Engineering adolescence: Maturation of human pluripotent stem cell-derived cardiomyocytes

Circulation Research

Volumn 114, Issue 3, 2014, Pages 511-523

  Yang, Xiulan ^a   Pabon, Lil ^a   Murry, Charles E ^a,b  

^a UNIVERSITY OF WASHINGTON   (United States)

^b University of Washington   (United States)

Author keywords

disease modeling; human pluripotent stem cell derived cardiomyocytes; maturation; pharmacologic screening

Indexed keywords

DISEASE MODELING; HUMAN PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES; MATURATION; PHARMACOLOGIC SCREENING;

ANIMALS; CELL DIFFERENTIATION; CELL ENGINEERING; CELLS, CULTURED; GENETIC ENGINEERING; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MODELS, ANIMAL; MYOCYTES, CARDIAC; PLURIPOTENT STEM CELLS; TIME FACTORS;

EID: 84894160639     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.114.300558     Document Type: Review

References (125)

1. Burridge PW, Keller G, Gold JD, Wu JC. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell. 2012;10:16-28.
2. Zhu WZ, Santana LF, Laflamme MA. Local control of excitation-contraction coupling in human embryonic stem cell-derived cardiomyocytes. PLoS One. 2009;4:e5407.
3. Shiba Y, Fernandes S, Zhu WZ, et al. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature. 2012;489:322-325.
4. Caspi O, Huber I, Kehat I, Habib M, Arbel G, Gepstein A, Yankelson L, Aronson D, Beyar R, Gepstein L. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol. 2007;50:1884-1893.
5. Müller M, Fleischmann BK, Selbert S, Ji GJ, Endl E, Middeler G, Müller OJ, Schlenke P, Frese S, Wobus AM, Hescheler J, Katus HA, Franz WM. Selection of ventricular-like cardiomyocytes from ES cells in vitro. FASEB J. 2000;14:2540-2548.
6. Fu JD, Jiang P, Rushing S, Liu J, Chiamvimonvat N, Li RA. Na+/Ca2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes. Stem Cells Dev. 2010;19:773-782.
7. Li F, Wang X, Capasso JM, Gerdes AM. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol. 1996;28:1737-1746.
8. Laflamme MA, Murry CE. Heart regeneration. Nature. 2011;473:326-335.
9. Maillet M, van Berlo JH, Molkentin JD. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol. 2013;14:38-48.
10. Zhu WZ, Xie Y, Moyes KW, Gold JD, Askari B, Laflamme MA. Neuregulin/ErbB signaling regulates cardiac subtype specification in differentiating human embryonic stem cells. Circ Res. 2010;107:776-786.
11. Drouin E, Charpentier F, Gauthier C, Laurent K, Le Marec H. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: evidence for presence of M cells. J Am Coll Cardiol. 1995;26:185-192.
12. Spach MS, Heidlage JF, Barr RC, Dolber PC. Cell size and communication: role in structural and electrical development and remodeling of the heart. Heart Rhythm. 2004;1:500-515.
13. Kadota S, Minami I, Morone N, Heuser JE, Agladze K, Nakatsuji N. Development of a reentrant arrhythmia model in human pluripotent stem cell-derived cardiac cell sheets. Eur Heart J. 2013;34:1147-1156.
14. Pillekamp F, Haustein M, Khalil M, Emmelheinz M, Nazzal R, Adelmann R, Nguemo F, Rubenchyk O, Pfannkuche K, Matzkies M, Reppel M, Bloch W, Brockmeier K, Hescheler J. Contractile properties of early human embryonic stem cell-derived cardiomyocytes: beta-adrenergic stimulation induces positive chronotropy and lusitropy but not inotropy. Stem Cells Dev. 2012;21:2111-2121.
15. Gerdes AM, Kellerman SE, Moore JA, Muffly KE, Clark LC, Reaves PY, Malec KB, McKeown PP, Schocken DD. Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation. 1992;86:426-430.
16. Louch WE, Sheehan KA, Wolska BM. Methods in cardiomyocyte isolation, culture, and gene transfer. J Mol Cell Cardiol. 2011;51:288-298.
17. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, van der Heyden M, Opthof T, Pera M, de la Riviere AB, Passier R, Tertoolen L. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003;107:2733-2740.
18. Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP, Thomson JA, Kamp TJ. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res. 2009;104:e30-e41.
19. Itzhaki I, Rapoport S, Huber I, Mizrahi I, Zwi-Dantsis L, Arbel G, Schiller J, Gepstein L. Calcium handling in human induced pluripotent stem cell derived cardiomyocytes. PLoS One. 2011;6:e18037.
20. Germanguz I, Sedan O, Zeevi-Levin N, Shtrichman R, Barak E, Ziskind A, Eliyahu S, Meiry G, Amit M, Itskovitz-Eldor J, Binah O. Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells. J Cell Mol Med. 2011;15:38-51.
21. Gherghiceanu M, Barad L, Novak A, Reiter I, Itskovitz-Eldor J, Binah O, Popescu LM. Cardiomyocytes derived from human embryonic and induced pluripotent stem cells: comparative ultrastructure. J Cell Mol Med. 2011;15:2539-2551.
22. Snir M, Kehat I, Gepstein A, Coleman R, Itskovitz-Eldor J, Livne E, Gepstein L. Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. Am J Physiol Heart Circ Physiol. 2003;285:H2355-H2363.
23. Bird SD, Doevendans PA, van Rooijen MA, Brutel de la Riviere A, Hassink RJ, Passier R, Mummery CL. The human adult cardiomyocyte phenotype. Cardiovasc Res. 2003;58:423-434.
24. Lundy SD, Zhu WZ, Regnier M, Laflamme MA. Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev. 2013;22:1991-2002.
25. Lahmers S, Wu Y, Call DR, Labeit S, Granzier H. Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res. 2004;94:505-513.
26. Opitz CA, Leake MC, Makarenko I, Benes V, Linke WA. Developmentally regulated switching of titin size alters myofibrillar stiffness in the perinatal heart. Circ Res. 2004;94:967-975.
27. Warren CM, Krzesinski PR, Campbell KS, Moss RL, Greaser ML. Titin isoform changes in rat myocardium during development. Mech Dev. 2004;121:1301-1312.
28. Krüger M, Linke WA. Titin-based mechanical signalling in normal and failing myocardium. J Mol Cell Cardiol. 2009;46:490-498.
29. Saggin L, Gorza L, Ausoni S, Schiaffino S. Troponin I switching in the developing heart. J Biol Chem. 1989;264:16299-16302.
30. Sabry MA, Dhoot GK. Identification and pattern of expression of a developmental isoform of troponin I in chicken and rat cardiac muscle. J Muscle Res Cell Motil. 1989;10:85-91.
31. Hunkeler NM, Kullman J, Murphy AM. Troponin I isoform expression in human heart. Circ Res. 1991;69:1409-1414.
32. Bhavsar PK, Dhoot GK, Cumming DV, Butler-Browne GS, Yacoub MH, Barton PJ. Developmental expression of troponin I isoforms in fetal human heart. FEBS Lett. 1991;292:5-8.
33. Metzger JM, Michele DE, Rust EM, Borton AR, Westfall MV. Sarcomere thin filament regulatory isoforms. Evidence of a dominant effect of slow skeletal troponin I on cardiac contraction. J Biol Chem. 2003;278:13118-13123.
34. Reiser PJ, Westfall MV, Schiaffino S, Solaro RJ. Tension production and thin-filament protein isoforms in developing rat myocardium. Am J Physiol. 1994;267:H1589-H1596.
35. Siedner S, Krüger M, Schroeter M, Metzler D, Roell W, Fleischmann BK, Hescheler J, Pfitzer G, Stehle R. Developmental changes in contractility and sarcomeric proteins from the early embryonic to the adult stage in the mouse heart. J Physiol. 2003;548:493-505.
36. Mahdavi V, Lompre AM, Chambers AP, Nadal-Ginard B. Cardiac myosin heavy chain isozymic transitions during development and under pathological conditions are regulated at the level of mRNA availability. Eur Heart J. 1984;5 (suppl F):181-191.
37. Xu XQ, Soo SY, Sun W, Zweigerdt R. Global expression profile of highly enriched cardiomyocytes derived from human embryonic stem cells. Stem Cells. 2009;27:2163-2174.
38. Ziman AP, Gómez-Viquez NL, Bloch RJ, Lederer WJ. Excitation-contraction coupling changes during postnatal cardiac development. J Mol Cell Cardiol. 2010;48:379-386.
