T, Morikawa Y, Leach J, Tao G, Willerson JT, Johnson RL, Martin JF. Hippo signaling impedes adult heart regeneration. Development. 2013;140(23):4683–90.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Xin M, Kim Y, Sutherland LB, Qi XX, McAnally J, Schwartz RJ, Richardson JA, Bassel-Duby R, Olson EN. Regulation of insulin-like growth factor signaling by yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal. 2011;4(196):ra70.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    von Gise A, Lin ZQ, Schlegelmilch K, Honor LB, Pan GM, Buck JN, Ma Q, Ishiwata T, Zhou B, Camargo FD, Pu WT. YAP1, the nuclear target of hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci U S A. 2012;109(7):2394–9.CrossRefGoogle Scholar
  68. 68.
    Tseng AS, Engel FB, Keating MT. The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem Biol. 2006;13(9):957–63.CrossRefPubMedGoogle Scholar
  69. 69.
    Kuhn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, Keating MT. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med. 2007;13(8):962–9.CrossRefPubMedGoogle Scholar
  70. 70.
    Lorts A, Schwanekamp JA, Elrod JW, Sargent MA, Molkentin JD. Genetic manipulation of periostin expression in the heart does not affect myocyte content, cell cycle activity, or cardiac repair. Circ Res. 2009;104(1):e1–7.CrossRefPubMedGoogle Scholar
  71. 71.
    Porrello ER, Mahmoud AI, Simpson E, Johnson BA, Grinsfelder D, Canseco D, Mammen PP, Rothermel BA, Olson EN, Sadek HA. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A. 2013;110(1):187–92.CrossRefPubMedGoogle Scholar
  72. 72.
    Hullinger TG, Montgomery RL, Seto AG, Dickinson BA, Semus HM, Lynch JM, Dalby CM, Robinson K, Stack C, Latimer PA, Hare JM, Olson EN, van Rooij E. Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res. 2012;110(1):71–81.CrossRefPubMedGoogle Scholar
  73. 73.
    Eulalio A, Mano M, Dal Ferro M, Zentilin L, Sinagra G, Zacchigna S, Giacca M. Functional screening identifies miRNAs inducing cardiac regeneration. Nature. 2012;492(7429):376–81.CrossRefPubMedGoogle Scholar
  74. 74.
    Chen JH, Huang ZP, Seok HY, Ding J, Kataoka M, Zhang Z, Hu XY, Wang G, Lin ZQ, Wang S, Pu WT, Liao RL, Wang DZ. mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. Circ Res. 2013;112(12):1557–66.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Tallini YN, Greene KS, Craven M, Spealman A, Breitbach M, Smith J, Fisher PJ, Steffey M, Hesse M, Doran RM, Woods A, Singh B, Yen A, Fleischmann BK, Kotlikoff MI. c-Kit expression identifies cardiovascular precursors in the neonatal heart. Proc Natl Acad Sci U S A. 2009;106(6):1808–13.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Kubo H, Jaleel N, Kumarapeli A, Berretta RM, Bratinov G, Shan XY, Wang HM, Houser SR, Margulies KB. Increased cardiac myocyte progenitors in failing human hearts. Circulation. 2008;118(6):649–57.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascirnbene A, De Angelis A, Yasuzawa-Amano S, Trofimova I, Siggins RW, LeCapitaine N, Cascapera S, Beltrami AP, D’Alessandro DA, Zias E, Quaini F, Urbanek K, Michler RE, Bolli R, Kajstura J, Leri A, Anversa P. Human cardiac stem cells. Proc Natl Acad Sci U S A. 2007;104(35):14068–73.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, Dai S, Li C, Chen N, Peng Y, Dawn B, Hunt G, Leri A, Kajstura J, Tiwari S, Shirk G, Anversa P, Bolli R. Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation. 2010;121(2):293–305.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Zaruba MM, Soonpaa M, Reuter S, Field LJ. Cardiomyogenic potential of c-Kit(+)-expressing cells derived from neonatal and adult mouse hearts. Circulation. 2010;121(18):1992–U1956.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, Srivastava D. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142(3):375–86.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, Conway SJ, Fu JD, Srivastava D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485(7400):593–8.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG, Hill JA, Bassel-Duby R, Olson EN. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012;485(7400):599–604.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Nam YJ, Song KH, Luo X, Daniel E, Lambeth K, West K, Hill JA, DiMaio JM, Baker LA, Bassel-Duby R, Olson EN. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A. 2013;110(14):5588–93.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Zhang RL, Han PD, Yang HB, Ouyang KF, Lee D, Lin YF, Ocorr K, Kang GS, Chen J, Stainier DYR, Yelon D, Chi NC. In vivo cardiac reprogramming contributes to zebrafish heart regeneration. Nature. 2013;498(7455):497–501.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2018

Authors and Affiliations

  • Xiaobing Fu
    • 1
  • Andong Zhao
    • 2
  • Tian Hu
    • 3
  1. 1.Key Laboratory of Wound Repair and Regeneration of PLAThe First Hospital Affiliated to the PLA General HospitalBeijingChina
  2. 2.Tianjin Medical UniversityTianjinChina
  3. 3.School of MedicineNankai UniversityTianjinChina

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