The case for induced pluripotent stem cell-derived cardiomyocytes in pharmacological screening

British Journal of Pharmacology

Volumn 169, Issue 2, 2013, Pages 304-317

  Khan, Jaffar M ^a   Lyon, Alexander R ^a   Harding, Sian E ^b  

^a ROYAL BROMPTON AND HAREFIELD NHS FOUNDATION TRUST   (United Kingdom)

^b IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

cardiac; cardiotoxicity; embryonic; high throughput; iPSC; safety; stem cell

Indexed keywords

ALFUZOSIN; ASTEMIZOLE; CALCIUM; CISAPRIDE; DOFETILIDE; ERYTHROMYCIN; FLECAINIDE; MOXIFLOXACIN; NIFEDIPINE; PINACIDIL; POTASSIUM CHANNEL HERG; QUINIDINE; RANOLAZINE; SOTALOL; TERFENADINE; THIORIDAZINE; TRASTUZUMAB; VERAPAMIL;

CELL FUNCTION; CHRONOTROPISM; CONGESTIVE HEART FAILURE; DRUG MECHANISM; DRUG SCREENING; ELECTROPHYSIOLOGY; EMBRYONIC STEM CELL; FIBROBLAST; GENE EXPRESSION; GENETIC VARIABILITY; GENOTYPE; HEART ARRHYTHMIA; HEART MUSCLE CELL; HUMAN; IMMUNOFLUORESCENCE; NONHUMAN; PHENOTYPE; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN STRUCTURE; QT PROLONGATION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; REVIEW; TOXICITY TESTING;

ADULT; ANIMALS; CELL DIFFERENTIATION; CELL LINE; DRUG DESIGN; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; EMBRYONIC STEM CELLS; FIBROBLASTS; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MYOCYTES, CARDIAC; REPRODUCIBILITY OF RESULTS; TOXICITY TESTS;

EID: 84876888499     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2012.02118.x     Document Type: Review

References (123)