39. Lieu DK, Liu J, Siu CW, McNerney GP, Tse HF, Abu-Khalil A, Huser T, Li RA. Absence of transverse tubules contributes to non-uniform Ca(2+) wavefronts in mouse and human embryonic stem cell-derived cardiomyocytes. Stem Cells Dev. 2009;18:1493-1500.
40. Satin J, Itzhaki I, Rapoport S, Schroder EA, Izu L, Arbel G, Beyar R, Balke CW, Schiller J, Gepstein L. Calcium handling in human embryonic stem cell-derived cardiomyocytes. Stem Cells. 2008;26:1961-1972.
41. Shepard TH, Muffley LA, Smith LT. Ultrastructural study of mitochondria and their cristae in embryonic rats and primate (N. nemistrina). Anat Rec. 1998;252:383-392.
42. Crompton M, Ellinger H, Costi A. Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J. 1988;255:357-360.
43. Hom JR, Quintanilla RA, Hoffman DL, de Mesy Bentley KL, Molkentin JD, Sheu SS, Porter GA Jr. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev Cell. 2011;21:469-478.
44. Schaper J, Meiser E, Stämmler G. Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice, and from human hearts. Circ Res. 1985;56:377-391.
45. Lopaschuk GD, Jaswal JS. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J Cardiovasc Pharmacol. 2010;56:130-140.
46. Kim C, Wong J, Wen J, Wang S, Wang C, Spiering S, Kan NG, Forcales S, Puri PL, Leone TC, Marine JE, Calkins H, Kelly DP, Judge DP, Chen HS. Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature. 2013;494:105-110.
47. Clubb FJ Jr, Bishop SP. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy. Lab Invest. 1984;50:571-577.
48. Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ. Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Physiol. 1996;271:H2183-H2189.
49. Jonker SS, Zhang L, Louey S, Giraud GD, Thornburg KL, Faber JJ. Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart. J Appl Physiol (1985). 2007;102:1130-1142.
50. Brodsky VYa, Chernyaev AL, Vasilyeva IA. Variability of the cardiomyocyte ploidy in normal human hearts. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;61:289-294.
51. Olivetti G, Cigola E, Maestri R, Corradi D, Lagrasta C, Gambert SR, Anversa P. Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. J Mol Cell Cardiol. 1996;28:1463-1477.
52. Guo W, Kamiya K, Toyama J. Modulated expression of transient outward current in cultured neonatal rat ventricular myocytes: comparison with development in situ. Cardiovasc Res. 1996;32:524-533.
53. Obreztchikova MN, Sosunov EA, Plotnikov A, Anyukhovsky EP, Gainullin RZ, Danilo P, Yeom ZH, Robinson RB, Rosen MR. Developmental changes in IKr and IKs contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia. Cardiovasc Res. 2003;59:339-350.
54. Sartiani L, Bettiol E, Stillitano F, Mugelli A, Cerbai E, Jaconi ME. Developmental changes in cardiomyocytes differentiated from human embryonic stem cells: a molecular and electrophysiological approach. Stem Cells. 2007;25:1136-1144.
55. Liu J, Fu JD, Siu CW, Li RA. Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation. Stem Cells. 2007;25:3038-3044.
56. Dolnikov K, Shilkrut M, Zeevi-Levin N, Gerecht-Nir S, Amit M, Danon A, Itskovitz-Eldor J, Binah O. Functional properties of human embryonic stem cell-derived cardiomyocytes: intracellular Ca2+ handling and the role of sarcoplasmic reticulum in the contraction. Stem Cells. 2006;24:236-245.
57. Liu J, Lieu DK, Siu CW, Fu JD, Tse HF, Li RA. Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression. Am J Physiol Cell Physiol. 2009;297:C152-C159.
58. Escobar AL, Ribeiro-Costa R, Villalba-Galea C, Zoghbi ME, Pérez CG, Mejía-Alvarez R. Developmental changes of intracellular Ca2+ transients in beating rat hearts. Am J Physiol Heart Circ Physiol. 2004;286:H971-H978.
59. Tanaka H, Shigenobu K. Effect of ryanodine on neonatal and adult rat heart: developmental increase in sarcoplasmic reticulum function. J Mol Cell Cardiol. 1989;21:1305-1313.
