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Pluripotent Stem Cells as a Platform for Cardiac Arrhythmia Drug Screening

  • Regenerative Medicine and Stem-cell Therapy (S Wu and P Hsieh, Section Editors)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Opinion statement

Since the first demonstrations of the differentiation of pluripotent stem cells to produce functional human cellular models such as cardiomyocytes, the scientific community has been captivated [1, 2••, 3]. In the time since that seminal work, the field has been catapulted forward by the demonstration that adult somatic cells can be reprogrammed to an induced state of pluripotency [4••], and more recently by the development of efficient and sophisticated genome editing tools [5••, 6••, 7], which together afford a theoretically unlimited supply of relevant genetic disease models. In particular, many of the early successes with induced pluripotent stem cell technology have been realized with cardiac arrhythmia syndromes [8••, 9–15]. There is interest in applying stem cell models in large-scale screens to discover novel therapeutics or drug toxicities. This manuscript aims to discuss the potential role of hPSC-derived cardiomyocyte models in therapeutic arrhythmia screens and review recent advances in the field that bring us closer to this reality.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Maltsev VA, Wobus AM, Rohwedel J, Bader M, Hescheler J. Cardiomyocytes differentiated in vitro from embryonic stem cells developmentally express cardiac-specific genes and ionic currents. Circ Res. 1994;75(2):233–44.

    Article  CAS  PubMed  Google Scholar 

  2. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Investig. 2001;108(3):407–14. doi:10.1172/JCI12131. Initial demonstration of human embryonic stem cells differentiated by the embryonic body method can form functional cardiomyocytes.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Xu C, Police S, Rao N, Carpenter MK. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res. 2002;91(6):501–8.

    Article  CAS  PubMed  Google Scholar 

  4. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi:10.1016/j.cell.2006.07.024. Nobel-prize winning work from the Yamanaka lab demonstrating that mature somatic cells can be reprogrammed to a pluripotent state.

    Article  CAS  PubMed  Google Scholar 

  5. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819–23. doi:10.1126/science.1231143. Independently, members of the Church and Zhang labs (see reference #6 below) demonstrated use of the CRISPR/Cas9 system in targeted mutagenesis in mammalian cells, marking a new age in genome editing technology.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339(6121):823–6. doi:10.1126/science.1232033.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Musunuru K. Genome editing of human pluripotent stem cells to generate human cellular disease models. Dis Models Mech. 2013;6(4):896–904. doi:10.1242/dmm.012054.

    Article  CAS  Google Scholar 

  8. Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. New Engl J Med. 2010;363(15):1397–409. doi:10.1056/NEJMoa0908679. Initial demonstration of an arrhythmogenic disease, in this case LQTI, modeled in human iPSC-derived cardiomyocytes.

    Article  CAS  PubMed  Google Scholar 

  9. Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature. 2011;471(7337):225–9. doi:10.1038/nature09747.

    Article  CAS  PubMed  Google Scholar 

  10. Matsa E, Rajamohan D, Dick E, Young L, Mellor I, Staniforth A, et al. Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur Heart J. 2011;32(8):952–62. doi:10.1093/eurheartj/ehr073.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature. 2011;471(7337):230–4. doi:10.1038/nature09855.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Davis RP, Casini S, van den Berg CW, Hoekstra M, Remme CA, Dambrot C, et al. Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease. Circulation. 2012;125(25):3079–91. doi:10.1161/CIRCULATIONAHA.111.066092.

    Article  PubMed  Google Scholar 

  13. Itzhaki I, Maizels L, Huber I, Gepstein A, Arbel G, Caspi O, et al. Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells. J Am Coll Cardiol. 2012;60(11):990–1000. doi:10.1016/j.jacc.2012.02.066.

    Article  CAS  PubMed  Google Scholar 

  14. Kim C, Wong J, Wen J, Wang S, Wang C, Spiering S, et al. Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature. 2013;494(7435):105–10. doi:10.1038/nature11799.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ma D, Wei H, Lu J, Ho S, Zhang G, Sun X, et al. Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2013;34(15):1122–33. doi:10.1093/eurheartj/ehs226.