1. Abdul Kadir SH, Ali NN, Mioulane M, Brito-Martins M, Abu-Hayyeh S, Foldes G, et al,. (2009). Embryonic stem cell-derived cardiomyocytes as a model to study fetal arrhythmia related to maternal disease. J Cell Mol Med 13: 3730-3741.
2. Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R, (2003). Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17: 126-140.
3. Behringer RR, (2007). Human-animal chimeras in biomedical research. Cell Stem Cell 1: 259-262.
4. Bers DM, (2002). Cardiac excitation-contraction coupling. Nature 415: 198-205.
5. Binah O, Dolnikov K, Sadan O, Shilkrut M, Zeevi-Levin N, Amit M, et al,. (2007). Functional and developmental properties of human embryonic stem cells-derived cardiomyocytes. J Electrocardiol 40 (Suppl.): S192-S196.
6. Boland MJ, Hazen JL, Nazor KL, Rodriguez AR, Gifford W, Martin G, et al,. (2009). Adult mice generated from induced pluripotent stem cells. Nature 461: 91-94.
7. Braam SR, Denning C, Matsa E, Young LE, Passier R, Mummery CL, (2008). Feeder-free culture of human embryonic stem cells in conditioned medium for efficient genetic modification. Nat Protoc 3: 1435-1443.
8. Braam SR, Tertoolen L, van de Stolpe A, Meyer T, Passier R, Mummery CL, (2010). Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Res 4: 107-116.
9. Brito-Martins M, Harding SE, Ali NN, (2008). beta(1)- and beta(2)-adrenoceptor responses in cardiomyocytes derived from human embryonic stem cells: comparison with failing and non-failing adult human heart. Br J Pharmacol 153: 751-759.
10. Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, Peters A, 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.
11. Cannell MB, Cheng H, Lederer WJ, (1995). The control of calcium release in heart muscle. Science 268: 1045-1049.
12. Cao F, Wagner RA, Wilson KD, Xie X, Fu JD, Drukker M, et al,. (2008). Transcriptional and functional profiling of human embryonic stem cell-derived cardiomyocytes. PLoS ONE 3: e3474.
13. Carlsson L, (2006). In vitro and in vivo models for testing arrhythmogenesis in drugs. J Intern Med 259: 70-80.
14. Carpenter L, Carr C, Yang CT, Stuckey DJ, Clarke K, Watt SM, (2012). Efficient differentiation of human induced pluripotent stem cells generates cardiac cells that provide protection following myocardial infarction in the rat. Stem Cells Dev 21: 977-986.
15. Cartwright P, McLean C, Sheppard A, Rivett D, Jones K, Dalton S, (2005). LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 132: 885-896.
16. Carvajal-Vergara X, Sevilla A, D'Souza SL, Ang YS, Schaniel C, Lee DF, et al,. (2010). Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465: 808-812.
17. Caspi O, Itzhaki I, Kehat I, Gepstein A, Arbel G, Huber I, et al,. (2009). In vitro electrophysiological drug testing using human embryonic stem cell derived cardiomyocytes. Stem Cells Dev 18: 161-172.
18. Chan TY, (2009). Aconite poisoning. Clin Toxicol (Phila) 47: 279-285.
19. Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, et al,. (2009). Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5: 111-123.
20. De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N, (2002). Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf 25: 263-286.
21. Demiryürek AT, Demiryürek S, (2005). Cardiotoxicity of digitalis glycosides: roles of autonomic pathways, autacoids and ion channels. Auton Autacoid Pharmacol 25: 35-52.
22. Deng J, Shoemaker R, Xie B, Gore A, LeProust EM, Antosiewicz-Bourget J, et al,. (2009). Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol 27: 353-360.
23. Dick E, Rajamohan D, Ronksley J, Denning C, (2010). Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening. Biochem Soc Trans 38: 1037-1045.
24. Dolnikov K, Shilkrut M, Zeevi-Levin N, Gerecht-Nir S, Amit M, Danon A, et al,. (2006). Functional properties of human embryonic stem cell-derived cardiomyocytes: intracellular Ca2+ handling and the role of sarcoplasmic reticulum in the contraction. Stem Cells 24: 236-245.
25. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, et al,. (2000). Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A 97: 10483-10488.
26. Extramiana F, Maison-Blanche P, Cabanis MJ, Ortemann-Renon C, Beaufils P, Leenhardt A, (2005). Clinical assessment of drug-induced QT prolongation in association with heart rate changes. Clin Pharmacol Ther 77: 247-258.
27. Feng J, Li GR, Fermini B, Nattel S, (1996). Properties of sodium and potassium currents of cultured adult human atrial myocytes. Am J Physiol 270: H1676-H1686.
28. Fermini B, Fossa AA, (2003). The impact of drug-induced QT interval prolongation on drug discovery and development. Nat Rev Drug Discov 2: 439-447.
29. Földes G, Mioulane M, Wright JS, Liu AQ, Novak P, Merkely B, et al,. (2011). Modulation of human embryonic stem cell-derived cardiomyocyte growth: a testbed for studying human cardiac hypertrophy? J Mol Cell Cardiol 50: 367-376.
30. Friese MA, Jensen LT, Willcox N, Fugger L, (2006). Humanized mouse models for organ-specific autoimmune diseases. Curr Opin Immunol 18: 704-709.
31. Frothingham R, (2001). Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy 21: 1468-1472.
32. Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M, (2009). Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 85: 348-362.
33. Gai H, Leung EL, Costantino PD, Aguila JR, Nguyen DM, Fink LM, et al,. (2009). Generation and characterization of functional cardiomyocytes using induced pluripotent stem cells derived from human fibroblasts. Cell Biol Int 33: 1184-1193.
34. Germanguz I, Sedan O, Zeevi-Levin N, Shtrichman R, Barak E, Ziskind A, et al,. (2011). Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells. J Cell Mol Med 15: 38-51.
35. Giorgi MA, Bolaños R, Gonzalez CD, Di Girolamo G, (2010). QT interval prolongation: preclinical and clinical testing arrhythmogenesis in drugs and regulatory implications. Curr Drug Saf 5: 54-57.
36. Gonzalez F, Barragan Monasterio M, Tiscornia G, Montserrat Pulido N, Vassena R, Batlle Morera L, et al,. (2009). Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector. Proc Natl Acad Sci U S A 106: 8918-8922.
37. Guo L, Abrams RM, Babiarz JE, Cohen JD, Kameoka S, Sanders MJ, et al,. (2011a). Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci 123: 281-289.
38. Guo L, Qian JY, Abrams R, Tang HM, Weiser T, Sanders MJ, et al,. (2011b). The electrophysiological effects of cardiac glycosides in human iPSC-derived cardiomyocytes and in guinea pig isolated hearts. Cell Physiol Biochem 27: 453-462.
39. Gupta MK, Illich DJ, Gaarz A, Matzkies M, Nguemo F, Pfannkuche K, et al,. (2010). Global transcriptional profiles of beating clusters derived from human induced pluripotent stem cells and embryonic stem cells are highly similar. BMC Dev Biol 10: 98.
40. Habib M, Caspi O, Gepstein L, (2008). Human embryonic stem cells for cardiomyogenesis. J Mol Cell Cardiol 45: 462-474.
41. Halbach M, Egert U, Hescheler J, Banach K, (2003). Estimation of action potential changes from field potential recordings in multicellular mouse cardiac myocyte cultures. Cell Physiol Biochem 13: 271-284.
42. Harding SE, Ali NN, Brito-Martins M, Gorelik J, (2007). The human embryonic stem cell-derived cardiomyocyte as a pharmacological model. Pharmacol Ther 113: 341-353.
43. He JQ, Ma Y, Lee Y, Thomson JA, Kamp TJ, (2003). Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ Res 93: 32-39.
44. ICH (2000). Safety Pharmacology Studies for Human Pharmaceuticals. ICH Safety Guideline S7A. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.
45. Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, et al,. (2011a). Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471: 225-229.
46. Itzhaki I, Rapoport S, Huber I, Mizrahi I, Zwi-Dantsis L, Arbel G, et al,. (2011b). Calcium handling in human induced pluripotent stem cell derived cardiomyocytes. PLoS ONE 6: e18037.
47. January CT, Riddle JM, Salata JJ, (1988). A model for early afterdepolarizations: induction with the Ca2+ channel agonist Bay K 8644. Circ Res 62: 563-571.
48. Jonsson MK, Duker G, Tropp C, Andersson B, Sartipy P, Vos MA, et al,. (2010). Quantified proarrhythmic potential of selected human embryonic stem cell-derived cardiomyocytes. Stem Cell Res 4: 189-200.
49. Jost N, Acsai K, Horváth B, Bányász T, Baczkõ I, Bitay M, et al,. (2009). Contribution of I Kr and I K1 to ventricular repolarization in canine and human myocytes: is there any influence of action potential duration? Basic Res Cardiol 104: 33-41.
50. Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K, (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458: 771-775.
51. Kang L, Wang J, Zhang Y, Kou Z, Gao S, (2009). iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell 5: 135-138.
52. Kannankeril PJ, Roden DM, (2007). Drug-induced long QT and torsade de pointes: recent advances. Curr Opin Cardiol 22: 39-43.
53. Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, Hotta A, 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: 228-240.
54. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, et al,. (2001). Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 108: 407-414.
55. Kim EY, Jeon K, Park HY, Han YJ, Yang BC, Park SB, et al,. (2010). Differences between cellular and molecular profiles of induced pluripotent stem cells generated from mouse embryonic fibroblasts. Cell Reprogram 12: 627-639.
56. Kola I, Landis J, (2004). Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3: 711-715.
57. Kong CW, Akar FG, Li RA, (2010). Translational potential of human embryonic and induced pluripotent stem cells for myocardial repair: insights from experimental models. Thromb Haemost 104: 30-38.
58. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, et al,. (2007). Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25: 1015-1024.
59. Li Y, McClintick J, Zhong L, Edenberg HJ, Yoder MC, Chan RJ, (2005). Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4. Blood 105: 635-637.
60. Lian Q, Chow Y, Esteban MA, Pei D, Tse HF, (2010). Future perspective of induced pluripotent stem cells for diagnosis, drug screening and treatment of human diseases. Thromb Haemost 104: 39-44.
61. Liu J, Fu JD, Siu CW, Li RA, (2007). Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation. Stem Cells 25: 3038-3044.
62. Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, et al,. (2008). Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci U S A 105: 2883-2888.
63. Lu HR, Mariën R, Saels A, De Clerck F, (2001). Species plays an important role in drug-induced prolongation of action potential duration and early afterdepolarizations in isolated Purkinje fibers. J Cardiovasc Electrophysiol 12: 93-102.
64. Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ, et al,. (2011). High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol 301: H2006-H2017.
65. MacDonald JS, Robertson RT, (2009). Toxicity testing in the 21st century: a view from the pharmaceutical industry. Toxicol Sci 110: 40-46.
66. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, et al,. (2007). Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1: 55-70.
67. Mandenius CF, Steel D, Noor F, Meyer T, Heinzle E, Asp J, et al,. (2011). Cardiotoxicity testing using pluripotent stem cell-derived human cardiomyocytes and state-of-the-art bioanalytics: a review. J Appl Toxicol 31: 191-205.
68. Marbán E, (2002). Cardiac channelopathies. Nature 415: 213-218.
69. Matsa E, Rajamohan D, Dick E, Young L, Mellor I, Staniforth A, et al,. (2011). Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur Heart J 32: 952-962.
70. Mauritz C, Schwanke K, Reppel M, Neef S, Katsirntaki K, Maier LS, et al,. (2008). Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 118: 507-517.
71. Meiry G, Reisner Y, Feld Y, Goldberg S, Rosen M, Ziv N, et al,. (2001). Evolution of action potential propagation and repolarization in cultured neonatal rat ventricular myocytes. J Cardiovasc Electrophysiol 12: 1269-1277.
72. Meyer T, Leisgen C, Gonser B, Günther E, (2004). QT-screen: high-throughput cardiac safety pharmacology by extracellular electrophysiology on primary cardiac myocytes. Assay Drug Dev Technol 2: 507-514.
73. Mitcheson JS, Hancox JC, Levi AJ, (1998). Cultured adult cardiac myocytes: future applications, culture methods, morphological and electrophysiological properties. Cardiovasc Res 39: 280-300.
74. Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flügel L, et al,. (2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363: 1397-1409.
75. Mummery C, Ward D, van den Brink CE, Bird SD, Doevendans PA, Opthof T, et al,. (2002). Cardiomyocyte differentiation of mouse and human embryonic stem cells. J Anat 200: 233-242.
76. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, et al,. (2003). Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107: 2733-2740.
77. Narazaki G, Uosaki H, Teranishi M, Okita K, Kim B, Matsuoka S, et al,. (2008). Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation 118: 498-506.
78. Narsinh KH, Sun N, Sanchez-Freire V, Lee AS, Almeida P, Hu S, et al,. (2011). Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. J Clin Invest 121: 1217-1221.
79. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, et al,. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95: 379-391.
80. Niwa H, Miyazaki J, Smith AG, (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24: 372-376.
81. Okita K, Ichisaka T, Yamanaka S, (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448: 313-317.
82. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S, (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science 322: 949-953.
83. Papkovsky DB, (2004). Methods in optical oxygen sensing: protocols and critical analyses. Methods Enzymol 381: 715-735.
84. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, et al,. (2008a). Disease-specific induced pluripotent stem cells. Cell 134: 877-886.
85. Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, et al,. (2008b). Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451: 141-146.
86. Pekkanen-Mattila M, Chapman H, Kerkelä E, Suuronen R, Skottman H, Koivisto AP, et al,. (2010). Human embryonic stem cell-derived cardiomyocytes: demonstration of a portion of cardiac cells with fairly mature electrical phenotype. Exp Biol Med 235: 522-530.
87. Pelzmann B, Schaffer P, Bernhart E, Lang P, Mächler H, Rigler B, et al,. (1998). L-type calcium current in human ventricular myocytes at a physiological temperature from children with tetralogy of Fallot. Cardiovasc Res 38: 424-432.
88. Ren Y, Lee MY, Schliffke S, Paavola J, Amos PJ, Ge X, et al,. (2011). Small molecule Wnt inhibitors enhance the efficiency of BMP-4-directed cardiac differentiation of human pluripotent stem cells. J Mol Cell Cardiol 51: 280-287.
89. Reppel M, Boettinger C, Hescheler J, (2004). Beta-adrenergic and muscarinic modulation of human embryonic stem cell-derived cardiomyocytes. Cell Physiol Biochem 14: 187-196.
90. Reppel M, Igelmund P, Egert U, Juchelka F, Hescheler J, Drobinskaya I, (2007). Effect of cardioactive drugs on action potential generation and propagation in embryonic stem cell-derived cardiomyocytes. Cell Physiol Biochem 19: 213-224.
91. Rosen MR, (1995). Consequences of the Sicilian Gambit. Eur Heart J 16 (Suppl. G): 32-36.
92. Saha K, Jaenisch R, (2009). Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell 5: 584-595.
