Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: A methods overview

Circulation Research

Volumn 111, Issue 3, 2012, Pages 344-358

  Mummery, Christine L ^a   Zhang, Jianhua ^b   Ng, Elizabeth S ^c   Elliott, David A ^c   Elefanty, Andrew G ^c   Kamp, Timothy J ^b  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^b UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC HEALTH   (United States)

^c MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

BONE MORPHOGENETIC PROTEIN; WNT PROTEIN;

APOPTOSIS; CELL CULTURE; CELL DIFFERENTIATION; CELL LINEAGE; CELL MATURATION; CELL PROLIFERATION; CULTURE MEDIUM; DROSOPHILA; DRUG DEVELOPMENT; EMBRYOID BODY; EMBRYONIC STEM CELL; EXTRACELLULAR MATRIX; GENE REGULATORY NETWORK; HEART MUSCLE CELL; HUMAN; IN VITRO STUDY; MEDICAL RESEARCH; MESODERM; METHODOLOGY; NONHUMAN; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROCESS OPTIMIZATION; PROTEIN EXPRESSION; RELIABILITY; REVIEW; TRANSCRIPTION REGULATION;

CELL CULTURE TECHNIQUES; CELL DIFFERENTIATION; EMBRYONIC STEM CELLS; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MYOCYTES, CARDIAC;

EID: 84864243791     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.110.227512     Document Type: Review

References (129)

1. Park IH, Lerou PH, Zhao R, Huo H, Daley GQ. Generation of humaninduced pluripotent stem cells. Nat Protoc. 2008;3:1180-1186.
2. 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. (Pubitemid 350138099)
3. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145-1147. (Pubitemid 28516247)
4. 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.
5. Carvajal-Vergara X, Sevilla A, DâSouza SL, et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature. 2010;465:808-812.
6. Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, Feldman O, Gepstein A, Arbel G, Hammerman H, Boulos M, Gepstein L. Modelling the long QT syndrome with induced pluripotent stem cells. Nature. 2011;47:225-229.
7. Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, Dorn T, Goedel A, Hohnke C, Hofmann F, Seyfarth M, Sinnecker D, Schomig A, Laugwitz KL. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. 2010;363:1397-1409.
8. Braam SR, Tertoolen L, van de Stolpe A, Meyer T, Passier R, Mummery CL. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Res. 2010;4:107-116.
9. Anson BD, Kolaja KL, Kamp TJ. Opportunities for use of human iPS cells in predictive toxicology. Clin Pharmacol Ther. 2011;89:754-758.
10. van Laake LW, Passier R, Doevendans PA, Mummery CL. Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circ Res. 2008;102:1008-1010. (Pubitemid 351667854)
11. van Laake LW, Passier R, Monshouwer-Kloots J, Verkleij AJ, Lips DJ, Freund C, den Ouden K, Ward-van Oostwaard D, Korving J, Tertoolen LG, van Echteld CJ, Doevendans PA, Mummery CL. Human embryonic stem cell-derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction. Stem Cell Res. 2007;1:9-24. (Pubitemid 350251944)
12. Abu-Issa R, Kirby ML. Heart field: from mesoderm to heart tube. Annu Rev Cell Dev Biol. 2007;23:45-68.
13. Olson EN. Gene regulatory networks in the evolution and development of the heart. Science. 2006;313:1922-1927. (Pubitemid 44497993)
14. Olson EN, Schneider MD. Sizing up the heart: development redux in disease. Genes Dev. 2003;17:1937-1956. (Pubitemid 36999321)
15. Brand T. Heart development: molecular insights into cardiac specification and early morphogenesis. Dev Biol. 2003;258:1-19. (Pubitemid 36637027)
16. Cohen ED, Tian Y, Morrisey EE. Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor selfrenewal. Development. 2008;135:789-798. (Pubitemid 351524132)
17. Park EJ, Watanabe Y, Smyth G, Miyagawa-Tomita S, Meyers E, Klingensmith J, Camenisch T, Buckingham M, Moon AM. An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart. Development. 2008;135: 3599-3610.
