Direct cardiac reprogramming: Progress and challenges in basic biology and clinical applications

Circulation Research

Volumn 116, Issue 8, 2015, Pages 1378-1391

  Sadahiro, Taketaro ^a,c   Yamanaka, Shinya ^d   Ieda, Masaki ^a,b  

^a KEIO UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^b JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

^c KYOTO UNIVERSITY   (Japan)

^d GLADSTONE INSTITUTE OF CARDIOVASCULAR DISEASE   (United States)

Author keywords

Fibroblasts; Induced pluripotent stem cells; Myocytes, cardiac

Indexed keywords

KRUPPEL LIKE FACTOR 4; MYC PROTEIN; OCTAMER TRANSCRIPTION FACTOR 4; TRANSCRIPTION FACTOR SOX2; TRANSCRIPTION FACTOR;

CELL REGENERATION; CYTOLOGY; ENDOTHELIUM CELL; HEART MUSCLE CELL; HUMAN; LIVER CELL; NERVE CELL; NONHUMAN; PANCREAS ISLET BETA CELL; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; ANIMAL; CELL LINEAGE; GENE EXPRESSION REGULATION; GENETICS; HEART DISEASES; HEART MUSCLE; METABOLISM; NUCLEAR REPROGRAMMING; PATHOLOGY; PATHOPHYSIOLOGY; PHENOTYPE; PROCEDURES; REGENERATION; REGENERATIVE MEDICINE; TRANSPLANTATION; TREATMENT OUTCOME;

ANIMALS; CELL LINEAGE; CELLULAR REPROGRAMMING; GENE EXPRESSION REGULATION; HEART DISEASES; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MYOCARDIUM; MYOCYTES, CARDIAC; PHENOTYPE; REGENERATION; REGENERATIVE MEDICINE; TRANSCRIPTION FACTORS; TREATMENT OUTCOME;

EID: 84930812429     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.116.305374     Document Type: Review

References (124)

