Genetic and Epigenetic Regulation of Human Cardiac Reprogramming and Differentiation in Regenerative Medicine

Annual Review of Genetics

Volumn 49, Issue , 2015, Pages 461-484

  Burridge, Paul W ^a,b   Sharma, Arun ^a   Wu, Joseph C ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Cardiomyocyte; Developmental biology; Embryonic stem cells; Epigenetics; Heart; Induced pluripotent stem cells

Indexed keywords

BONE MORPHOGENETIC PROTEIN; DICKKOPF 1 PROTEIN; DNA; LONG UNTRANSLATED RNA; MICRORNA; PROTEIN NODAL; WNT PROTEIN;

ARTICLE; CARDIAC STEM CELL; CELL DIFFERENTIATION; CELL MATURATION; CELL PROLIFERATION; DNA METHYLATION; ECTODERM; EMBRYO DEVELOPMENT; EMBRYO MEMBRANE; EPICARDIUM; EPIGENETICS; GASTRULATION; GENE REGULATORY NETWORK; HEART DEVELOPMENT; HEART MUSCLE CELL; HISTONE MODIFICATION; HUMAN; HUMAN GENETICS; MESOTHELIUM; NONHUMAN; NUCLEAR REPROGRAMMING; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REGENERATIVE MEDICINE; SIGNAL TRANSDUCTION; WNT SIGNALING PATHWAY; ANIMAL; CARDIAC MUSCLE CELL; CELL REPROGRAMMING TECHNIQUE; CYTOLOGY; GENETIC EPIGENESIS; GROWTH, DEVELOPMENT AND AGING; HEART; INDUCED PLURIPOTENT STEM CELL; PHYSIOLOGY; PROCEDURES;

ANIMALS; CELL DIFFERENTIATION; CELL PROLIFERATION; CELLULAR REPROGRAMMING TECHNIQUES; DNA METHYLATION; EPIGENESIS, GENETIC; GENE REGULATORY NETWORKS; HEART; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MICRORNAS; MYOCYTES, CARDIAC; REGENERATIVE MEDICINE;

EID: 84948752224     PISSN: 00664197     EISSN: 15452948     Source Type: Book Series    
DOI: 10.1146/annurev-genet-112414-054911     Document Type: Article

References (148)

1. Ang SL, Constam DB. 2004. A gene network establishing polarity in the early mouse embryo. Semin. Cell Dev. Biol. 15:555-61
2. Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, et al. 2006. The role of PI3K/AKT, MAPK/ERK and NFκβ signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Hum. Mol. Genet. 15:1894-913
3. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, et al. 2003. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763-76
4. Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, et al. 2007. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448:1015-21
5. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, et al. 2009. Evidence for cardiomyocyte renewal in humans. Science 324:98-102
6. Bersell K, Arab S, Haring B, Kuhn B. 2009. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138:257-70
7. Bicknell KA, Coxon CH, Brooks G. 2004. Forced expression of the cyclin B1-CDC2 complex induces proliferation in adult rat cardiomyocytes. Biochem. J. 382:411-16
8. Bizy A, Guerrero-Serna G, Hu B, Ponce-Balbuena D, Willis BC, et al. 2013. Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes. Stem Cell Res. 11:1335-47
9. Blin G, Nury D, Stefanovic S, Neri T, Guillevic O, et al. 2010. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. J. Clin. Investig. 120:1125-39
10. Bolli R, Chugh AR, D'Amario D, Loughran JH, Stoddard MF, et al. 2011. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378:1847-57
11. Bondue A, Lapouge G, PaulissenC, SemeraroC, Iacovino M, et al. 2008. Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell 3:69-84
12. Bondue A, Tannler S, Chiapparo G, Chabab S, Ramialison M, et al. 2011. Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation. J. Cell Biol. 192:751-65
13. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, et al. 2005. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947-56
14. Buckingham M, Meilhac S, Zaffran S. 2005. Building the mammalian heart from two sources of myocardial cells. Nat. Rev. Genet. 6:826-35
15. Burridge PW, Anderson D, Priddle H, Barbadillo Munoz MD, Chamberlain S, et al. 2007. Improved human embryonic stem cell embryoid body homogeneity and cardiomyocyte differentiation from a novel V-96 plate aggregation system highlights interline variability. Stem Cells 25:929-38
16. Burridge PW, KellerG,Gold JD,WuJC. 2012. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell 10:16-28
17. Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, et al. 2014. Chemically defined generation of human cardiomyocytes. Nat. Methods 11:855-60
18. Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, et al. 2011. A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLOS ONE 6:e18293
19. Cao N, Liang H, Huang J, Wang J, Chen Y, et al. 2013. Highly efficient induction and long-term maintenance ofmultipotent cardiovascular progenitors from human pluripotent stem cells under defined conditions. Cell Res. 23:1119-32
20. Chamberlain AA, LinM, Lister RL, Maslov AA, Wang Y, et al. 2014. DNA methylation is developmentally regulated for genes essential for cardiogenesis. J. Am. Heart Assoc. 3:e000976
21. Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, et al. 2007. Nanog safeguards pluripotency and mediates germline development. Nature 450:1230-34
22. Chan SS, Shi X, Toyama A, Arpke RW, Dandapat A, et al. 2013. Mesp1 patternsmesoderm into cardiac, hematopoietic, or skeletal myogenic progenitors in a context-dependent manner. Cell Stem Cell 12:587-601
23. Chen J, Huang ZP, Seok HY, Ding J, Kataoka M, et al. 2013. mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. Circ. Res. 112:1557-66
24. Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, et al. 2008. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. PNAS 105:2111-16
25. Chen L, Wang Y, Pan Y, Zhang L, Shen C, et al. 2013. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem. Biophys. Res. Commun. 431:566-71
26. Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, et al. 2003. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. PNAS 100:10794-99
27. Chong JJ, Yang X, Don CW, Minami E, Liu YW, et al. 2014. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510:273-77
28. Chuva de Sousa Lopes SM, Hassink RJ, Feijen A, van Rooijen MA, Doevendans PA, et al. 2006. Patterning the heart, a template for human cardiomyocyte development. Dev. Dyn. 235:1994-2002
29. Dalton S. 2013. Signaling networks in human pluripotent stem cells. Curr. Opin. Cell Biol. 25:241-46
30. David R, Brenner C, Stieber J, Schwarz F, Brunner S, et al. 2008. MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat. Cell Biol. 10:338-45
31. Davidson KC, Adams AM, Goodson JM,McDonald CE, Potter JC, et al. 2012. Wnt/β-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4. PNAS 109:4485-90
32. Davis RL, Weintraub H, Lassar AB. 1987. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987-1000
33. Devalla HD, Schwach V, Ford JW, Milnes JT, El-Haou S, et al. 2015. Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology. EMBO Mol. Med. 7:394-410
34. Devine WP, Wythe JD, George M, Koshiba-Takeuchi K, Bruneau BG. 2014. Early patterning and specification of cardiac progenitors in gastrulating mesoderm. eLife 3:e03848
35. DeyD,Han L, BauerM, Sanada F,Oikonomopoulos A, et al. 2013. Dissecting the molecular relationship among various cardiogenic progenitor cells. Circ. Res. 112:1253-62
36. Ding Q, Lee YK, Schaefer EA, Peters DT, Veres A, et al. 2013. A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell 12:238-51
37. Dodou E, Verzi MP, Anderson JP, Xu SM, Black BL. 2004. Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development 131:3931-42
38. Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, et al. 2011. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat. Cell Biol. 13:215-22
39. Ellison GM, Vicinanza C, Smith AJ, Aquila I, Leone A, et al. 2013. Adult c-kitpos cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell 154:827-42
40. Engel FB, Schebesta M, Duong MT, Lu G, Ren S, et al. 2005. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 19:1175-87
41. Evans MJ, Kaufman MH. 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154-56
42. Filipczyk A, Gkatzis K, Fu J, Hoppe PS, Lickert H, et al. 2013. Biallelic expression of Nanog protein in mouse embryonic stem cells. Cell Stem Cell 13:12-13
43. Foley AC, Mercola M. 2005. Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. Genes Dev. 19:387-96
44. Fu JD, Stone NR, Liu L, Spencer CI, Qian L, et al. 2013. Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Rep. 1:235-47