60. Haddock PS, Coetzee WA, Cho E, Porter L, Katoh H, Bers DM, Jafri MS, Artman M. Subcellular [Ca2+]i gradients during excitation-contraction coupling in newborn rabbit ventricular myocytes. Circ Res. 1999;85:415-427.
61. Huang J, Hove-Madsen L, Tibbits GF. Ontogeny of Ca2+-induced Ca2+ release in rabbit ventricular myocytes. Am J Physiol Cell Physiol. 2008;294:C516-C525.
62. Janowski E, Cleemann L, Sasse P, Morad M. Diversity of Ca2+ signaling in developing cardiac cells. Ann N Y Acad Sci. 2006;1080:154-164.
63. Liu W, Yasui K, Opthof T, Ishiki R, Lee JK, Kamiya K, Yokota M, Kodama I. Developmental changes of Ca(2+) handling in mouse ventricular cells from early embryo to adulthood. Life Sci. 2002;71:1279-1292.
64. Hasenfuss G, Mulieri LA, Blanchard EM, Holubarsch C, Leavitt BJ, Ittleman F, Alpert NR. Energetics of isometric force development in control and volume-overload human myocardium. Comparison with animal species. Circ Res. 1991;68:836-846.
65. Tulloch NL, Muskheli V, Razumova MV, Korte FS, Regnier M, Hauch KD, Pabon L, Reinecke H, Murry CE. Growth of engineered human myocardium with mechanical loading and vascular coculture. Circ Res. 2011;109:47-59.
66. Zimmermann WH, Schneiderbanger K, Schubert P, Didié M, Münzel F, Heubach JF, Kostin S, Neuhuber WL, Eschenhagen T. Tissue engineering of a differentiated cardiac muscle construct. Circ Res. 2002;90:223-230.
67. Korte FS, Herron TJ, Rovetto MJ, McDonald KS. Power output is linearly related to MyHC content in rat skinned myocytes and isolated working hearts. Am J Physiol Heart Circ Physiol. 2005;289:H801-H812.
68. Kita-Matsuo H, Barcova M, Prigozhina N, et al. Lentiviral vectors and protocols for creation of stable hESC lines for fluorescent tracking and drug resistance selection of cardiomyocytes. PLoS One. 2009;4:e5046.
69. Liu J, Sun N, Bruce MA, Wu JC, Butte MJ. Atomic force mechanobiology of pluripotent stem cell-derived cardiomyocytes. PLoS One. 2012;7:e37559.
70. Angst BD, Khan LU, Severs NJ, Whitely K, Rothery S, Thompson RP, Magee AI, Gourdie RG. Dissociated spatial patterning of gap junctions and cell adhesion junctions during postnatal differentiation of ventricular myocardium. Circ Res. 1997;80:88-94.
71. Chen HS, Kim C, Mercola M. Electrophysiological challenges of cell-based myocardial repair. Circulation. 2009;120:2496-2508.
72. Zwi L, Caspi O, Arbel G, Huber I, Gepstein A, Park IH, Gepstein L. Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation. 2009;120:1513-1523.
73. Gupta MK, Illich DJ, Gaarz A, Matzkies M, Nguemo F, Pfannkuche K, Liang H, Classen S, Reppel M, Schultze JL, Hescheler J, Sari? T. Global transcriptional profiles of beating clusters derived from human induced pluripotent stem cells and embryonic stem cells are highly similar. BMC Dev Biol. 2010;10:98.
74. Yokoo N, Baba S, Kaichi S, Niwa A, Mima T, Doi H, Yamanaka S, Nakahata T, Heike T. The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. Biochem Biophys Res Commun. 2009;387:482-488.
75. Peters NS, Severs NJ, Rothery SM, Lincoln C, Yacoub MH, Green CR. Spatiotemporal relation between gap junctions and fascia adherens junctions during postnatal development of human ventricular myocardium. Circulation. 1994;90:713-725.
76. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006;7:589-600.
77. Földes G, Mioulane M, Wright JS, Liu AQ, Novak P, Merkely B, Gorelik J, Schneider MD, Ali NN, Harding SE. Modulation of human embryonic stem cell-derived cardiomyocyte growth: a testbed for studying human cardiac hypertrophy? J Mol Cell Cardiol. 2011;50:367-376.
78. Hazeltine LB, Simmons CS, Salick MR, Lian X, Badur MG, Han W, Delgado SM, Wakatsuki T, Crone WC, Pruitt BL, Palecek SP. Effects of substrate mechanics on contractility of cardiomyocytes generated from human pluripotent stem cells. Int J Cell Biol. 2012;2012:508294.