1. Yusuf S, Probstfield J, Verter J, The SOLVD Investigators Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New Engl J Med 1991; 325: 293-302.
2. Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dobbels F, Kirk R, Rahmel AO, Hertz MI., The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Report-2011. J Heart Lung Transplant 2011; 30: 1078-1094. doi: 10.1016/j.healun.2011.08.003
3. Garbern JC, Lee RT., Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell 2013; 12: 689-698. doi: 10.1016/j.stem.2013.05.008
4. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P., Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114: 763-776.
5. 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: 187-192. doi: 10.1073/pnas.1208863110
6. Xin M, Kim Y, Sutherland LB, Murakami M, Qi X, McAnally J, Porrello ER, Mahmoud AI, Tan W, Shelton JM, Richardson JA, Sadek HA, Bassel-Duby R, Olson EN., Hippo pathway effector Yap promotes cardiac regeneration. Proc Natl Acad Sci U S A 2013; 110: 13839-13844. doi: 10.1073/pnas.1313192110
7. 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: 433-436. doi: 10.1038/nature11682
8. Shiba Y, Fernandes S, Zhu WZ, Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 2012; 489: 322-325. doi: 10.1038/nature11317
9. Chong JJ, Yang X, Don CW, Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 2014; 510: 273-277. doi: 10.1038/nature13233
10. Lalit PA, Hei DJ, Raval AN, Kamp TJ., Induced pluripotent stem cells for post-myocardial infarction repair: remarkable opportunities and challenges. Circ Res 2014; 114: 1328-1345. doi: 10.1161/CIRCRESAHA.114.300556
11. Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S, Ikeda E, Yamanaka S, Miura K., Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res 2013; 112: 523-533. doi: 10.1161/CIRCRESAHA.111.256149
12. Yang X, Pabon L, Murry CE., Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res 2014; 114: 511-523. doi: 10.1161/CIRCRESAHA.114.300558
13. Lee K, Kim Y, Lee SJ, Qiang Y, Lee D, Lee HW, Kim H, Je HS, Südhof TC, Ko J., MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development. Proc Natl Acad Sci U S A 2013; 110: 336-341. doi: 10.1073/pnas.1219987110
14. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S., Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 861-872. doi: 10.1016/j.cell.2007.11.019
15. Takahashi K, Yamanaka S., Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663-676. doi: 10.1016/j.cell.2006.07.024
16. Han JK, Chang SH, Cho HJ, Choi SB, Ahn HS, Lee J, Jeong H, Youn SW, Lee HJ, Kwon YW, Cho HJ, Oh BH, Oettgen P, Park YB, Kim HS., Direct conversion of adult skin fibroblasts to endothelial cells by defined factors. Circulation 2014; 130: 1168-1178. doi: 10.1161/CIRCULATIONAHA.113.007727
17. Riddell J, Gazit R, Garrison BS, Guo G, Saadatpour A, Mandal PK, Ebina W, Volchkov P, Yuan GC, Orkin SH, Rossi DJ., Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 2014; 157: 549-564. doi: 10.1016/j.cell.2014.04.006
18. Huang P, He Z, Ji S, Sun H, Xiang D, Liu C, Hu Y, Wang X, Hui L., Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 2011; 475: 386-389. doi: 10.1038/nature10116
19. Sekiya S, Suzuki A., Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 2011; 475: 390-393. doi: 10.1038/nature10263
20. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M., Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010; 463: 1035-1041. doi: 10.1038/nature08797
21. 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. doi: 10.1016/j.cell.2010.07.002
22. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA., In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008; 455: 627-632. doi: 10.1038/nature07314
23. 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: 593-598. doi: 10.1038/nature11044
24. 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: 599-604. doi: 10.1038/nature11139
25. Nam YJ, Song K, 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: 5588-5593. doi: 10.1073/pnas.1301019110
26. Wada R, Muraoka N, Inagawa K, Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci U S A 2013; 110: 12667-12672. doi: 10.1073/pnas.1304053110
27. Fu JD, Stone NR, Liu L, Spencer CI, Qian L, Hayashi Y, Delgado-Olguin P, Ding S, Bruneau BG, Srivastava D., Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Reports 2013; 1: 235-247. doi: 10.1016/j.stemcr.2013.07.005
28. Chen JX, Krane M, Deutsch MA, Wang L, Rav-Acha M, Gregoire S, Engels MC, Rajarajan K, Karra R, Abel ED, Wu JC, Milan D, Wu SM., Inefficient reprogramming of fibroblasts into cardiomyocytes using Gata4, Mef2c, and Tbx5. Circ Res 2012; 111: 50-55. doi: 10.1161/CIRCRESAHA.112.270264
