Volume: 3 Issue: 2
Year: 2015, Page: 15-17,
Objective: A cure for cardiovascular disease remains a major unachieved medical need. Recent investigations have started to uncover the mechanisms of mammalian heart regeneration. Adult cardiomyocytes have slight regenerative capacity following injuries and also myocardium heals by fibroblast proliferation and scar formation. Mixtures of Cardiac-specific defined factors can generate cardiomyocytes from cardiac fibroblasts. By the use of Cardiac-specific transcription factors: Gata4, Mef2c, and Tbx5 (GMT), GMT plus Hand2 (GHMT), or Mef2c, Myocd, and Tbx5 in vitro Mouse fibroblasts can be directly converted into cardiomyocyte-like cells. Human fibroblasts can be reprogrammed into differentiated cardiomyocyte-like cells by overexpressing GMT plus Myocd and Mesp1 or Gata4, Hand2, Tbx5, Myocd, miR-1, and miR-133. Cardiac reprogramming technology may be a possible approach that could regenerate diseased hearts.
This article reviews the current studies in cardiac reprogramming, and discusses the possibilities and disputes of direct cardiac reprogramming towards regenerative therapy.
Keywords: Cardiovascular Diseases, Fibroblasts, Humans, Mice, Myocytes, Regeneration, Transcription Factors,Wound Healing.
1. Christopher. L. Murray, Alan D Lopez. The global burden of disease. World Health organization; 1997 Feb. 19. ISBN: 0-9655466-0-8.
2. 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.
3. Sandler VM, Lis R, Liu Y, Kedem A, James D, Elemento O, et al. Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Nature. 2014 Jul 17;511(7509):312-8.
4. 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; 142:375–386.
5. Kohei Inagawa, Kazutaka. Induction of CardiomyocyteLike Cells in Infarct Hearts by Gene Transfer of Gata4, Mef2c, and Tbx5. Cir Res. 2012; 111: 1147-1156.
6. Gulick J, Subramaniam A, Neumann J, Robbins J. Isolation and characterization of the mouse cardiac myosin heavy chain genes. J Biol Chem. 1991; 266:9180–9185.
7. Hudon-David F, Bouzeghrane F, Couture P, Thibault G. Thy-1 expression by cardiac fibroblasts: lack of association with myofibroblast contractile markers. J Mol Cell Cardiol. 2007; 42:991–1000.
8. Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong TT, Shaw RM, Srivastava D. Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell. 2009; 16:233–244.
9. David R, Brenner C, Stieber J, Schwarz F, Brunner S, Vollmer M, Mentele E, Muller-Hocker J,Kitajima S, Lickert H, et al. MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat Cell Biol. 2008; 10:338–345.
10. Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S. Suppression of induced pluripotent stem cell generation by the p53- p21 pathway. Nature. 2009; 460:1132–1135.
11. Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjarn M, Hansen HF, Berger U, Gullans S, Kearney P, Sarnow P, Straarup EM, Kauppinen S. LNA-mediated micro RNA silencing in non-human primates. Nature. 2008; 452:896–899.
12. Bader AG, Brown D, Stoudemire J, Lammers P. Developing therapeutic micro RNAs for cancer. Gene Ther. 2011;18:1121–1126.
13. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, et al: Micro RNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012; 110: 1465-1473.
14. Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: The scientific foundations of cardiac repair. J Clin Invest. 2005; 115(3):572–583.
15. Ieda M, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010; 142(3):375–386.
16. Song K, et al. Heart repair by reprogramming nonmyocytes with cardiac transcription factors. Nature. 2012; 485(7400):599–604.
17. Qian L, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485(7400):593–598.
18. Jayawardena TM, et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012; 110(11):1465–1473.
19. Srivastava D, Ieda M. Critical factors for cardiac reprogramming. Circ Res. 2012; 111(1):58.
20. Kazutaka Miyamotoand Masaki IedaSpecial Issue (Mini Review) Direct Cardiac Reprogramming Inflammation and Regeneration Vol.34 No.5 November 2014.
Shah Navid,Khan Bashir.Perspective of Direct Reprogramming of fibroblast to Cardiomyocyte. Perspectives in medical research 2015;3:2:15-17.