    Article  CAS  PubMed  Google Scholar 

  16. Roden DM, Hong CC. Stem cell-derived cardiomyocytes as a tool for studying proarrhythmia: a better canary in the coal mine? Circulation. 2013;127(16):1641–3. doi:10.1161/CIRCULATIONAHA.113.002127.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Sun N, Yazawa M, Liu J, Han L, Sanchez-Freire V, Abilez OJ, et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med. 2012;4(130):130ra47. doi:10.1126/scitranslmed.3003552.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Lan F, Lee AS, Liang P, Sanchez-Freire V, Nguyen PK, Wang L, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013;12(1):101–13. doi:10.1016/j.stem.2012.10.010.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Roden DM. Drug-induced prolongation of the QT interval. New Engl J Med. 2004;350(10):1013–22. doi:10.1056/NEJMra032426.

    Article  CAS  PubMed  Google Scholar 

  20. Liang P, Lan F, Lee AS, Gong T, Sanchez-Freire V, Wang Y, et al. Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation. 2013;127(16):1677–91. doi:10.1161/CIRCULATIONAHA.113.001883. Using patch clamp electrophysiology, the Wu laboratory at Stanford compared multiple human iPSC-CMs: those derived from patients with the LQT1 syndrome, hypertrophic cardiomyopathy (β-MHC mutation), and dilated cardiomyopathy (TNNT2 mutation), and found drug toxicity effects (i.e., EADs in LQT1 cells) in increased frequency in diseased lines compared to lines created from sibling controls or ES cells.

    Article  CAS  PubMed  Google Scholar 

  21. Khan JM, Lyon AR, Harding SE. The case for induced pluripotent stem cell-derived cardiomyocytes in pharmacological screening. Br J Pharmacol. 2013;169(2):304–17. doi:10.1111/j.1476-5381.2012.02118.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Mercola M, Colas A, Willems E. Induced pluripotent stem cells in cardiovascular drug discovery. Circ Res. 2013;112(3):534–48. doi:10.1161/CIRCRESAHA.111.250266.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Zhang J, Klos M, Wilson GF, Herman AM, Lian X, Raval KK, et al. Extracellular matrix promotes highly efficient cardiac differentiation of human pluripotent stem cells: the matrix sandwich method. Circ Res. 2012;111(9):1125–36. doi:10.1161/CIRCRESAHA.112.273144. The "matrix-sandwich" method is a highly preferred method of inducing cardiac differentaition in a monolayer format in hPSCs, with efficiencies as high as > 80 %.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, et al. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci. 2012;109(27):E1848–57. doi:10.1073/pnas.1200250109.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Chen G, Gulbranson DR, Hou Z, Bolin JM, Ruotti V, Probasco MD, et al. Chemically defined conditions for human iPSC derivation and culture. Nat Methods. 2011;8(5):424–9. doi:10.1038/nmeth.1593.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Magyar J, Iost N, Kortvely A, Banyasz T, Virag L, Szigligeti P, et al. Effects of endothelin-1 on calcium and potassium currents in undiseased human ventricular myocytes. Pflugers Arch. 2000;441(1):144–9.

    Article  CAS  PubMed  Google Scholar 

  27. Hoekstra M, Mummery CL, Wilde AAM, Bezzina CR, Verkerk AO. Induced pluripotent stem-cell–derived cardiomyocytes as models for cardiac arrhythmias. Front Physiol. 2012;3. doi:10.3389/fphys.2012.00346. One of the most comprehensive reviews of utilizing hPSC-CMs as models for arrhythmia. The authors review, individually, the present body of work of iPSC models for various LQT syndromes and CPVT. Authors also review evidence for the major cardiac currents and their respective properties in hPSC-CMs.

  28. Peng S, Lacerda AE, Kirsch GE, Brown AM, Bruening-Wright A. The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes. J Pharmacol Toxicol Meth. 2010;61(3):277–86. doi:10.1016/j.vascn.2010.01.014.

    Article  CAS  Google Scholar 

  29. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003;107(21):2733–40. doi:10.1161/01.CIR.0000068356.38592.68. The visceral endoderm coculture method of cardiomyocyte differentation from hPSCs.

    Article  CAS  PubMed  Google Scholar 

  30. Robertson C, Tran DD, George SC. Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells. 2013;31(5):829–37. doi:10.1002/stem.1331.