29. Srivastava D, Ieda M., Critical factors for cardiac reprogramming. Circ Res 2012; 111: 5-8. doi: 10.1161/CIRCRESAHA.112.271452
30. Davis RL, Weintraub H, Lassar AB., Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987; 51: 987-1000.
31. Gurdon JB., From nuclear transfer to nuclear reprogramming: the reversal of cell differentiation. Annu Rev Cell Dev Biol 2006; 22: 1-22. doi: 10.1146/annurev.cellbio.22.090805.140144
32. GURDON JB., The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol 1962; 10: 622-640.
33. Boland MJ, Hazen JL, Nazor KL, Rodriguez AR, Gifford W, Martin G, Kupriyanov S, Baldwin KK., Adult mice generated from induced pluripotent stem cells. Nature 2009; 461: 91-94. doi: 10.1038/nature08310
34. Kang L, Wang J, Zhang Y, Kou Z, Gao S., iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell 2009; 5: 135-138. doi: 10.1016/j.stem.2009.07.001
35. Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo CL, Ma QW, Wang L, Zeng F, Zhou Q., iPS cells produce viable mice through tetraploid complementation. Nature 2009; 461: 86-90. doi: 10.1038/nature08267
36. Okita K, Ichisaka T, Yamanaka S., Generation of germline-competent induced pluripotent stem cells. Nature 2007; 448: 313-317. doi: 10.1038/nature05934
37. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K., Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 2007; 1: 55-70. doi: 10.1016/j.stem.2007.05.014
38. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R., In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007; 448: 318-324. doi: 10.1038/nature05944
39. Stadtfeld M, Maherali N, Breault DT, Hochedlinger K., Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2008; 2: 230-240. doi: 10.1016/j.stem.2008.02.001
40. Maherali N, Hochedlinger K., Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 2008; 3: 595-605. doi: 10.1016/j.stem.2008.11.008
41. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA., Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318: 1917-1920. doi: 10.1126/science.1151526
42. Park IH, Lerou PH, Zhao R, Huo H, Daley GQ., Generation of human-induced pluripotent stem cells. Nat Protoc 2008; 3: 1180-1186. doi: 10.1038/nprot.2008.92
43. Li W, Wei W, Zhu S, Zhu J, Shi Y, Lin T, Hao E, Hayek A, Deng H, Ding S., Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 2009; 4: 16-19. doi: 10.1016/j.stem.2008.11.014
44. Liu H, Zhu F, Yong J, Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 2008; 3: 587-590. doi: 10.1016/j.stem.2008.10.014
45. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S., The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003; 113: 631-642.
46. Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, Loh KM, Carter AC, Di Giorgio FP, Koszka K, Huangfu D, Akutsu H, Liu DR, Rubin LL, Eggan K., A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 2009; 5: 491-503. doi: 10.1016/j.stem.2009.09.012
47. Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, Yamanaka S., Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 2008; 321: 699-702. doi: 10.1126/science.1154884
48. Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, Vassena R, Bilić J, Pekarik V, Tiscornia G, Edel M, Boué S, Izpisúa Belmonte JC., Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 2008; 26: 1276-1284. doi: 10.1038/nbt.1503
49. Seki T, Yuasa S, Oda M, Egashira T, Yae K, Kusumoto D, Nakata H, Tohyama S, Hashimoto H, Kodaira M, Okada Y, Seimiya H, Fusaki N, Hasegawa M, Fukuda K., Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 2010; 7: 11-14. doi: 10.1016/j.stem.2010.06.003
50. Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR., Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 2008; 454: 646-650. doi: 10.1038/nature07061
51. Hanna J, Markoulaki S, Schorderet P, Carey BW, Beard C, Wernig M, Creyghton MP, Steine EJ, Cassady JP, Foreman R, Lengner CJ, Dausman JA, Jaenisch R., Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 2008; 133: 250-264. doi: 10.1016/j.cell.2008.03.028
52. Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, Melton DA., Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 2008; 26: 795-797. doi: 10.1038/nbt1418
53. Costa Y, Ding J, Theunissen TW, NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 2013; 495: 370-374. doi: 10.1038/nature11925
54. Maekawa M, Yamaguchi K, Nakamura T, Shibukawa R, Kodanaka I, Ichisaka T, Kawamura Y, Mochizuki H, Goshima N, Yamanaka S., Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. Nature 2011; 474: 225-229. doi: 10.1038/nature10106
