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Direct Cardiac Reprogramming

  • Sho Haginiwa
  • Masaki IedaEmail author
Chapter
  • 507 Downloads
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol., volume 4)

Abstract

Recent advances in medical treatment and the development of new mechanical devices have greatly improved the prognosis for heart disease patients. However, heart disease, particularly heart failure, is still a major health issue with continuously increasing numbers of affected patients. Because adult heart muscle has a low regenerative capacity, cardiac function declines with age after cardiac injury. A potential approach to solve this problem is regenerative medicine, aiming at the remuscularization of damaged hearts. Studies conducted in small animals and humans revealed that transplanting various types of cells into failing hearts resulted in the repair of injured hearts and improved cardiac function, but the effects were modest, and further improvement is needed before the method can be widely applied in the clinic. Moreover, true muscle regeneration or cardiac differentiation from so far clinically tested adult stem cells seems to be a rare event, and the beneficial effects of these cell-based therapies are likely due to paracrine factors secreted by the transplanted cells. To regenerate cardiac muscle, it is important to first understand the mechanism of cardiac cell fate determination. Several groups including ours recently found that somatic cells can be directly reprogrammed into cardiomyocyte-like cells using combinations of master regulators. The cardiac reprogramming approach is applicable not only in vitro but also in vivo. It can repair injured hearts and improve cardiac function. Thus, this new technology may open an avenue for regenerative therapy for heart disease.

Notes

Acknowledgments

M.I. was supported by research grants from JST CREST, AMED PRIME, JSPS, Keio University Program for the Advancement of Next Generation Research Projects, Banyu Life Science, Senshin Medical Research Foundation, and Takeda Science Foundation.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors.