    Article  CAS  PubMed  Google Scholar 

  31. Bellin M, Casini S, Davis RP, D'Aniello C, Haas J, Ward-van Oostwaard D, et al. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome. EMBO J. 2013;32(24):3161–75. doi:10.1038/emboj.2013.240.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Knollmann BC. Induced pluripotent stem cell-derived cardiomyocytes: boutique science or valuable arrhythmia model? Circ Res. 2013;112(6):969-76; discussion 76. doi:10.1161/CIRCRESAHA.112.300567. It has increasingly been recognized that genetic differences between iPSC and ESC lines may underlie variability in their respective phenotypes and drug responses. These authors generated isogenic control lines via genome editing by correcting a KCNH2 mutation in a LQT2 hiPSC line and introducing it into a WT hESC control line. By making comparisons within the same genetic background, such isogenic control strategies may emerge as a preferred method to compare phenotypic effects of mutations.

  33. Zhang Q, Jiang J, Han P, Yuan Q, Zhang J, Zhang X, et al. Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals. Cell Res. 2011;21(4):579–87. doi:10.1038/cr.2010.163.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ, et al. 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(5):H2006–17. doi:10.1152/ajpheart.00694.2011. The January group rigorously evaluated various cardiac currents in cells from one single iPSC line from Cellular Dynamics, Madison, WI.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Satin J, Kehat I, Caspi O, Huber I, Arbel G, Itzhaki I, et al. Mechanism of spontaneous excitability in human embryonic stem-cell–derived cardiomyocytes. J Physiol. 2004;559(Pt 2):479–96. doi:10.1113/jphysiol.2004.068213.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Wang K, Terrenoire C, Sampson KJ, Iyer V, Osteen JD, Lu J, et al. Biophysical properties of slow potassium channels in human embryonic stem-cell–derived cardiomyocytes implicate subunit stoichiometry. J Physiol. 2011;589(Pt 24):6093–104. doi:10.1113/jphysiol.2011.220863.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Bett GC, Kaplan AD, Lis A, Cimato TR, Tzanakakis ES, Zhou Q, et al. Electronic "expression" of the inward rectifier in cardiocytes derived from human-induced pluripotent stem cells. Heart Rhythm. 2013;10(12):1903–10. doi:10.1016/j.hrthm.2013.09.061.

    Article  PubMed  Google Scholar 

  38. Itzhaki I, Rapoport S, Huber I, Mizrahi I, Zwi-Dantsis L, Arbel G, et al. Calcium handling in human induced pluripotent stem-cell–derived cardiomyocytes. PLoS One. 2011;6(4):e18037. doi:10.1371/journal.pone.0018037.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Norstrom A, Akesson K, Hardarson T, Hamberger L, Bjorquist P, Sartipy P. Molecular and pharmacological properties of human embryonic stem cell-derived cardiomyocytes. Exp Biol Med (Maywood). 2006;231(11):1753–62.

    Google Scholar 

  40. Guo L, Coyle L, Abrams RM, Kemper R, Chiao ET, Kolaja KL. Refining the Human iPSC-Cardiomyocyte Arrhythmic Risk Assessment Model. Toxicol Sci. 2013;136(2):581–94. doi:10.1093/toxsci/kft205.

    Article  CAS  PubMed  Google Scholar 

  41. Sheng X, Reppel M, Nguemo F, Mohammad FI, Kuzmenkin A, Hescheler J, et al. Human pluripotent stem cell-derived cardiomyocytes: response to TTX and lidocain reveals strong cell to cell variability. PLoS One. 2012;7(9):e45963. doi:10.1371/journal.pone.0045963.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Egashira T, Yuasa S, Suzuki T, Aizawa Y, Yamakawa H, Matsuhashi T, et al. Disease characterization using LQTS-specific induced pluripotent stem cells. Cardiovasc Res. 2012;95(4):419–29. doi:10.1093/cvr/cvs206.

    Article  CAS  PubMed  Google Scholar 

  43. Lahti AL, Kujala VJ, Chapman H, Koivisto AP, Pekkanen-Mattila M, Kerkela E, et al. Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Dis Models Mech. 2012;5(2):220–30. doi:10.1242/dmm.008409.