79. Kamakura T, Makiyama T, Sasaki K, Yoshida Y, Wuriyanghai Y, Chen J, Hattori T, Ohno S, Kita T, Horie M, Yamanaka S, Kimura T. Ultrastructural maturation of human-induced pluripotent stem cell-derived cardiomyocytes in a long-term culture. Circ J. 2013;77:1307-1314.
80. Jacot JG, Martin JC, Hunt DL. Mechanobiology of cardiomyocyte development. J Biomech. 2010;43:93-98.
81. Prakash YS, Cody MJ, Housmans PR, Hannon JD, Sieck GC. Comparison of cross-bridge cycling kinetics in neonatal vs. adult rat ventricular muscle. J Muscle Res Cell Motil. 1999;20:717-723.
82. Jacot JG, McCulloch AD, Omens JH. Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophys J. 2008;95:3479-3487.
83. Jacot JG, Kita-Matsuo H, Wei KA, Chen HS, Omens JH, Mercola M, McCulloch AD. Cardiac myocyte force development during differentiation and maturation. Ann N Y Acad Sci. 2010;1188:121-127.
84. Rodriguez AG, Han SJ, Regnier M, Sniadecki NJ. Substrate stiffness increases twitch power of neonatal cardiomyocytes in correlation with changes in myofibril structure and intracellular calcium. Biophys J. 2011;101:2455-2464.
85. Bray MA, Sheehy SP, Parker KK. Sarcomere alignment is regulated by myocyte shape. Cell Motil Cytoskeleton. 2008;65:641-651.
86. Wang PY, Yu J, Lin JH, Tsai WB. Modulation of alignment, elongation and contraction of cardiomyocytes through a combination of nanotopography and rigidity of substrates. Acta Biomater. 2011;7:3285-3293.
87. Heidi Au HT, Cui B, Chu ZE, Veres T, Radisic M. Cell culture chips for simultaneous application of topographical and electrical cues enhance phenotype of cardiomyocytes. Lab Chip. 2009;9:564-575.
88. McDevitt TC, Angello JC, Whitney ML, Reinecke H, Hauschka SD, Murry CE, Stayton PS. In vitro generation of differentiated cardiac myofibers on micropatterned laminin surfaces. J Biomed Mater Res. 2002;60:472-479.
89. Kim DH, Lipke EA, Kim P, Cheong R, Thompson S, Delannoy M, Suh KY, Tung L, Levchenko A. Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Proc Natl Acad Sci USA. 2010;107:565-570.
90. Radisic M, Park H, Shing H, Consi T, Schoen FJ, Langer R, Freed LE, Vunjak-Novakovic G. Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proc Natl Acad Sci USA. 2004;101:18129-18134.
91. Sathaye A, Bursac N, Sheehy S, Tung L. Electrical pacing counteracts intrinsic shortening of action potential duration of neonatal rat ventricular cells in culture. J Mol Cell Cardiol. 2006;41:633-641.
92. Xia Y, Buja LM, Scarpulla RC, McMillin JB. Electrical stimulation of neonatal cardiomyocytes results in the sequential activation of nuclear genes governing mitochondrial proliferation and differentiation. Proc Natl Acad Sci USA. 1997;94:11399-11404.
93. Martherus RS, Vanherle SJ, Timmer ED, Zeijlemaker VA, Broers JL, Smeets HJ, Geraedts JP, Ayoubi TA. Electrical signals affect the cardiomyocyte transcriptome independently of contraction. Physiol Genomics. 2010;42A:283-289.
94. Deng XF, Rokosh DG, Simpson PC. Autonomous and growth factor-induced hypertrophy in cultured neonatal mouse cardiac myocytes. Comparison with rat. Circ Res. 2000;87:781-788.
95. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344:501-509.
96. Krüger M, Sachse C, Zimmermann WH, Eschenhagen T, Klede S, Linke WA. Thyroid hormone regulates developmental titin isoform transitions via the phosphatidylinositol-3-kinase/AKT pathway. Circ Res. 2008;102:439-447.
97. Chattergoon NN, Giraud GD, Louey S, Stork P, Fowden AL, Thornburg KL. Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J. 2012;26:397-408.
98. Lee YK, Ng KM, Chan YC, Lai WH, Au KW, Ho CY, Wong LY, Lau CP, Tse HF, Siu CW. Triiodothyronine promotes cardiac differentiation and maturation of embryonic stem cells via the classical genomic pathway. Mol Endocrinol. 2010;24:1728-1736.