18. Ilagan R, Abu-Issa R, Brown D, Yang YP, Jiao K, Schwartz RJ, Klingensmith J, Meyers EN. Fgf8 is required for anterior heart field development. Development. 2006;133:2435-2445. (Pubitemid 44044563)
19. Wu SM. Mesp1 at the heart of mesoderm lineage specification. Cell Stem Cell. 2008;3:1-2.
20. Bondue A, Tannler S, Chiapparo G, Chabab S, Ramialison M, Paulissen C, Beck B, Harvey R, Blanpain C. Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation. J Cell Biol. 2011;192:751-765.
21. Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C, Leiden JM. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 1997;11: 1048-1060. (Pubitemid 27199883)
22. Molkentin JD, Lin Q, Duncan SA, Olson EN. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 1997;11:1061-1072. (Pubitemid 27199884)
23. Watt AJ, Battle MA, Li J, Duncan SA. GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc Natl Acad Sci U S A. 2004;101:12573-12578. (Pubitemid 39122065)
24. Pu WT, Ishiwata T, Juraszek AL, Ma Q, Izumo S. GATA4 is a dosagesensitive regulator of cardiac morphogenesis. Dev Biol. 2004;275: 235-244. (Pubitemid 39298188)
25. Zeisberg EM, Ma Q, Juraszek AL, Moses K, Schwartz RJ, Izumo S, Pu WT. Morphogenesis of the right ventricle requires myocardial expression of Gata4. J Clin Invest. 2005;115:1522-1531. (Pubitemid 40814660)
26. Zhao R, Watt AJ, Battle MA, Li J, Bondow BJ, Duncan SA. Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice. Dev Biol. 2008;317:614-619.
27. Beqqali A, Kloots J, Ward-van Oostwaard D, Mummery C, Passier R. Genome-wide transcriptional profiling of human embryonic stem cells differentiating to cardiomyocytes. Stem Cells. 2006;24:1956-1967. (Pubitemid 44474172)
28. Martin-Puig S, Wang Z, Chien KR. Lives of a heart cell: tracing the origins of cardiac progenitors. Cell Stem Cell. 2008;2:320-331. (Pubitemid 351455247)
29. Stevens LC. Embryonic potency of embryoid bodies derived from a transplantable testicular teratoma of the mouse. Dev Biol. 1960;2: 285-297.
30. Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol. 1985;87:27-45. (Pubitemid 15029925)
31. Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res. 2002;91:189-201. (Pubitemid 34875673)
32. Keller G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 2005;19:1129-1155. (Pubitemid 40696181)
33. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, Livne E, Binah O, Itskovitz-Eldor J, Gepstein L. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001;108:407-414. (Pubitemid 32730787)
34. He JQ, Ma Y, Lee Y, Thomson JA, Kamp TJ. Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ Res. 2003;93:32-39. (Pubitemid 36859038)
35. Xu C, Police S, Rao N, Carpenter MK. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res. 2002;91:501-508.
36. 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.
37. Osafune K, Caron L, Borowiak M, Martinez RJ, Fitz-Gerald CS, Sato Y, Cowan CA, Chien KR, Melton DA. Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol. 2008;26:313-315. (Pubitemid 351355125)
38. Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM, Field LJ, Keller GM. Human cardiovascular progenitor cells develop from a KDR embryonic-stem-cell-derived population. Nature. 2008;453:524-528. (Pubitemid 351733312)
39. Elliott DA, Braam SR, Koutsis K, et al. NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat Methods. 2011;8:1037-1040.
40. Johansson BM, Wiles MV. Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development. Mol Cell Biol. 1995;15:141-151. (Pubitemid 24379910)
41. Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, Hotta A, Ellis J, Keller G. Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell. 2011;8:228-240.