    Article  CAS  Google Scholar 

  44. Ma D, Wei H, Zhao Y, Lu J, Li G, Sahib NB, et al. Modeling type 3 long QT syndrome with cardiomyocytes derived from patient-specific induced pluripotent stem cells. Int J Cardiol. 2013;168(6):5277–86. doi:10.1016/j.ijcard.2013.08.015.

    Article  PubMed  Google Scholar 

  45. Fatima A, Kaifeng S, Dittmann S, Xu G, Gupta MK, Linke M, et al. The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients. PLoS One. 2013;8(12):e83005. doi:10.1371/journal.pone.0083005.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Terrenoire C, Wang K, Tung KW, Chung WK, Pass RH, Lu JT, et al. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J Gen Physiol. 2013;141(1):61–72. doi:10.1085/jgp.201210899.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Jonsson MK, Vos MA, Mirams GR, Duker G, Sartipy P, de Boer TP, et al. Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG. J Mol Cell Cardiol. 2012;52(5):998–1008. doi:10.1016/j.yjmcc.2012.02.002.

    Article  CAS  PubMed  Google Scholar 

  48. Jung CB, Moretti A, Mederos y Schnitzler M, Iop L, Storch U, Bellin M, et al. Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol Med. 2012;4(3):180–91. doi:10.1002/emmm.201100194.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Kujala K, Paavola J, Lahti A, Larsson K, Pekkanen-Mattila M, Viitasalo M, et al. Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations. PLoS One. 2012;7(9):e44660. doi:10.1371/journal.pone.0044660.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Zhang XH, Haviland S, Wei H, Saric T, Fatima A, Hescheler J, et al. Ca2+ signaling in human induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) from normal and catecholaminergic polymorphic ventricular tachycardia (CPVT)-afflicted subjects. Cell Calcium. 2013;54(2):57–70. doi:10.1016/j.ceca.2013.04.004.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Novak A, Barad L, Zeevi-Levin N, Shick R, Shtrichman R, Lorber A, et al. Cardiomyocytes generated from CPVTD307H patients are arrhythmogenic in response to beta-adrenergic stimulation. J Cell Mol Med. 2012;16(3):468–82. doi:10.1111/j.1582-4934.2011.01476.x.

    Article  CAS  PubMed  Google Scholar 

  52. Satin J, Itzhaki I, Rapoport S, Schroder EA, Izu L, Arbel G, et al. Calcium handling in human embryonic stem cell-derived cardiomyocytes. Stem Cells. 2008;26(8):1961–72. doi:10.1634/stemcells.2007-0591.

    Article  CAS  PubMed  Google Scholar 

  53. Caspi O, Huber I, Gepstein A, Arbel G, Maizels L, Boulos M, et al. Modeling of arrhythmogenic right ventricular cardiomyopathy with human induced pluripotent stem cells. Circ Cardiovasc Genet. 2013;6(6):557–68. doi:10.1161/CIRCGENETICS.113.000188.

    Article  CAS  PubMed  Google Scholar 

  54. Huang HP, Chen PH, Hwu WL, Chuang CY, Chien YH, Stone L, et al. Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification. Hum Mol Genet. 2011;20(24):4851–64. doi:10.1093/hmg/ddr424.

    Article  CAS  PubMed  Google Scholar 

  55. Zwi L, Caspi O, Arbel G, Huber I, Gepstein A, Park IH, et al. Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation. 2009;120(15):1513–23. doi:10.1161/CIRCULATIONAHA.109.868885.

    Article  CAS  PubMed  Google Scholar 

  56. Mummery CL, Zhang J, Ng ES, Elliott DA, Elefanty AG, Kamp TJ. Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. Circ Res. 2012;111(3):344–58. doi:10.1161/CIRCRESAHA.110.227512.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, Peters A, et al. A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS One. 2011;6(4):e18293. doi:10.1371/journal.pone.0018293.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Xu C, Police S, Hassanipour M, Li Y, Chen Y, Priest C, et al. Efficient generation and cryopreservation of cardiomyocytes derived from human embryonic stem cells. Regen Med. 2011;6(1):53–66. doi:10.2217/rme.10.91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. 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(6):e11134. doi:10.1371/journal.pone.0011134.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  60. Cao N, Liu Z, Chen Z, Wang J, Chen T, Zhao X, et al. Ascorbic acid enhances the cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells. Cell Res. 2012;22(1):219–36. doi:10.1038/cr.2011.195.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Chetty S, Pagliuca FW, Honore C, Kweudjeu A, Rezania A, Melton DA. A simple tool to improve pluripotent stem cell differentiation. Nat Methods. 2013;10(6):553–6. doi:10.1038/nmeth.2442.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Xu C. Differentiation and enrichment of cardiomyocytes from human pluripotent stem cells. J Mol Cell Cardiol. 2012;52(6):1203–12. doi:10.1016/j.yjmcc.2012.03.012.