45. Gonzalez R, Lee JW, Schultz PG. 2011. Stepwise chemically induced cardiomyocyte specification of human embryonic stem cells. Angew. Chem. Int. Ed. 50:11181-85
46. Gottlieb PD, Pierce SA, Sims RJ, Yamagishi H,Weihe EK, et al. 2002. Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis. Nat. Genet. 31:25-32
47. Grote P,Wittler L, Hendrix D, Koch F,Wahrisch S, et al. 2013. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev. Cell 24:206-14
48. Hang CT, Yang J, Han P, Cheng HL, Shang C, et al. 2010. Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature 466:62-67
49. Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, et al. 2011. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332:458-61
50. Herrmann F, Gross A, Zhou D, Kestler HA, Kuhl M. 2012. A Boolean model of the cardiac gene regulatory network determining first and second heart field identity. PLOS ONE 7:e46798
51. Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, et al. 2001. Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat. Genet. 28:276-80
52. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, et al. 2010. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375-86
53. InagawaK,MiyamotoK,YamakawaH,Muraoka N, Sadahiro T, et al. 2012. Induction of cardiomyocytelike cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. Circ. Res. 111:1147-56
54. James D, Levine AJ, Besser D, Hemmati-Brivanlou A. 2005. TGFβ/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132:1273-82
55. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, et al. 2012. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ. Res. 110:1465-73
56. Josowitz R, Lu J, Falce C, D'Souza SL, Wu M, et al. 2014. Identification and purification of human induced pluripotent stem cell-derived atrial-like cardiomyocytes based on sarcolipin expression. PLOS ONE 9:e101316
57. Kaiser J. 2004. Gene therapy. Side effects sideline hemophilia trial. Science 304:1423-25
58. Kalmar T, Lim C, Hayward P, Munoz-Descalzo S, Nichols J, et al. 2009. Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. PLOS Biol. 7:e1000149
59. Karantalis V, DiFede DL, Gerstenblith G, Pham S, Symes J, et al. 2014. Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial. Circ. Res. 114:1302-10
60. Karikkineth BC, ZimmermannWH. 2013. Myocardial tissue engineering and heartmuscle repair. Curr. Pharm. Biotechnol. 14:4-11
61. Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, et al. 2011. Stage-specific optimization of Activin/Nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8:228-40
62. Katz TC, Singh MK,Degenhardt K, Rivera-Feliciano J, Johnson RL, et al. 2012. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev. Cell 22:639-50
63. Kehat I, Kenyagin-Karsenti D, SnirM, Segev H, AmitM, et al. 2001. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J. Clin. Investig. 108:407-14
64. Kempf H, Olmer R, Kropp C, Ruckert M, Jara-Avaca M, et al. 2014. Controlling expansion and cardiomyogenic differentiation of human pluripotent stem cells in scalable suspension culture. Stem Cell Rep. 3:1132-46
65. Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, et al. 2013. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 152:570-83
66. Knezevic I, Patel A, Sundaresan NR, GuptaMP, Solaro RJ, et al. 2012. A novel cardiomyocyte-enriched microRNA, miR-378, targets insulin-like growth factor 1 receptor: implications in postnatal cardiac remodeling and cell survival. J. Biol. Chem. 287:12913-26
67. Kuhn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, et al. 2007. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat. Med. 13:962-69
68. Kwon C, Arnold J, Hsiao EC, Taketo MM, Conklin BR, Srivastava D. 2007. Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. PNAS 104:10894-99
69. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, et al. 2007. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat. Biotechnol. 25:1015-24
70. Lescroart F, Chabab S, Lin X, Rulands S, Paulissen C, et al. 2014. Early lineage restriction in temporally distinct populations of Mesp1 progenitors during mammalian heart development. Nat. Cell Biol. 16:829-40