42. Davis RP, Ng ES, Costa M, Mossman AK, Sourris K, Elefanty AG, Stanley EG. Targeting a GFP reporter gene to the mixl1 locus of human embryonic stem cells identifies human primitive streak-like cells and enables isolation of primitive hematopoietic precursors. Blood. 2008; 111:1876-1884. (Pubitemid 351451496)
43. Kubo A, Shinozaki K, Shannon JM, Kouskoff V, Kennedy M, Woo S, Fehling HJ, Keller G. Development of definitive endoderm from embryonic stem cells in culture. Development. 2004;131:1651-1662. (Pubitemid 38559291)
44. Ueno S, Weidinger G, Osugi T, Kohn AD, Golob JL, Pabon L, Reinecke H, Moon RT, Murry CE. Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc Natl Acad Sci U S A. 2007;104:9685-9690. (Pubitemid 47175327)
45. Ren Y, Lee MY, Schliffke S, Paavola J, Amos PJ, Ge X, Ye M, Zhu S, Senyei G, Lum L, Ehrlich BE, Qyang Y. Small molecule Wnt inhibitors enhance the efficiency of BMP-4-directed cardiac differentiation of human pluripotent stem cells. J Mol Cell Cardiol. 2011;51:280-287.
46. Freund C, Ward-van Oostwaard D, Monshouwer-Kloots J, van den Brink S, van Rooijen M, Xu X, Zweigerdt R, Mummery C, Passier R. Insulin redirects differentiation from cardiogenic mesoderm and endoderm to neuroectoderm in differentiating human embryonic stem cells. Stem Cells. 2008;26:724-733.
47. Costa M, Dottori M, Sourris K, Jamshidi P, Hatzistavrou T, Davis R, Azzola L, Jackson S, Lim SM, Pera M, Elefanty AG, Stanley EG. A method for genetic modification of human embryonic stem cells using electroporation. Nat Protoc. 2007;2:792-796. (Pubitemid 46745575)
48. Ng ES, Davis RP, Azzola L, Stanley EG, Elefanty AG. Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood. 2005;106:1601-1603. (Pubitemid 41208571)
49. Burridge PW, Anderson D, Priddle H, Barbadillo MMD, Chamberlain S, Allegrucci C, Young LE, Denning C. Improved human embryonic stem cell embryoid body homogeneity and cardiomyocyte differentiation from a novel v-96 plate aggregation system highlights interline variability. Stem Cells. 2007;25:929-938. (Pubitemid 46572590)
50. Ungrin MD, Joshi C, Nica A, Bauwens C, Zandstra PW. Reproducible, ultra high-throughput formation of multicellular organization from single cell suspension-derived human embryonic stem cell aggregates. PLoS One. 2008;3:e1565.
51. Khademhosseini A, Ferreira L, Blumling J 3rd, Yeh J, Karp JM, Fukuda J, Langer R. Co-culture of human embryonic stem cells with murine embryonic fibroblasts on microwell-patterned substrates. Biomaterials. 2006;27:5968-5977. (Pubitemid 44414975)
52. Mohr JC, de Pablo JJ, Palecek SP. 3-D microwell culture of human embryonic stem cells. Biomaterials. 2006;27:6032-6042. (Pubitemid 44414976)
53. Mohr JC, Zhang J, Azarin SM, Soerens AG, de Pablo JJ, Thomson JA, Lyons GE, Palecek SP, Kamp TJ. The microwell control of embryoid body size in order to regulate cardiac differentiation of human embryonic stem cells. Biomaterials. 2010;31:1885-1893.
54. Bauwens CL, Peerani R, Niebruegge S, Woodhouse KA, Kumacheva E, Husain M, Zandstra PW. Control of human embryonic stem cell colony and aggregate size heterogeneity influences differentiation trajectories. Stem Cells. 2008;26:2300-2310.