    Article  CAS  PubMed  Google Scholar 

  63. Bizy A, Guerrero-Serna G, Hu B, Ponce-Balbuena D, Willis BC, Zarzoso M, et al. Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes. Stem Cell Res. 2013;11(3):1335–47. doi:10.1016/j.scr.2013.09.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Elliott DA, Braam SR, Koutsis K, Ng ES, Jenny R, Lagerqvist EL, et al. NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat Methods. 2011;8(12):1037–40. doi:10.1038/nmeth.1740.

    Article  CAS  PubMed  Google Scholar 

  65. Kita-Matsuo H, Barcova M, Prigozhina N, Salomonis N, Wei K, Jacot JG, 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(4):e5046. doi:10.1371/journal.pone.0005046. Enrichment of cardiomyocyte populations from heterogeneous differentiated preparations of hPSCs can be done by various methods. Transgenic α-MHC promoter driven selectional markers is a common preferred method across many groups.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Tohyama S, Hattori F, Sano M, Hishiki T, Nagahata Y, Matsuura T, et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2013;12(1):127–37. doi:10.1016/j.stem.2012.09.013.

    Article  CAS  PubMed  Google Scholar 

  67. Hattori F, Chen H, Yamashita H, Tohyama S, Satoh YS, Yuasa S, et al. Nongenetic method for purifying stem cell-derived cardiomyocytes. Nat Methods. 2010;7(1):61–6. doi:10.1038/nmeth.1403.

    Article  CAS  PubMed  Google Scholar 

  68. Dubois NC, Craft AM, Sharma P, Elliott DA, Stanley EG, Elefanty AG, et al. SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nat Biotechnol. 2011;29(11):1011–8. doi:10.1038/nbt.2005.

    Article  CAS  PubMed  Google Scholar 

  69. Uosaki H, Fukushima H, Takeuchi A, Matsuoka S, Nakatsuji N, Yamanaka S, et al. Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface expression. PLoS One. 2011;6(8):e23657. doi:10.1371/journal.pone.0023657.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Nunes SS, Miklas JW, Liu J, Aschar-Sobbi R, Xiao Y, Zhang B, et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat Methods. 2013;10(8):781–7. doi:10.1038/nmeth.2524.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Lieu DK, Fu JD, Chiamvimonvat N, Tung KC, McNerney GP, Huser T, et al. Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythmia Electrophysiol. 2013;6(1):191–201. doi:10.1161/CIRCEP.111.973420.

    Article  Google Scholar 

  72. Lee P, Klos M, Bollensdorff C, Hou L, Ewart P, Kamp TJ, et al. Simultaneous voltage and calcium mapping of genetically purified human induced pluripotent stem cell-derived cardiac myocyte monolayers. Circ Res. 2012;110(12):1556–63. doi:10.1161/CIRCRESAHA.111.262535. Fluorescent indicators of voltage and calcium dynamics may emerge as a preferred, non-invasive method for hPSC-CM phenotyping, as undertaken in cell monolayers in this study by Lee and colleagues.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Mitcheson JS, Hancox JC, Levi AJ. Cultured adult cardiac myocytes: future applications, culture methods, morphological and electrophysiological properties. Cardiovasc Res. 1998;39(2):280–300.

    Article  CAS  PubMed  Google Scholar 

  74. Louch WE, Sheehan KA, Wolska BM. Methods in cardiomyocyte isolation, culture, and gene transfer. J Mol Cell Cardiol. 2011;51(3):288–98. doi:10.1016/j.yjmcc.2011.06.012.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Kim C, Majdi M, Xia P, Wei KA, Talantova M, Spiering S, et al. Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation. Stem Cell Dev. 2010;19(6):783–95. doi:10.1089/scd.2009.0349.