71. Li J, Gao E, Vite A, Yi R, Gomez L, et al. 2015. α-Catenins control cardiomyocyte proliferation by regulating Yap activity. Circ. Res. 116:70-79
72. Lian X, Hsiao C, Wilson G, ZhuK,Hazeltine LB, et al. 2012. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. PNAS 109:E1848-57
73. Lickert H, Takeuchi JK, Von Both I,Walls JR, McAuliffe F, et al. 2004. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development. Nature 432:107-12
74. Lieu DK, Fu JD, Chiamvimonvat N, Tung KC, McNerney GP, et al. 2013. Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Arrhythm. Electrophysiol. 6:191-201
75. Lin Z, Zhou P, von Gise A, Gu F, Ma Q, et al. 2015. Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circ. Res. 116:35-45
76. Lindsley RC, Gill JG, Murphy TL, Langer EM, Cai M, et al. 2008. Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ESCs. Cell Stem Cell 3:55-68
77. Liu N, Bezprozvannaya S, Williams AH, Qi X, Richardson JA, et al. 2008. MicroRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 22:3242-54
78. Lundy SD, Zhu WZ, Regnier M, Laflamme MA. 2013. Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev. 22:1991-2002
79. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, et al. 2012. Intracoronary cardiospherederived cells for heart regeneration aftermyocardial infarction(CADUCEUS):a prospective, randomised phase 1 trial. Lancet 379:895-904
80. Matkovich SJ, Edwards JR, Grossenheider TC, de Guzman Strong C, Dorn GW II. 2014. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. PNAS 111:12264-69
81. McDevitt TC, Laflamme MA, Murry CE. 2005. Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway. J. Mol. Cell. Cardiol. 39:865-73
82. Menasche P, Vanneaux V, Fabreguettes JR, Bel A, Tosca L, et al. 2015. Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience. Eur. Heart J. 36:743-50
83. Mendjan S, Mascetti VL, Ortmann D, Ortiz M, Karjosukarso DW, et al. 2014. NANOG and CDX2 pattern distinct subtypes of human mesoderm during exit from pluripotency. Cell Stem Cell 15:310-25
84. Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, et al. 2007. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 21:1790-802
85. Moretti A, Caron L, Nakano A, Lam JT, Bernshausen A, et al. 2006. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127:1151-65
86. Mysliwiec MR, Carlson CD, Tietjen J, Hung H, Ansari AZ, Lee Y. 2012. Jarid2 ( Jumonji, AT rich interactive domain 2) regulates NOTCH1 expression via histone modification in the developing heart. J. Biol. Chem. 287:1235-41
87. Navarro P, Festuccia N, ColbyD,Gagliardi A, Mullin NP, et al. 2012. OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells. EMBO J. 31:4547-62
88. Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, et al. 2009. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature 460:287-91
89. Nowbar AN, Mielewczik M, Karavassilis M, Dehbi HM, Shun-Shin MJ, et al. 2014. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ 348:g2688
90. Ong SG, LeeWH, HuangM, Dey D, Kodo K, et al. 2014. Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer. Circulation 130:S60-69
91. Oyama T, Nagai T, Wada H, Naito AT, Matsuura K, et al. 2007. Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo. J. Cell Biol. 176:329-41
92. Paige SL, Osugi T, AfanasievOK, Pabon L, Reinecke H, Murry CE. 2010. Endogenous Wnt/β-catenin signaling is required for cardiac differentiation in human embryonic stem cells. PLOS ONE 5:e11134
93. Park EJ, Ogden LA, Talbot A, Evans S, Cai CL, et al. 2006. Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. Development 133:2419-33
94. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, et al. 2011. Transient regenerative potential of the neonatal mouse heart. Science 331:1078-80
95. Porrello ER, Mahmoud AI, Simpson E, Johnson BA, Grinsfelder D, et al. 2013. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. PNAS 110:187-92
96. Poss KD,Wilson LG, Keating MT. 2002. Heart regeneration in zebrafish. Science 298:2188-90
97. Prall OW, Menon MK, Solloway MJ, Watanabe Y, Zaffran S, et al. 2007. An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell 128:947-59
98. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, et al. 2012. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485:593-98
99. Qian L, Wythe JD, Liu J, Cartry J, Vogler G, et al. 2011. Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species. J. Cell Biol. 193:1181-96
100. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. 2013. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8:2281-308
101. Rana P, Anson B, Engle S, Will Y. 2012. Characterization of human induced pluripotent stem cell derived cardiomyocytes: bioenergetics and utilization in safety screening. Toxicol. Sci. 130:117-31
102. Rao PK, Toyama Y, Chiang HR, Gupta S, Bauer M, et al. 2009. Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure. Circ. Res. 105:585-94
103. Robertson EJ, Norris DP, Brennan J, Bikoff EK. 2003. Control of early anterior-posterior patterning in the mouse embryo by TGF-βsignalling. Philos. Trans. R. Soc. B 358:1351-57
104. Sandstedt J, Jonsson M, Kajic K, Sandstedt M, Lindahl A, et al. 2012. Left atrium of the human adult heart contains a population of side population cells. Basic Res. Cardiol. 107:255
105. Shiba Y, Fernandes S, Zhu WZ, Filice D, Muskheli V, et al. 2012. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489:322-25
106. Shimoji K, Yuasa S, Onizuka T, Hattori F, Tanaka T, et al. 2010. G-CSF promotes the proliferation of developing cardiomyocytes in vivo and in derivation from ESCs and iPSCs. Cell Stem Cell 6:227-37
107. Shirai M, Osugi T, Koga H, Kaji Y, Takimoto E, et al. 2002. The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis. J. Clin. Investig. 110:177-84
108. Sluijter JP, van Mil A, van Vliet P, Metz CH, Liu J, et al. 2010. MicroRNA-1 and -499 regulate differentiation and proliferation in human-derived cardiomyocyte progenitor cells. Arterioscler. Thromb. Vasc. Biol. 30:859-68
109. Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, et al. 2007. Regenerative potential of cardiospherederived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115:896-908
110. SollowayMJ, Harvey RP. 2003. Molecular pathways in myocardial development: a stem cell perspective. Cardiovasc. Res. 58:264-77
111. Song K, Nam YJ, Luo X, Qi X, TanW, et al. 2012. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485:599-604
112. Spater D, Abramczuk MK, Buac K, Zangi L, Stachel MW, et al. 2013. A HCN4 +cardiomyogenic progenitor derived from the first heart field and human pluripotent stem cells. Nat. Cell Biol. 15:1098-106
113. Takahashi K, Yamanaka S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663-76
114. Takaya T, Kawamura T, Morimoto T, Ono K, Kita T, et al. 2008. Identification of p300-targeted acetylated residues in GATA4 during hypertrophic responses in cardiac myocytes. J. Biol. Chem. 283:9828-35
115. Takeuchi JK, Bruneau BG. 2009. Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459:708-11
116. Takeuchi JK, Lou X, Alexander JM, SugizakiH, Delgado-Olguin P, et al. 2011. Chromatin remodelling complex dosage modulates transcription factor function in heart development. Nat. Commun. 2:187
117. Tam PP, Loebel DA. 2007. Gene function in mouse embryogenesis: get set for gastrulation. Nat. Rev. Genet. 8:368-81
118. Thomson JA, Itskovitz-Eldor J, Shapiro SS, WaknitzMA, Swiergiel JJ, et al. 1998. Embryonic stem cell lines derived from human blastocysts. Science 282:1145-47
119. Thum T, Gross C, Fiedler J, Fischer T, Kissler S, et al. 2008. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456:980-84
120. Tran TH,Wang X, Browne C, Zhang Y, Schinke M, et al. 2009. Wnt3a-induced mesoderm formation and cardiomyogenesis in human embryonic stem cells. Stem Cells 27:1869-78
121. Tseng AS, Engel FB, Keating MT. 2006. The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem. Biol. 13:957-63
122. Uchida S, De Gaspari P, Kostin S, Jenniches K, Kilic A, et al. 2013. Sca1-derived cells are a source of myocardial renewal in the murine adult heart. Stem Cell Rep. 1:397-410