55. Peerani R, Rao BM, Bauwens C, Yin T, Wood GA, Nagy A, Kumacheva E, Zandstra PW. Niche-mediated control of human embryonic stem cell self-renewal and differentiation. EMBO J. 2007;26: 4744-4755. (Pubitemid 350126801)
56. DâAmour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol. 2005;23:1534-1541. (Pubitemid 41752931)
57. Laflamme MA, Chen KY, Naumova AV, et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007;25:1015-1024. (Pubitemid 47517637)
58. Paige SL, Osugi T, Afanasiev OK, Pabon L, Reinecke H, Murry CE. Endogenous Wnt/beta-catenin signaling is required for cardiac differentiation in human embryonic stem cells. PLoS One. 2010;5:e11134.
59. Ng ES, Davis R, Stanley EG, Elefanty AG. A protocol describing the use of a recombinant protein-based, animal product-free medium (APEL) for human embryonic stem cell differentiation as spin embryoid bodies. Nat Protoc. 2008;3:768-776. (Pubitemid 351639021)
60. Mignone JL, Kreutziger KL, Paige SL, Murry CE. Cardiogenesis from human embryonic stem cells. Circ J. 2010;74:2517-2526.
61. Zhang J, Raval KK, Lian X, Herman AM, Wilson GF, Barron MR, Yu J, Palecek SP, Thompson JA, Kamp TJ. Matrix-promoted efficient cardiac differentiation of human iPS and ES cells. Circulation. 2010; 122:A20724 (abst).
62. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den BS, Hassink R, van der HM, 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. (Pubitemid 36667249)
63. Passier R, Oostwaard DW, Snapper J, Kloots J, Hassink RJ, Kuijk E, Roelen B, de la Riviere AB, Mummery C. Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures. Stem Cells. 2005;23:772-780. (Pubitemid 40791792)
64. Xu XQ, Graichen R, Soo SY, Balakrishnan T, Rahmat SN, Sieh S, Tham SC, Freund C, Moore J, Mummery C, Colman A, Zweigerdt R, Davidson BP. Chemically defined medium supporting cardiomyocyte differentiation of human embryonic stem cells. Differentiation. 2008; 76:958-970.
65. Freund C, Davis RP, Gkatzis K, Ward-van Oostwaard D, Mummery CL. The first reported generation of human induced pluripotent stem cells (iPS cells) and iPS cell-derived cardiomyocytes in the Netherlands. Neth Heart J. 2010;18:51-54.
66. Mummery C, Ward D, Passier R. Differentiation of human embryonic stem cells to cardiomyocytes by coculture with endoderm in serum free medium. Curr Protoc Stem Cell Biol. 2007;2:1:F. 2.1-1F. 2.14.
67. Narazaki G, Uosaki H, Teranishi M, Okita K, Kim B, Matsuoka S, Yamanaka S, Yamashita JK. Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation. 2008;118:498-506.
68. Evseenko D, Zhu Y, Schenke-Layland K, Kuo J, Latour B, Ge S, Scholes J, Dravid G, Li X, MacLellan WR, Crooks GM. Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells. Proc Natl Acad Sci U S A. 2010;107: 13742-13747.
69. Blin G, Nury D, Stefanovic S, et al. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. J Clin Invest. 2010;120:1125-1139.
70. Kattman SJ, Huber TL, Keller GM. Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev Cell. 2006;11:723-732. (Pubitemid 44644969)
71. Moretti A, Caron L, Nakano A, Lam JT, Bernshausen A, Chen Y, Qyang Y, Bu L, Sasaki M, Martin-Puig S, Sun Y, Evans SM, Laugwitz KL, Chien KR. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell. 2006;127: 1151-1165. (Pubitemid 44895618)
72. Wu SM, Fujiwara Y, Cibulsky SM, Clapham DE, Lien CL, Schultheiss TM, Orkin SH. Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell. 2006;127: 1137-1150. (Pubitemid 44914005)
73. Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature. 2009; 460:113-117.
74. Dubois NC, Craft AM, Sharma P, Elliott DA, Stanley EG, Elefanty AG, Gramolini A, Keller G. SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nat Biotechnol. 2011;29:1011-1018.