55. Tanabe K, Nakamura M, Narita M, Takahashi K, Yamanaka S., Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts. Proc Natl Acad Sci U S A 2013; 110: 12172-12179. doi: 10.1073/pnas.1310291110
56. Rais Y, Zviran A, Geula S, Deterministic direct reprogramming of somatic cells to pluripotency. Nature 2013; 502: 65-70. doi: 10.1038/nature12587
57. Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, Ge J, Xu J, Zhang Q, Zhao Y, Deng H., Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 2013; 341: 651-654. doi: 10.1126/science.1239278
58. Nature's 10: ten people who mattered this year. Nature 2014; 516: 311-319. doi: 10.1038/516311a
59. Baeyens L, Lemper M, Leuckx G, Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol 2014; 32: 76-83. doi: 10.1038/nbt.2747
60. Chanda S, Ang CE, Davila J, Pak C, Mall M, Lee QY, Ahlenius H, Jung SW, Südhof TC, Wernig M., Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Reports 2014; 3: 282-296. doi: 10.1016/j.stemcr.2014.05.020
61. Wapinski OL, Vierbuchen T, Qu K, Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 2013; 155: 621-635. doi: 10.1016/j.cell.2013.09.028
62. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch RE, Tsien RW, Crabtree GR., MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 2011; 476: 228-231. doi: 10.1038/nature10323
63. Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC, Wernig M., Induction of human neuronal cells by defined transcription factors. Nature 2011; 476: 220-223. doi: 10.1038/nature10202
64. Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller FJ, Koch P, Brüstle O., Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods 2012; 9: 575-578. doi: 10.1038/nmeth.1972
65. Son EY, Ichida JK, Wainger BJ, Toma JS, Rafuse VF, Woolf CJ, Eggan K., Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 2011; 9: 205-218. doi: 10.1016/j.stem.2011.07.014
66. Caiazzo M, Dell'Anno MT, Dvoretskova E, Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 2011; 476: 224-227. doi: 10.1038/nature10284
67. Kim J, Su SC, Wang H, Cheng AW, Cassady JP, Lodato MA, Lengner CJ, Chung CY, Dawlaty MM, Tsai LH, Jaenisch R., Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 2011; 9: 413-419. doi: 10.1016/j.stem.2011.09.011
68. Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Björklund A, Lindvall O, Jakobsson J, Parmar M., Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A 2011; 108: 10343-10348. doi: 10.1073/pnas.1105135108
69. Ring KL, Tong LM, Balestra ME, Javier R, Andrews-Zwilling Y, Li G, Walker D, Zhang WR, Kreitzer AC, Huang Y., Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell 2012; 11: 100-109. doi: 10.1016/j.stem.2012.05.018
70. Cassady JP, D'Alessio AC, Sarkar S, Dani VS, Fan ZP, Ganz K, Roessler R, Sur M, Young RA, Jaenisch R., Direct lineage conversion of adult mouse liver cells and B lymphocytes to neural stem cells. Stem Cell Reports 2014; 3: 948-956. doi: 10.1016/j.stemcr.2014.10.001
71. Zaret KS., Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat Rev Genet 2008; 9: 329-340. doi: 10.1038/nrg2318
72. Cirillo LA, Lin FR, Cuesta I, Friedman D, Jarnik M, Zaret KS., Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol Cell 2002; 9: 279-289.
73. Cirillo LA, Zaret KS., An early developmental transcription factor complex that is more stable on nucleosome core particles than on free DNA. Mol Cell 1999; 4: 961-969.
74. Morris SA, Cahan P, Li H, Zhao AM, San Roman AK, Shivdasani RA, Collins JJ, Daley GQ., Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell 2014; 158: 889-902. doi: 10.1016/j.cell.2014.07.021
75. Huang P, Zhang L, Gao Y, Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 2014; 14: 370-384. doi: 10.1016/j.stem.2014.01.003
76. Du Y, Wang J, Jia J, Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell 2014; 14: 394-403. doi: 10.1016/j.stem.2014.01.008
77. Batta K, Florkowska M, Kouskoff V, Lacaud G., Direct reprogramming of murine fibroblasts to hematopoietic progenitor cells. Cell Rep 2014; 9: 1871-1884. doi: 10.1016/j.celrep.2014.11.002
78. Takeuchi JK, Bruneau BG., Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 2009; 459: 708-711. doi: 10.1038/nature08039
79. Bondue A, Lapouge G, Paulissen C, Semeraro C, Iacovino M, Kyba M, Blanpain C., Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell 2008; 3: 69-84. doi: 10.1016/j.stem.2008.06.009
80. Polo JM, Anderssen E, Walsh RM, A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 2012; 151: 1617-1632. doi: 10.1016/j.cell.2012.11.039