99. Ito H, Hiroe M, Hirata Y, Tsujino M, Adachi S, Shichiri M, Koike A, Nogami A, Marumo F. Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation. 1993;87:1715-1721.
100. Montessuit C, Palma T, Viglino C, Pellieux C, Lerch R. Effects of insulin-like growth factor-I on the maturation of metabolism in neonatal rat cardiomyocytes. Pflugers Arch. 2006;452:380-386.
101. McDevitt TC, Laflamme MA, Murry CE. Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway. J Mol Cell Cardiol. 2005;39:865-873.
102. Fu JD, Rushing SN, Lieu DK, Chan CW, Kong CW, Geng L, Wilson KD, Chiamvimonvat N, Boheler KR, Wu JC, Keller G, Hajjar RJ, Li RA. Distinct roles of microRNA-1 and-499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes. PLoS One. 2011;6:e27417.
103. Callis TE, Pandya K, Seok HY, Tang RH, Tatsuguchi M, Huang ZP, Chen JF, Deng Z, Gunn B, Shumate J, Willis MS, Selzman CH, Wang DZ. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest. 2009;119:2772-2786.
104. van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science. 2007;316:575-579.
105. Liau B, Christoforou N, Leong KW, Bursac N. Pluripotent stem cell-derived cardiac tissue patch with advanced structure and function. Biomaterials. 2011;32:9180-9187.
106. Vaidya D, Tamaddon HS, Lo CW, Taffet SM, Delmar M, Morley GE, Jalife J. Null mutation of connexin43 causes slow propagation of ventricular activation in the late stages of mouse embryonic development. Circ Res. 2001;88:1196-1202.
107. Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res. 2001;88:333-339.
108. Kim C, Majdi M, Xia P, Wei KA, Talantova M, Spiering S, Nelson B, Mercola M, Chen HS. Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation. Stem Cells Dev. 2010;19:783-795.
109. Nunes SS, Miklas JW, Liu J, et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat Methods. 2013;10:781-787.
110. 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 USA. 2013;110:5588-5593.
111. 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.
112. 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.
113. 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.
114. 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.
115. 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.
116. Carvajal-Vergara X, Sevilla A, D'Souza SL, et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature. 2010;465:808-812.
117. Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flügel L, Dorn T, Goedel A, Höhnke C, Hofmann F, Seyfarth M, Sinnecker D, Schömig A, Laugwitz KL. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. 2010;363:1397-1409.
118. Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature. 2011;471:230-234.
119. Huang HP, Chen PH, Hwu WL, Chuang CY, Chien YH, Stone L, Chien CL, Li LT, Chiang SC, Chen HF, Ho HN, Chen CH, Kuo HC. Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification. Hum Mol Genet. 2011;20:4851-4864.
120. Lan F, Lee AS, Liang P, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013;12:101-113.
121. Sun N, Yazawa M, Liu J, et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med. 2012;4:130ra47.
122. Braam SR, Passier R, Mummery CL. Cardiomyocytes from human pluripotent stem cells in regenerative medicine and drug discovery. Trends Pharmacol Sci. 2009;30:536-545.
123. Guo L, Abrams RM, Babiarz JE, Cohen JD, Kameoka S, Sanders MJ, Chiao E, Kolaja KL. Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2011;123:281-289.
124. Jonsson MK, Vos MA, Mirams GR, Duker G, Sartipy P, de Boer TP, van Veen TA. Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG. J Mol Cell Cardiol. 2012;52:998-1008.
125. Reinecke H, Zhang M, Bartosek T, Murry CE. Survival, integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts. Circulation. 1999;100:193-202.