123. Uosaki H, Magadum A, Seo K, Fukushima H, Takeuchi A, et al. 2013. Identification of chemicals inducing cardiomyocyte proliferation in developmental stage-specific manner with pluripotent stem cells. Circ. Cardiovasc. Genet. 6:624-33
124. van Berlo JH,Kanisicak O, MailletM, Vagnozzi RJ,Karch J, et al. 2014. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509:337-41
125. van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, et al. 2009. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev. Cell 17:662-73
126. van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, et al. 2008. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. PNAS 105:13027-32
127. van Vliet P, Roccio M, Smits AM, van Oorschot AA, Metz CH, et al. 2008. Progenitor cells isolated from the human heart: a potential cell source for regenerative therapy. Neth. Heart J. 16:163-69
128. Voss AK, Vanyai HK, Collin C, Dixon MP, McLennan TJ, et al. 2012. MOZ regulates the Tbx1 locus, and Moz mutation partially phenocopies DiGeorge syndrome. Dev. Cell 23:652-63
129. Wang Z, Oron E, Nelson B, Razis S, Ivanova N. 2012. Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells. Cell Stem Cell 10:440-54
130. Wang Z, Zhai W, Richardson JA, Olson EN, Meneses JJ, et al. 2004. Polybromo protein BAF180 functions in mammalian cardiac chamber maturation. Genes Dev. 18:3106-16
131. Watanabe Y, Zaffran S, Kuroiwa A, Higuchi H, Ogura T, et al. 2012. Fibroblast growth factor 10 gene regulation in the second heart field by Tbx1, Nkx2-5, and Islet1 reveals a genetic switch for downregulation in the myocardium. PNAS 109:18273-80
132. Wessels A, Sedmera D. 2003. Developmental anatomy of the heart: a tale of mice and man. Physiol. Genomics 15:165-76
133. Willems E, Spiering S, Davidovics H, Lanier M, Xia Z, et al. 2011. Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm. Circ. Res. 109:360-64
134. Wilson KD, Hu S, Venkatasubrahmanyam S, Fu JD, Sun N, et al. 2010. Dynamic microRNA expression programs during cardiac differentiation of human embryonic stem cells: role for miR-499. Circ. Cardiovasc. Genet. 3:426-35
135. Wystub K, Besser J, Bachmann A, Boettger T, Braun T. 2013. miR-1/133a clusters cooperatively specify the cardiomyogenic lineage by adjustment of myocardin levels during embryonic heart development. PLOS Genet. 9:e1003793
136. Yang B, LinH, Xiao J, Lu Y, Luo X, et al. 2007. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat. Med. 13:486-91
137. Yang L, SoonpaaMH, Adler ED, Roepke TK,Kattman SJ, et al. 2008. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 453:524-28
138. Yang L, Xiao X. 2013. Creation of a cardiotropic adeno-associated virus: the story of viral directed evolution. Virol. J. 10:50
139. Yang X, Pabon L, Murry CE. 2014. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114:511-23
140. Yang X, Rodriguez M, Pabon L, Fischer KA, Reinecke H, et al. 2014. Tri-iodo-L-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. J. Mol. Cell. Cardiol. 72:296-304
141. Yao TP, Oh SP, Fuchs M, Zhou ND, Ch'ng LE, et al. 1998. Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93:361-72
142. Ye L, Chang YH, Xiong Q, Zhang P, Zhang L, et al. 2014. Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Cell Stem Cell 15:750-61
143. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, et al. 2007. Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917-20
144. Zeineddine D, Papadimou E,ChebliK,Gineste M, Liu J, et al. 2006. Oct-3/4 dose dependently regulates specification of embryonic stem cells toward a cardiac lineage and early heart development. Dev. Cell 11:535-46
145. Zhang Q, Jiang J, Han P, Yuan Q, Zhang J, et al. 2011. Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals. Cell Res. 21:579-87
146. Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, et al. 2007. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303-17
147. Zhou B, Ma Q, Rajagopal S, Wu SM, Domian I, et al. 2008. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454:109-13
148. Zhu WZ, Xie Y, Moyes KW, Gold JD, Askari B, Laflamme MA. 2010. Neuregulin/ErbB signaling regulates cardiac subtype specification in differentiating human embryonic stem cells. Circ. Res. 107:776-86