References

  1. Addis RC, Epstein JA (2013) Induced regeneration – the progress and promise of direct reprogramming for heart repair. Nat Med 19:829–836PubMedGoogle Scholar
  2. Addis RC, Ifkovits JL, Pinto F, Kellam LD, Esteso P, Rentschler S, Christoforou N, Epstein JA, Gearhart JD (2013) Optimization of direct fibroblast reprogramming to cardiomyocytes using calcium activity as a functional measure of success. J Mol Cell Cardiol 60:97–106PubMedPubMedCentralGoogle Scholar
  3. Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD, Lan F, Diecke S, Huber B, Mordwinkin NM et al (2014) Chemically defined generation of human cardiomyocytes. Nat Methods 11:855–860PubMedPubMedCentralGoogle Scholar
  4. Cahan P, Li H, Morris SA, Lummertz da Rocha E, Daley GQ, Collins JJ (2014) CellNet: network biology applied to stem cell engineering. Cell 158:903–915PubMedPubMedCentralGoogle Scholar
  5. Carey BW, Markoulaki S, Hanna JH, Faddah DA, Buganim Y, Kim J, Ganz K, Steine EJ, Cassady JP, Creyghton MP et al (2011) Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell 9:588–598PubMedGoogle Scholar
  6. Chen JX, Krane M, Deutsch MA, Wang L, Rav-Acha M, Gregoire S, Engels MC, Rajarajan K, Karra R, Abel ED et al (2012) Inefficient reprogramming of fibroblasts into cardiomyocytes using gata4, mef2c, and tbx5. Circ Res 111:50–55PubMedPubMedCentralGoogle Scholar
  7. Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, Mahoney WM, Van Biber B, Cook SM, Palpant NJ et al (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510:273–277PubMedPubMedCentralGoogle Scholar
  8. Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000PubMedGoogle Scholar
  9. Fu JD, Stone NR, Liu L, Spencer CI, Qian L, Hayashi Y, Delgado-Olguin P, Ding S, Bruneau BG, Srivastava D (2013) Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Rep 1:235–247Google Scholar
  10. Han JK, Chang SH, Cho HJ, Choi SB, Ahn HS, Lee J, Jeong H, Youn SW, Lee HJ, Kwon YW et al (2014) Direct conversion of adult skin fibroblasts to endothelial cells by defined factors. Circulation 130:1168–1178PubMedGoogle Scholar
  11. Hirai H, Tani T, Kikyo N (2010) Structure and functions of powerful transactivators: VP16, MyoD and FoxA. Int J Dev Biol 54:1589–1596PubMedPubMedCentralGoogle Scholar
  12. Hirai H, Katoku-Kikyo N, Keirstead SA, Kikyo N (2013) Accelerated direct reprogramming of fibroblasts into cardiomyocyte-like cells with the MyoD transactivation domain. Cardiovasc Res 100:105–113PubMedPubMedCentralGoogle Scholar
  13. Huang P, He Z, Ji S, Sun H, Xiang D, Liu C, Hu Y, Wang X, Hui L (2011) Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475(7356):386–389PubMedGoogle Scholar
  14. Huang P, Zhang L, Gao Y, He Z, Yao D, Wu Z, Cen J, Chen X, Liu C, Hu Y et al (2014) Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 14:370–384PubMedGoogle Scholar
  15. Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong TT, Shaw RM, Srivastava D (2009) Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell 16:233–244PubMedPubMedCentralGoogle Scholar
  16. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, Srivastava D (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375–386PubMedPubMedCentralGoogle Scholar
  17. Ifkovits JL, Addis RC, Epstein JA, Gearhart JD (2014) Inhibition of TGFbeta signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS One 9:e89678PubMedPubMedCentralGoogle Scholar
  18. Inagawa K, Ieda M (2013) Direct reprogramming of mouse fibroblasts into cardiac myocytes. J Cardiovasc Transl Res 6:37–45PubMedGoogle Scholar
  19. Inagawa K, Miyamoto K, Yamakawa H, Muraoka N, Sadahiro T, Umei T, Wada R, Katsumata Y, Kaneda R, Nakade K et al (2012) Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. Circ Res 111:1147–1156PubMedPubMedCentralGoogle Scholar
  20. Islas JF, Liu Y, Weng KC, Robertson MJ, Zhang S, Prejusa A, Harger J, Tikhomirova D, Chopra M, Iyer D et al (2012) Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. Proc Natl Acad Sci U S A 109:13016–13021PubMedPubMedCentralGoogle Scholar
  21. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K, Zhang Z, Rosenberg P, Mirotsou M, Dzau VJ (2012) MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res 110:1465–1473PubMedPubMedCentralGoogle Scholar
  22. Jayawardena TM, Finch EA, Zhang L, Zhang H, Hodgkinson C, Pratt RE, Rosenberg PB, Mirotsou M, Dzau VJ (2014) MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. Circ Res 116(3):418–424PubMedPubMedCentralGoogle Scholar
  23. Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, Hotta A, Ellis J, Keller G (2011) Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8:228–240PubMedGoogle Scholar
  24. Lalit PA, Hei DJ, Raval AN, Kamp TJ (2014) Induced pluripotent stem cells for post-myocardial infarction repair: remarkable opportunities and challenges. Circ Res 114:1328–1345PubMedPubMedCentralGoogle Scholar
  25. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M et al (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653PubMedPubMedCentralGoogle Scholar
  26. Li R, Liang J, Ni S, Zhou T, Qing X, Li H, He W, Chen J, Li F, Zhuang Q et al (2010) A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7:51–63PubMedGoogle Scholar
  27. Liu N, Olson EN (2010) MicroRNA regulatory networks in cardiovascular development. Dev Cell 18:510–525PubMedPubMedCentralGoogle Scholar
  28. Liu H, Zhu F, Yong J, Zhang P, Hou P, Li H, Jiang W, Cai J, Liu M, Cui K et al (2008) Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 3:587–590PubMedGoogle Scholar
  29. Mathison M, Gersch RP, Nasser A, Lilo S, Korman M, Fourman M, Hackett N, Shroyer K, Yang J, Ma Y et al (2012) 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:e005652PubMedPubMedCentralGoogle Scholar
  30. Morris SA, Cahan P, Li H, Zhao AM, San Roman AK, Shivdasani RA, Collins JJ, Daley GQ (2014) Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell 158:889–902PubMedPubMedCentralGoogle Scholar
  31. Muraoka N, Ieda M (2014) Direct reprogramming of fibroblasts into myocytes to reverse fibrosis. Annu Rev Physiol 76:21–37PubMedGoogle Scholar