75. Klug MG, Soonpaa MH, Koh GY, Field LJ. Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J Clin Invest. 1996;98:216-224. (Pubitemid 26243839)
76. Fijnvandraat AC, van Ginneken AC, Schumacher CA, Boheler KR, Lekanne Deprez RH, Christoffels VM, Moorman AF. Cardiomyocytes purified from differentiated embryonic stem cells exhibit characteristics of early chamber myocardium. J Mol Cell Cardiol. 2003;35:1461-1472. (Pubitemid 37491189)
77. Gassanov N, Er F, Zagidullin N, Hoppe UC. Endothelin induces differentiation of ANP-EGFP expressing embryonic stem cells towards a pacemaker phenotype. FASEB J. 2004;18:1710-1712. (Pubitemid 39561659)
78. Metzger JM, Lin WI, Samuelson LC. Vital staining of cardiac myocytes during embryonic stem cell cardiogenesis in vitro. Circ Res. 1996;78: 547-552. (Pubitemid 26106869)
79. Meyer N, Jaconi M, Landopoulou A, Fort P, Puceat M. A fluorescent reporter gene as a marker for ventricular specification in ES-derived cardiac cells. FEBS Lett. 2000;478:151-158. (Pubitemid 30462277)
80. Muller M, Fleischmann BK, Selbert S, Ji GJ, Endl E, Middeler G, Muller 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.
81. Anderson D, Self T, Mellor IR, Goh G, Hill SJ, Denning C. Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Mol Ther. 2007;15:2027-2036. (Pubitemid 350011743)
82. 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.
83. Xu XQ, Zweigerdt R, Soo SY, Ngoh ZX, Tham SC, Wang ST, Graichen R, Davidson B, Colman A, Sun W. Highly enriched cardiomyocytes from human embryonic stem cells. Cytotherapy. 2008;10:376-389. (Pubitemid 351983161)
84. Huber I, Itzhaki I, Caspi O, Arbel G, Tzukerman M, Gepstein A, Habib M, Yankelson L, Kehat I, Gepstein L. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J. 2007;21:2551-2563. (Pubitemid 47230684)
85. 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.
86. 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.
87. Cao F, Lin S, Xie X, Ray P, Patel M, Zhang X, Drukker M, Dylla SJ, Connolly AJ, Chen X, Weissman IL, Gambhir SS, Wu JC. In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation. 2006;113:1005-1014. (Pubitemid 43879476)
88. Giudice A, Trounson A. Genetic modification of human embryonic stem cells for derivation of target cells. Cell Stem Cell. 2008;2:422-433. (Pubitemid 351598085)
89. Elefanty AG, Stanley EG. Reshaping pluripotent stem cells. Nat Biotechnol. 2009;27:823-824.
90. Uosaki H, Fukushima H, Takeuchi A, Matsuoka S, Nakatsuji N, Yamanaka S, Yamashita JK. Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface expression. PLoS One. 2011;6:e23657.
91. Hattori F, Chen H, Yamashita H, et al. Nongenetic method for purifying stem cell-derived cardiomyocytes. Nat Methods. 2010;7:61-66.
92. Domian IJ, Chiravuri M, van der Meer P, Feinberg AW, Shi X, Shao Y, Wu SM, Parker KK, Chien KR. Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science. 2009; 326:426-429.
93. Azarin SM, Palecek SP. Development of scalable culture systems for human embryonic stem cells. Biochem Eng J. 2010;48:378.
94. Krawetz R, Taiani JT, Liu S, Meng G, Li X, Kallos MS, Rancourt DE. Large-scale expansion of pluripotent human embryonic stem cells in stirred-suspension bioreactors. Tissue Eng Part C Methods. 2010;16: 573-582.
95. Bauwens C, Yin T, Dang S, Peerani R, Zandstra PW. Development of a perfusion fed bioreactor for embryonic stem cell-derived cardiomyocyte generation: oxygen-mediated enhancement of cardiomyocyte output. Biotechnol Bioeng. 2005;90:452-461. (Pubitemid 40779195)
96. Schroeder M, Niebruegge S, Werner A, Willbold E, Burg M, Ruediger M, Field LJ, Lehmann J, Zweigerdt R. Differentiation and lineage selection of mouse embryonic stem cells in a stirred bench scale bioreactor with automated process control. Biotechnol Bioeng. 2005;92: 920-933.
