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Direct Cardiac Reprogramming

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Part of the book series: Cardiac and Vascular Biology ((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.

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References

  • Addis RC, Epstein JA (2013) Induced regeneration – the progress and promise of direct reprogramming for heart repair. Nat Med 19:829–836

    Article  CAS  PubMed  Google Scholar 

  • 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 60:97–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 11:855–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cahan P, Li H, Morris SA, Lummertz da Rocha E, Daley GQ, Collins JJ (2014) CellNet: network biology applied to stem cell engineering. Cell 158:903–915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 9:588–598

    Article  CAS  PubMed  Google Scholar 

  • 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 111:50–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 510:273–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000

    Article  CAS  PubMed  Google Scholar 

  • 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 1:235–247

    Article  CAS  Google Scholar 

  • 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 130:1168–1178

    Article  CAS  PubMed  Google Scholar 

  • Hirai H, Tani T, Kikyo N (2010) Structure and functions of powerful transactivators: VP16, MyoD and FoxA. Int J Dev Biol 54:1589–1596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 100:105–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):386–389

    Article  CAS  PubMed  Google Scholar 

  • 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 14:370–384

    Article  CAS  PubMed  Google Scholar 

  • 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 16:233–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 142:375–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ifkovits JL, Addis RC, Epstein JA, Gearhart JD (2014) Inhibition of TGFbeta signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS One 9:e89678

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • 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 111:1147–1156

    Article  CAS  PubMed  Google Scholar 

  • 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 109:13016–13021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 110:1465–1473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):418–424

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 8:228–240

    Article  CAS  PubMed  Google Scholar 

  • Lalit PA, Hei DJ, Raval AN, Kamp TJ (2014) Induced pluripotent stem cells for post-myocardial infarction repair: remarkable opportunities and challenges. Circ Res 114:1328–1345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 433:647–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 7:51–63

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 3:587–590

    Article  CAS  PubMed  Google Scholar 

  • 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:e005652

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 158:889–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muraoka N, Ieda M (2014) Direct reprogramming of fibroblasts into myocytes to reverse fibrosis. Annu Rev Physiol 76:21–37

    Article  CAS  PubMed  Google Scholar 

  • Muraoka N, Ieda M (2015) Stoichiometry of transcription factors is critical for cardiac reprogramming. Circ Res 116:216–218

    Article  CAS  PubMed  Google Scholar 

  • 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 33:1565–1581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 110:5588–5593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 141:4267–4278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 112:523–533

    Article  CAS  PubMed  Google Scholar 

  • 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 151:1617–1632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 53:323–332

    Article  CAS  PubMed  Google Scholar 

  • 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 485:593–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qian L, Berry EC, Fu JD, Ieda M, Srivastava D (2013) Reprogramming of mouse fibroblasts into cardiomyocyte-like cells in vitro. Nat Protoc 8:1204–1215

    Article  PubMed  CAS  Google Scholar 

  • 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):331–335

    Article  CAS  PubMed  Google Scholar 

  • 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 157:549–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 126:3437–3447

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 489:322–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 485:599–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Okita K, Nakagawa M, Yamanaka S (2007a) Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2:3081–3089

    Article  CAS  PubMed  Google Scholar 

  • 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 131:861–872

    Article  CAS  PubMed  Google Scholar 

  • 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 3:691–698

    Article  CAS  Google Scholar 

  • Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–1041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 110:12667–12672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):237–244

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 5:1128–1142

    Article  CAS  Google Scholar 

  • Yang X, Pabon L, Murry CE (2014) Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res 114:511–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida Y, Yamanaka S (2012a) An emerging strategy of gene therapy for cardiac disease. Circ Res 111:1108–1110

    Article  CAS  PubMed  Google Scholar 

  • Yoshida Y, Yamanaka S (2012b) Labor pains of new technology: direct cardiac reprogramming. Circ Res 111:3–4

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Samal E, Srivastava D (2005) Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436:214–220

    Article  CAS  PubMed  Google Scholar 

  • 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 129:303–317

    Article  CAS  PubMed  Google Scholar 

  • 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 6:8243

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 112:11864–11869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.

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The authors declare that they have no conflict of interest.

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

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Correspondence to Masaki Ieda .

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Haginiwa, S., Ieda, M. (2017). Direct Cardiac Reprogramming. In: Ieda, M., Zimmermann, WH. (eds) Cardiac Regeneration. Cardiac and Vascular Biology, vol 4. Springer, Cham. https://doi.org/10.1007/978-3-319-56106-6_6

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