81. Carey BW, Markoulaki S, Hanna JH, Faddah DA, Buganim Y, Kim J, Ganz K, Steine EJ, Cassady JP, Creyghton MP, Welstead GG, Gao Q, Jaenisch R., Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell 2011; 9: 588-598. doi: 10.1016/j.stem.2011.11.003
82. Takahashi K, Okita K, Nakagawa M, Yamanaka S., Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2007; 2: 3081-3089. doi: 10.1038/nprot.2007.418
83. Buganim Y, Faddah DA, Cheng AW, Itskovich E, Markoulaki S, Ganz K, Klemm SL, van Oudenaarden A, Jaenisch R., Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 2012; 150: 1209-1222. doi: 10.1016/j.cell.2012.08.023
84. Wang L, Liu Z, Yin C, Asfour H, Chen OM, Li Y, Bursac N, Liu J, Qian L., Stoichiometry of Gata4, Mef2c, and Tbx5 influences the efficiency and quality of induced cardiac myocyte reprogramming. Circulation Res 2014; 116: 237-244. doi: 10.1161/CIRCRESAHA.116.305547
85. Nam YJ, Lubczyk C, Bhakta M, Zang T, Fernandez-Perez A, McAnally J, Bassel-Duby R, Olson EN, Munshi NV., Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors. Development 2014; 141: 4267-4278. doi: 10.1242/dev.114025
86. Hirai H, Katoku-Kikyo N, Keirstead SA, Kikyo N., Accelerated direct reprogramming of fibroblasts into cardiomyocyte-like cells with the MyoD transactivation domain. Cardiovasc Res 2013; 100: 105-113. doi: 10.1093/cvr/cvt167
87. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K, Zhang Z, Rosenberg P, Mirotsou M, Dzau VJ., MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res 2012; 110: 1465-1473. doi: 10.1161/CIRCRESAHA.112.269035
88. Addis RC, Ifkovits JL, Pinto F, Kellam LD, Esteso P, Rentschler S, Christoforou N, Epstein JA, Gearhart JD., Optimization of direct fibroblast reprogramming to cardiomyocytes using calcium activity as a functional measure of success. J Mol Cell Cardiol 2013; 60: 97-106. doi: 10.1016/j.yjmcc.2013.04.004
89. Addis RC, Epstein JA., Induced regeneration-the progress and promise of direct reprogramming for heart repair. Nat Med 2013; 19: 829-836. doi: 10.1038/nm.3225
90. Ifkovits JL, Addis RC, Epstein JA, Gearhart JD., Inhibition of TGFβ signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS One 2014 9 e89678. doi: 10.1371/journal.pone.0089678
91. Muraoka N, Yamakawa H, Miyamoto K, MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J 2014; 33: 1565-1581. doi: 10.15252/embj.201387605
92. Protze S, Khattak S, Poulet C, Lindemann D, Tanaka EM, Ravens U., A new approach to transcription factor screening for reprogramming of fibroblasts to cardiomyocyte-like cells. J Mol Cell Cardiol 2012; 53: 323-332. doi: 10.1016/j.yjmcc.2012.04.010
93. Christoforou N, Chellappan M, Adler AF, Kirkton RD, Wu T, Addis RC, Bursac N, Leong KW., Transcription factors MYOCD, SRF, Mesp1 and SMARCD3 enhance the cardio-inducing effect of GATA4, TBX5, and MEF2C during direct cellular reprogramming. PLoS One 2013 8 e63577. doi: 10.1371/journal.pone.0063577
94. Zhou L, Liu Y, Lu L, Lu X, Dixon RA., Cardiac gene activation analysis in mammalian non-myoblasic cells by Nkx2-5, Tbx5, Gata4 and Myocd. PLoS One 2012 7 e48028. doi: 10.1371/journal.pone.0048028
95. Inagawa K, Miyamoto K, Yamakawa H, Muraoka N, Sadahiro T, Umei T, Wada R, Katsumata Y, Kaneda R, Nakade K, Kurihara C, Obata Y, Miyake K, Fukuda K, Ieda M., Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. Circ Res 2012; 111: 1147-1156. doi: 10.1161/CIRCRESAHA.112.271148
96. Mathison M, Gersch RP, Nasser A, Lilo S, Korman M, Fourman M, Hackett N, Shroyer K, Yang J, Ma Y, Crystal RG, Rosengart TK., In vivo cardiac cellular reprogramming efficacy is enhanced by angiogenic preconditioning of the infarcted myocardium with vascular endothelial growth factor. J Am Heart Assoc 2012 1 e005652. doi: 10.1161/JAHA.112.005652
97. Carey BW, Markoulaki S, Hanna J, Saha K, Gao Q, Mitalipova M, Jaenisch R., Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci U S A 2009; 106: 157-162. doi: 10.1073/pnas.0811426106
98. Inagawa K, Ieda M., Direct reprogramming of mouse fibroblasts into cardiac myocytes. J Cardiovasc Transl Res 2013; 6: 37-45. doi: 10.1007/s12265-012-9412-5
99. Jayawardena TM, Finch EA, Zhang L, Zhang H, Hodgkinson CP, Pratt RE, Rosenberg PB, Mirotsou M, Dzau VJ., MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. Circ Res 2015; 116: 418-424. doi: 10.1161/CIRCRESAHA.116.304510
100. Liu N, Bezprozvannaya S, Williams AH, Qi X, Richardson JA, Bassel-Duby R, Olson EN., microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev 2008; 22: 3242-3254. doi: 10.1101/gad.1738708