    Article  CAS  Google Scholar 

  76. Uesugi M, Ojima A, Taniguchi T, Miyamoto N, Sawada K. Low-density plating is sufficient to induce cardiac hypertrophy and electrical remodeling in highly purified human iPS cell-derived cardiomyocytes. J Pharmacol Toxicol Meth. 2013. doi:10.1016/j.vascn.2013.11.002.

    Google Scholar 

  77. Neher E, Sakmann B. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature. 1976;260(5554):799–802.

    Article  CAS  PubMed  Google Scholar 

  78. Milligan CJ, Moller C. Automated planar patch-clamp. Methods Mol Biol. 2013;998:171–87. doi:10.1007/978-1-62703-351-0_13.

    Article  PubMed  Google Scholar 

  79. Stoelzle S, Obergrussberger A, Bruggemann A, Haarmann C, George M, Kettenhofen R, et al. State-of-the-Art Automated Patch Clamp Devices: Heat Activation, Action Potentials, and High Throughput in Ion Channel Screening. Front Pharmacol. 2011;2:76. doi:10.3389/fphar.2011.00076.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Yajuan X, Xin L, Zhiyuan L. A comparison of the performance and application differences between manual and automated patch-clamp techniques. Curr Chem Genom. 2012;6:87–92. doi:10.2174/1875397301206010087.

    Article  Google Scholar 

  81. Harris K, Aylott M, Cui Y, Louttit JB, McMahon NC, Sridhar A. Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays. Toxicol Sci. 2013;134(2):412–26. doi:10.1093/toxsci/kft113.

    Article  CAS  PubMed  Google Scholar 

  82. Igelmund P, Fleischmann BK, Fischer IR, Soest J, Gryshchenko O, Bohm-Pinger MM, et al. Action potential propagation failures in long-term recordings from embryonic stem cell-derived cardiomyocytes in tissue culture. Pflugers Arch. 1999;437(5):669–79.

    Article  CAS  PubMed  Google Scholar 

  83. Caspi O, Itzhaki I, Kehat I, Gepstein A, Arbel G, Huber I, et al. In vitro electrophysiological drug testing using human embryonic stem-cell–derived cardiomyocytes. Stem Cell Dev. 2009;18(1):161–72. doi:10.1089/scd.2007.0280.

    Article  CAS  Google Scholar 

  84. Mandel Y, Weissman A, Schick R, Barad L, Novak A, Meiry G, et al. Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior. Circulation. 2012;125(7):883–93. doi:10.1161/CIRCULATIONAHA.111.045146.

    Article  PubMed Central  PubMed  Google Scholar 

  85. Herron TJ, Lee P, Jalife J. Optical imaging of voltage and calcium in cardiac cells & tissues. Circ Res. 2012;110(4):609–23. doi:10.1161/CIRCRESAHA.111.247494. A comprehensive and up-to-date review of optical mapping of voltage and calcium signals using small molecule dyes in cardiac tissue and cells.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Schaffer P, Ahammer H, Muller W, Koidl B, Windisch H. Di-4-ANEPPS causes photodynamic damage to isolated cardiomyocytes. Pflugers Arch. 1994;426(6):548–51.

    Article  CAS  PubMed  Google Scholar 

  87. Hardy ME, Lawrence CL, Standen NB, Rodrigo GC. Can optical recordings of membrane potential be used to screen for drug-induced action potential prolongation in single cardiac myocytes? J Pharmacol Toxicol Meth. 2006;54(2):173–82. doi:10.1016/j.vascn.2006.02.013.

    Article  CAS  Google Scholar 

  88. Liau B, Zhang D, Bursac N. Functional cardiac tissue engineering. Regen Med. 2012;7(2):187–206. doi:10.2217/rme.11.122.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Sirenko O, Crittenden C, Callamaras N, Hesley J, Chen YW, Funes C, et al. Multiparameter in vitro assessment of compound effects on cardiomyocyte physiology using iPSC cells. J Biomol Screen. 2013;18(1):39–53. doi:10.1177/1087057112457590.