  32. Muraoka N, Ieda M (2015) Stoichiometry of transcription factors is critical for cardiac reprogramming. Circ Res 116:216–218PubMedGoogle Scholar
  33. Muraoka N, Yamakawa H, Miyamoto K, Sadahiro T, Umei T, Isomi M, Nakashima H, Akiyama M, Wada R, Inagawa K et al (2014) MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J 33:1565–1581PubMedPubMedCentralGoogle Scholar
  34. Nam YJ, Song K, Luo X, Daniel E, Lambeth K, West K, Hill JA, Dimaio JM, Baker LA, Bassel-Duby R et al (2013) Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A 110:5588–5593PubMedPubMedCentralGoogle Scholar
  35. Nam YJ, Lubczyk C, Bhakta M, Zang T, Fernandez-Perez A, McAnally J, Bassel-Duby R, Olson EN, Munshi NV (2014) Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors. Development 141:4267–4278PubMedPubMedCentralGoogle Scholar
  36. Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S, Ikeda E, Yamanaka S, Miura K (2013) Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res 112:523–533PubMedGoogle Scholar
  37. Polo JM, Anderssen E, Walsh RM, Schwarz BA, Nefzger CM, Lim SM, Borkent M, Apostolou E, Alaei S, Cloutier J et al (2012) A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151:1617–1632PubMedPubMedCentralGoogle Scholar
  38. Protze S, Khattak S, Poulet C, Lindemann D, Tanaka EM, Ravens U (2012) A new approach to transcription factor screening for reprogramming of fibroblasts to cardiomyocyte-like cells. J Mol Cell Cardiol 53:323–332PubMedGoogle Scholar
  39. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, Conway SJ, Fu JD, Srivastava D (2012) In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485:593–598PubMedPubMedCentralGoogle Scholar
  40. Qian L, Berry EC, Fu JD, Ieda M, Srivastava D (2013) Reprogramming of mouse fibroblasts into cardiomyocyte-like cells in vitro. Nat Protoc 8:1204–1215PubMedGoogle Scholar
  41. Rackham OJ, Firas J, Fang H, Oates ME, Holmes ML, Knaupp AS, Consortium F, Suzuki H, Nefzger CM, Daub CO et al (2016) A predictive computational framework for direct reprogramming between human cell types. Nat Genet 48(3):331–335PubMedGoogle Scholar
  42. Riddell J, Gazit R, Garrison BS, Guo G, Saadatpour A, Mandal PK, Ebina W, Volchkov P, Yuan GC, Orkin SH et al (2014) Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157:549–564PubMedPubMedCentralGoogle Scholar
  43. Sadahiro T, Yamanaka S, Ieda M (2015) Direct cardiac reprogramming: progress and challenges in basic biology and clinical applications. Circ Res 116:1378–1391PubMedGoogle Scholar
  44. Saga Y, Miyagawa-Tomita S, Takagi A, Kitajima S, Miyazaki J, Inoue T (1999) MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Development 126:3437–3447PubMedGoogle Scholar
  45. Sekiya S, Suzuki A (2011) Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475:390–393PubMedPubMedCentralGoogle Scholar
  46. Shiba Y, Fernandes S, Zhu WZ, Filice D, Muskheli V, Kim J, Palpant NJ, Gantz J, Moyes KW, Reinecke H et al (2012) Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489:322–325PubMedPubMedCentralGoogle Scholar
  47. Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG et al (2012) Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485:599–604PubMedPubMedCentralGoogle Scholar
  48. Srivastava D, Ieda M (2012) Critical factors for cardiac reprogramming. Circ Res 111:5–8PubMedPubMedCentralGoogle Scholar
  49. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedPubMedCentralGoogle Scholar
  50. Takahashi K, Okita K, Nakagawa M, Yamanaka S (2007a) Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2:3081–3089PubMedGoogle Scholar
  51. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007b) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872Google Scholar
  52. Unternaehrer JJ, Zhao R, Kim K, Cesana M, Powers JT, Ratanasirintrawoot S, Onder T, Shibue T, Weinberg RA, Daley GQ (2014) The epithelial-mesenchymal transition factor SNAIL paradoxically enhances reprogramming. Stem Cell Rep 3:691–698Google Scholar
  53. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–1041PubMedPubMedCentralGoogle Scholar
  54. Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T, Umei T, Kaneda R, Suzuki T, Kamiya K et al (2013) Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci U S A 110:12667–12672PubMedPubMedCentralGoogle Scholar
  55. Wang L, Liu Z, Yin C, Asfour H, Chen OM, Li Y, Bursac N, Liu J, Qian L (2014) Stoichiometry of Gata4, Mef2c, and Tbx5 influences the efficiency and quality of induced cardiac myocyte reprogramming. Circ Res 116(2):237–244PubMedPubMedCentralGoogle Scholar
  56. Yamakawa H, Muraoka N, Miyamoto K, Sadahiro T, Isomi M, Haginiwa S, Kojima H, Umei T, Akiyama M, Kuishi Y et al (2015) Fibroblast growth factors and vascular endothelial growth factor promote cardiac reprogramming under defined conditions. Stem Cell Rep 5:1128–1142Google Scholar
  57. Yang X, Pabon L, Murry CE (2014) Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res 114:511–523PubMedPubMedCentralGoogle Scholar
  58. Yoshida Y, Yamanaka S (2012a) An emerging strategy of gene therapy for cardiac disease. Circ Res 111:1108–1110PubMedGoogle Scholar
  59. Yoshida Y, Yamanaka S (2012b) Labor pains of new technology: direct cardiac reprogramming. Circ Res 111:3–4PubMedGoogle Scholar
  60. Zhao Y, Samal E, Srivastava D (2005) Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436:214–220PubMedGoogle Scholar
  61. Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303–317PubMedGoogle Scholar
  62. Zhao Y, Londono P, Cao Y, Sharpe EJ, Proenza C, O'Rourke R, Jones KL, Jeong MY, Walker LA, Buttrick PM et al (2015) High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat Commun 6:8243PubMedPubMedCentralGoogle Scholar
  63. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455:627–632PubMedGoogle Scholar
  64. Zhou H, Dickson ME, Kim MS, Bassel-Duby R, Olson EN (2015) Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes. Proc Natl Acad Sci U S A 112:11864–11869PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of CardiologyKeio University School of MedicineTokyoJapan
  2. 2.AMED, PRIMETokyoJapan

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