93. Sakakibara Y, Furukawa T, Singer DH, Jia H, Backer CL, Arentzen CE, et al,. (1993). Sodium current in isolated human ventricular myocytes. Am J Physiol 265: H1301-H1309.
94. Sartiani L, Bettiol E, Stillitano F, Mugelli A, Cerbai E, Jaconi ME, (2007). Developmental changes in cardiomyocytes differentiated from human embryonic stem cells: a molecular and electrophysiological approach. Stem Cells 25: 1136-1144.
95. Satin J, Kehat I, Caspi O, Huber I, Arbel G, Itzhaki I, et al,. (2004). Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. J Physiol 559: 479-496.
96. Satin J, Itzhaki I, Rapoport S, Schroder EA, Izu L, Arbel G, et al,. (2008). Calcium handling in human embryonic stem cell-derived cardiomyocytes. Stem Cells 26: 1961-1972.
97. Sedan O, Dolnikov K, Zeevi-Levin N, Leibovich N, Amit M, Itskovitz-Eldor J, et al,. (2008). 1,4,5-Inositol trisphosphate-operated intracellular Ca(2+) stores and angiotensin-II/endothelin-1 signaling pathway are functional in human embryonic stem cell-derived cardiomyocytes. Stem Cells 26: 3130-3138.
98. Shinozawa T, Furukawa H, Sato E, Takami K, (2012). A novel purification method of murine embryonic stem cell- and human-induced pluripotent stem cell-derived cardiomyocytes by simple manual dissociation. J Biomol Screen 14: 239-245.
99. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al,. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783-792.
100. Snir M, Kehat I, Gepstein A, Coleman R, Itskovitz-Eldor J, Livne E, et al,. (2003). Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. Am J Physiol Heart Circ Physiol 285: H2355-H2363.
101. Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, et al,. (2009). Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136: 964-977.
102. Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K, (2008). Induced pluripotent stem cells generated without viral integration. Science 322: 945-949.
103. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al,. (2006). Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355: 1018-1028.
104. Takahashi K, Yamanaka S, (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676.
105. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al,. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861-872.
106. Tanaka T, Tohyama S, Murata M, Nomura F, Kaneko T, Chen H, et al,. (2009). In vitro pharmacologic testing using human induced pluripotent stem cell-derived cardiomyocytes. Biochem Biophys Res Commun 385: 497-502.
107. Thomsen MB, Beekman JD, Attevelt NJ, Takahara A, Sugiyama A, Chiba K, et al,. (2006a). No proarrhythmic properties of the antibiotics Moxifloxacin or Azithromycin in anaesthetized dogs with chronic-AV block. Br J Pharmacol 149: 1039-1048.
108. Thomsen MB, Matz J, Volders PG, Vos MA, (2006b). Assessing the proarrhythmic potential of drugs: current status of models and surrogate parameters of torsades de pointes arrhythmias. Pharmacol Ther 112: 150-170.
109. Wadhwa D, Fallah-Rad N, Grenier D, Krahn M, Fang T, Ahmadie R, et al,. (2009). Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat 117: 357-364.
110. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, et al,. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448: 318-324.
111. Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R, et al,. (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458: 766-770.
112. Xu C, Police S, Rao N, Carpenter MK, (2002). Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res 91: 501-508.
113. Xu H, Yi BA, Wu H, Bock C, Gu H, Lui KO, et al,. (2012). Highly efficient derivation of ventricular cardiomyocytes from induced pluripotent stem cells with a distinct epigenetic signature. Cell Res 22: 142-154.
114. Xu XQ, Soo SY, Sun W, Zweigerdt R, (2009). Global expression profile of highly enriched cardiomyocytes derived from human embryonic stem cells. Stem Cells 27: 2163-2174.
115. Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, et al,. (2008). Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 453: 524-528.
116. Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, et al,. (2011). Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471: 230-234.
117. Yokoo N, Baba S, Kaichi S, Niwa A, Mima T, Doi H, et al,. (2009). The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. Biochem Biophys Res Commun 387: 482-488.
118. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al,. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917-1920.
119. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, et al,. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science 324: 797-801.
120. Zaza A, (2010). Control of the cardiac action potential: The role of repolarization dynamics. J Mol Cell Cardiol 48: 106-111.
121. Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP, et al,. (2009). Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 104: e30-e41.
122. Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, et al,. (2009). iPS cells produce viable mice through tetraploid complementation. Nature 461: 86-90.
123. Zwi L, Caspi O, Arbel G, Huber I, Gepstein A, Park IH, et al,. (2009). Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation 120: 1513-1523.