    Article  PubMed  CAS  Google Scholar 

  90. Cerignoli F, Charlot D, Whittaker R, Ingermanson R, Gehalot P, Savchenko A, et al. High throughput measurement of Ca(2)(+) dynamics for drug risk assessment in human stem cell-derived cardiomyocytes by kinetic image cytometry. J Pharmacol Toxicol Meth. 2012;66(3):246–56. doi:10.1016/j.vascn.2012.08.167.

    Article  CAS  Google Scholar 

  91. Jin L, Han Z, Platisa J, Wooltorton JR, Cohen LB, Pieribone VA. Single action potentials and subthreshold electrical events imaged in neurons with a fluorescent protein voltage probe. Neuron. 2012;75(5):779–85. doi:10.1016/j.neuron.2012.06.040.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Cao G, Platisa J, Pieribone VA, Raccuglia D, Kunst M, Nitabach MN. Genetically targeted optical electrophysiology in intact neural circuits. Cell. 2013;154(4):904–13. doi:10.1016/j.cell.2013.07.027.

    Article  CAS  PubMed  Google Scholar 

  93. Kralj JM, Douglass AD, Hochbaum DR, Maclaurin D, Cohen AE. Optical recording of action potentials in mammalian neurons using a microbial rhodopsin. Nat Methods. 2012;9(1):90–5. doi:10.1038/nmeth.1782.

    Article  CAS  Google Scholar 

  94. Tsutsui H, Jinno Y, Tomita A, Niino Y, Yamada Y, Mikoshiba K, et al. Improved detection of electrical activity with a voltage probe based on a voltage-sensing phosphatase. J Physiol. 2013;591(Pt 18):4427–37. doi:10.1113/jphysiol.2013.257048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhao Y, Araki S, Wu J, Teramoto T, Chang YF, Nakano M, et al. An expanded palette of genetically encoded Ca(2)(+) indicators. Science. 2011;333(6051):1888–91. doi:10.1126/science.1208592.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Leyton-Mange JS, Mills RW, Macri VS, Jang MY, Butte FN, Ellinor PT, et al. Rapid Cellular Phenotyping of Human Pluripotent Stem Cell-Derived Cardiomyocytes using a Genetically Encoded Fluorescent Voltage Sensor. Stem Cell Reports. 2014;2(2):163–70. doi:10.1016/j.stemcr.2014.01.003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Sheehy SP, Pasqualini F, Grosberg A, Park SJ, Aratyn-Schaus Y, Parker KK. Quality metrics for stem cell-derived cardiac myocytes. Stem Cell Reports. 2014;2(3):282–94. doi:10.1016/j.stemcr.2014.01.015.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Chi KR. Revolution dawning in cardiotoxicity testing. Nat Rev Drug Discov. 2013;12(8):565–7. doi:10.1038/nrd4083.

    Article  CAS  PubMed  Google Scholar 

  99. Mehta A, Sequiera GL, Ramachandra CJ, Sudibyo Y, Chung Y, Jingwei S, et al. Re-trafficking of HERG Reverses Long QT Syndrome 2 Phenotype in Human iPS-derived Cardiomyocytes. Cardiovasc Res. 2014. doi:10.1093/cvr/cvu060.

    Google Scholar 

  100. Fatima A, Xu G, Shao K, Papadopoulos S, Lehmann M, Arnaiz-Cot JJ, et al. In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol. 2011;28(4):579–92. doi:10.1159/000335753.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors thank Drs. Nathan Tucker, Robert Mills, and Patrick Ellinor for critical reading of this manuscript and helpful comments. This works was supported by the Corrigan Minehan Foundation (DJM), Harvard Stem Cell Institute (DJM), and NIH grants R01HL109004 (DJM) and T32HL007208 (JLM).

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Dr. Jordan S. Leyton-Mange and Dr. David J. Milan each declare no potential conflicts of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Cardiovasc Res Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA

    Jordan S. Leyton-Mange MD & David J. Milan MD

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  1. Jordan S. Leyton-Mange MD
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  2. David J. Milan MD
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Correspondence to David J. Milan MD.

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This article is part of the Topical Collection on Regenerative Medicine and Stem-Cell Therapy

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Leyton-Mange, J.S., Milan, D.J. Pluripotent Stem Cells as a Platform for Cardiac Arrhythmia Drug Screening. Curr Treat Options Cardio Med 16, 334 (2014). https://doi.org/10.1007/s11936-014-0334-1

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