97. Zweigerdt R, Burg M, Willbold E, Abts H, Ruediger M. Generation of confluent cardiomyocyte monolayers derived from embryonic stem cells in suspension: a cell source for new therapies and screening strategies. Cytotherapy. 2003;5:399-413. (Pubitemid 37369027)
98. Zandstra PW, Bauwens C, Yin T, Liu Q, Schiller H, Zweigerdt R, Pasumarthi KB, Field LJ. Scalable production of embryonic stem cellderived cardiomyocytes. Tissue Eng. 2003;9:767-778. (Pubitemid 37048117)
99. Niebruegge S, Nehring A, Bar H, Schroeder M, Zweigerdt R, Lehmann J. Cardiomyocyte production in mass suspension culture: embryonic stem cells as a source for great amounts of functional cardiomyocytes. Tissue Eng Part A. 2008;14:1591-1601.
100. Jing D, Parikh A, Tzanakakis ES. Cardiac cell generation from encapsulated embryonic stem cells in static and scalable culture systems. Cell Transplant. 2010;19:1397-1412.
101. Yirme G, Amit M, Laevsky I, Osenberg S, Itskovitz-Eldor J. Establishing a dynamic process for the formation, propagation, and differentiation of human embryoid bodies. Stem Cells Dev. 2008;17:1227-1241.
102. Niebruegge S, Bauwens CL, Peerani R, Thavandiran N, Masse S, Sevaptisidis E, Nanthakumar K, Woodhouse K, Husain M, Kumacheva E, Zandstra PW. Generation of human embryonic stem cell-derived mesoderm and cardiac cells using size-specified aggregates in an oxygen-controlled bioreactor. Biotechnol Bioeng. 2009;102:493-507.
103. Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ, Kolaja KL, Swanson BJ, January CT. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol. 2011; 301:H2006-H2017.
104. 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. (Pubitemid 46684873)
105. 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.
106. Davis RP, Casini S, van den Berg CW, Hoekstra M, Remme CA, Dambrot C, Salvatori D, Ward-van Oostwaard D, Wilde AA, Bezzina CR, Verkerk AO, Freund C, Mummery CL. Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease. Circulation. epub ahead of print May 29, 2012. doi:10.1161/CIRCULATIONAHA.111.066092.
107. Kehat I, Gepstein A, Spira A, Itskovitz-Eldor J, Gepstein L. Highresolution electrophysiological assessment of human embryonic stem cell-derived cardiomyocytes: a novel in vitro model for the study of conduction. Circ Res. 2002;91:659-661. (Pubitemid 35204947)
108. Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith ZD, Ziller M, Croft GF, Amoroso MW, Oakley DH, Gnirke A, Eggan K, Meissner A. Reference maps of human ES and iPS cell variation enable highthroughput characterization of pluripotent cell lines. Cell. 2011;144: 439-452.
109. Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, Peters A, Mahairaki V, Koliatsos VE, Tung L, Zambidis ET. A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS One. 2011;6:e18293.
110. Takahashi T, Lord B, Schulze PC, Fryer RM, Sarang SS, Gullans SR, Lee RT. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation. 2003;107:1912-1916. (Pubitemid 36444134)
111. Ding S, Schultz PG. A role for chemistry in stem cell biology. Nat Biotechnol. 2004;22:833-840. (Pubitemid 38886601)
112. Sadek H, Hannack B, Choe E, Wang J, Latif S, Garry MG, Garry DJ, Longgood J, Frantz DE, Olson EN, Hsieh J, Schneider JW. Cardiogenic small molecules that enhance myocardial repair by stem cells. Proc Natl Acad Sci U S A. 2008;105:6063-6068. (Pubitemid 351758399)
113. Willems E, Spiering S, Davidovics H, Lanier M, Xia Z, Dawson M, Cashman J, Mercola M. Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cellderived mesoderm. Circ Res. 2011;109:360-364.