101. Islas JF, Liu Y, Weng KC, Robertson MJ, Zhang S, Prejusa A, Harger J, Tikhomirova D, Chopra M, Iyer D, Mercola M, Oshima RG, Willerson JT, Potaman VN, Schwartz RJ., Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. Proc Natl Acad Sci U S A 2012; 109: 13016-13021. doi: 10.1073/pnas.1120299109
102. Nam YJ, Song K, Olson EN., Heart repair by cardiac reprogramming. Nat Med 2013; 19: 413-415. doi: 10.1038/nm.3147
103. Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang G, Chen J, Ding S., Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 2011; 13: 215-222. doi: 10.1038/ncb2164
104. Wang H, Cao N, Spencer CI, Nie B, Ma T, Xu T, Zhang Y, Wang X, Srivastava D, Ding S., Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4. Cell Rep 2014; 6: 951-960. doi: 10.1016/j.celrep.2014.01.038
105. Szabo E, Rampalli S, Risueño RM, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M., Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 2010; 468: 521-526. doi: 10.1038/nature09591
106. Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, Lipton SA, Zhang K, Ding S., Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci U S A 2011; 108: 7838-7843. doi: 10.1073/pnas.1103113108
107. Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL., Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 2010; 7: 64-77. doi: 10.1016/j.stem.2010.04.015
108. Li R, Liang J, Ni S, A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 2010; 7: 51-63. doi: 10.1016/j.stem.2010.04.014
109. Unternaehrer JJ, Zhao R, Kim K, Cesana M, Powers JT, Ratanasirintrawoot S, Onder T, Shibue T, Weinberg RA, Daley GQ., The epithelial-mesenchymal transition factor SNAIL paradoxically enhances reprogramming. Stem Cell Reports 2014; 3: 691-698. doi: 10.1016/j.stemcr.2014.09.008
110. Cahan P, Li H, Morris SA, Lummertz da Rocha E, Daley GQ, Collins JJ., CellNet: network biology applied to stem cell engineering. Cell 2014; 158: 903-915. doi: 10.1016/j.cell.2014.07.020
111. Ieda M, Kanazawa H, Kimura K, Sema3a maintains normal heart rhythm through sympathetic innervation patterning. Nat Med 2007; 13: 604-612. doi: 10.1038/nm1570
112. Chien KR, Domian IJ, Parker KK., Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science 2008; 322: 1494-1497. doi: 10.1126/science.1163267
113. Sasse P, Zhang J, Cleemann L, Morad M, Hescheler J, Fleischmann BK., Intracellular Ca2+ oscillations, a potential pacemaking mechanism in early embryonic heart cells. J Gen Physiol 2007; 130: 133-144. doi: 10.1085/jgp.200609575
114. Kapoor N, Liang W, Marbán E, Cho HC., Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol 2013; 31: 54-62. doi: 10.1038/nbt.2465
115. Wiese C, Grieskamp T, Airik R, Mommersteeg MT, Gardiwal A, de Gier-de Vries C, Schuster-Gossler K, Moorman AF, Kispert A, Christoffels VM., Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circ Res 2009; 104: 388-397. doi: 10.1161/CIRCRESAHA.108.187062
116. Lakatta EG, Maltsev VA., Reprogramming paces the heart. Nat Biotechnol 2013; 31: 31-32. doi: 10.1038/nbt.2480
117. Bakker ML, Boink GJ, Boukens BJ, Verkerk AO, van den Boogaard M, den Haan AD, Hoogaars WM, Buermans HP, de Bakker JM, Seppen J, Tan HL, Moorman AF, 't Hoen PA, Christoffels VM., T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells. Cardiovasc Res 2012; 94: 439-449. doi: 10.1093/cvr/cvs120
118. Rentschler S, Yen AH, Lu J, Petrenko NB, Lu MM, Manderfield LJ, Patel VV, Fishman GI, Epstein JA., Myocardial Notch signaling reprograms cardiomyocytes to a conduction-like phenotype. Circulation 2012; 126: 1058-1066. doi: 10.1161/CIRCULATIONAHA.112.103390
119. Blum B, Benvenisty N., The tumorigenicity of human embryonic stem cells. Adv Cancer Res 2008; 100: 133-158. doi: 10.1016/S0065-230X(08)00005-5
120. Zhang M, Methot D, Poppa V, Fujio Y, Walsh K, Murry CE., Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol 2001; 33: 907-921. doi: 10.1006/jmcc.2001.1367
121. Nussbaum J, Minami E, Laflamme MA, Virag JA, Ware CB, Masino A, Muskheli V, Pabon L, Reinecke H, Murry CE., Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J 2007; 21: 1345-1357. doi: 10.1096/fj.06-6769com
122. Tsuji O, Miura K, Okada Y, Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci U S A 2010; 107: 12704-12709. doi: 10.1073/pnas.0910106107
123. Palpant NJ, Murry CE., Regenerative medicine: Reprogramming the injured heart. Nature 2012; 485: 585-586. doi: 10.1038/485585a
124. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S., Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008; 322: 949-953. doi: 10.1126/science.1164270