114. Lian X, Hsiao S, Wilson G, Zhu K, Hazeltine LB, Azarin SM, Raval K, Zhang J, Kamp TJ, Palecek SP. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci U S A. Published ahead of print May 29, 2012. doi:10.1073/pnas. 1200250109. http://www.pnas.org/content/early/2012/05/23/1200250109.long. Accessed May 29, 2012.
115. Graichen R, Xu X, Braam SR, Balakrishnan T, Norfiza S, Sieh S, Soo SY, Tham SC, Mummery C, Colman A, Zweigerdt R, Davidson BP. Enhanced cardiomyogenesis of human embryonic stem cells by a small molecular inhibitor of p38 MAPK. Differentiation. 2008;76: 357-370. (Pubitemid 351522761)
116. Yanes O, Clark J, Wong DM, Patti GJ, Sanchez-Ruiz A, Benton HP, Trauger SA, Desponts C, Ding S, Siuzdak G. Metabolic oxidation regulates embryonic stem cell differentiation. Nat Chem Biol. 2010;6: 411-417.
117. Smith J, Ladi E, Mayer-Proschel M, Noble M. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci US A. 2000;97:10032-10037.
118. Ezashi T, Das P, Roberts RM. Low O2 tensions and the prevention of differentiation of hES cells. Proc Natl Acad Sci U S A. 2005;102: 4783-4788. (Pubitemid 40471531)
119. Lin Q, Lee YJ, Yun Z. Differentiation arrest by hypoxia. J Biol Chem. 2006;281:30678-30683. (Pubitemid 44582123)
120. Buggisch M, Ateghang B, Ruhe C, Strobel C, Lange S, Wartenberg M, Sauer H. Stimulation of ES-cell-derived cardiomyogenesis and neonatal cardiac cell proliferation by reactive oxygen species and NADPH oxidase. J Cell Sci. 2007;120:885-894. (Pubitemid 46523490)
121. Li J, Stouffs M, Serrander L, Banfi B, Bettiol E, Charnay Y, Steger K, Krause KH, Jaconi ME. The NADPH oxidase NOX4 drives cardiac differentiation: role in regulating cardiac transcription factors and MAP kinase activation. Mol Biol Cell. 2006;17:3978-3988. (Pubitemid 44330881)
122. Rozario T, DeSimone DW. The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol. 2010;341:126-140.
123. Chien KR, Domian IJ, Parker KK. Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science. 2008;322: 1494-1497.
124. Melkoumian Z, Weber JL, Weber DM, et al. Synthetic peptideacrylate surfaces for long-term self-renewal and cardiomyocyte differentiation of human embryonic stem cells. Nat Biotechnol. 2010; 28:606-610.
125. Rodin S, Domogatskaya A, Strom S, Hansson EM, Chien KR, Inzunza J, Hovatta O, Tryggvason K. Long-term self-renewal of human pluripotent stem cells on human recombinant laminin-511. Nat Biotechnol. 2010;28:611-615.
126. Villa-Diaz LG, Nandivada H, Ding J, Nogueira-de-Souza NC, Krebsbach PH, OâShea KS, Lahann J, Smith GD. Synthetic polymer coatings for long-term growth of human embryonic stem cells. Nat Biotechnol. 2010;28:581-583.
127. Klim JR, Li L, Wrighton PJ, Piekarczyk MS, Kiessling LL. A defined glycosaminoglycan-binding substratum for human pluripotent stem cells. Nat Methods. 2010;7:989-994.
128. Dixon JE, Dick E, Rajamohan D, Shakesheff KM, Denning C. Directed differentiation of human embryonic stem cells to interrogate the cardiac gene regulatory network. Mol Ther. 2011;19:1695-1703.
129. Passier R, van Laake LW, Mummery CL. Stem-cell-based therapy and lessons from the heart. Nature. 2008;453:322-329. (Pubitemid 351693138)