In Vitro Uses of Human Pluripotent Stem Cell-Derived Cardiomyocytes

Article

Abstract

Functional cardiomyocytes can be efficiently derived from human pluripotent stem cells (hPSCs), which collectively include embryonic and induced pluripotent stem cells. This cellular platform presents exciting new opportunities for development of pharmacologically relevant in vitro screens to detect cardiotoxicity, validate novel drug candidates in preclinical trials and understand complex congenital cardiovascular disorders, to advance current clinical therapies. Here, we discuss the progress and impediments the field has faced in using hPSC-derived cardiomyocytes for these in vitro applications, and highlight that rigorous protocol optimisation and standardisation, scalability and automation are remaining obstacles for the generation of pure, mature and clinically relevant hPSC cardiomyocytes.

Keywords

Human pluripotent stem cells Cardiomyocytes Drug screening Toxicology Safety pharmacology Disease modelling Genetic manipulation 

Notes

Acknowledgments

The authors’ work is supported by the British Heart Foundation, Medical Research Council, Engineering and Physical Sciences Research Council, and Biotechnology and Biological Sciences Research Council.

Conflict of Interest

The authors declare no conflict of interest.

References

  1. 1.
    Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.PubMedGoogle Scholar
  2. 2.
    Reubinoff, B. E., Pera, M. F., Fong, C. Y., Trounson, A., & Bongso, A. (2000). Embryonic stem cell lines from human blastocysts: Somatic differentiation in vitro. Nature Biotechnology, 18(4), 399–404. doi: 10.1038/74447.PubMedGoogle Scholar
  3. 3.
    Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920. doi: 10.1126/science.1151526.PubMedGoogle Scholar
  4. 4.
    Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151), 313–317. doi: 10.1038/nature05934.PubMedGoogle Scholar
  5. 5.
    Davis, R. P., van den Berg, C. W., Casini, S., Braam, S. R., & Mummery, C. L. (2011). Pluripotent stem cell models of cardiac disease and their implication for drug discovery and development. Trends in Molecular Medicine, 17(9), 475–484. doi: 10.1016/j.molmed.2011.05.001.PubMedGoogle Scholar
  6. 6.
    Pera, M. F., Reubinoff, B., & Trounson, A. (2000). Human embryonic stem cells. Journal of Cell Science, 113(Pt 1), 5–10.PubMedGoogle Scholar
  7. 7.
    Denning, C., Allegrucci, C., Priddle, H., Barbadillo-Munoz, M. D., Anderson, D., Self, T., et al. (2006). Common culture conditions for maintenance and cardiomyocyte differentiation of the human embryonic stem cell lines, BG01 and HUES-7. International Journal of Developmental Biology, 50(1), 27–37. doi: 10.1387/ijdb.052107cd.PubMedGoogle Scholar
  8. 8.
    Harb, N., Archer, T. K., & Sato, N. (2008). The Rho-Rock-Myosin signaling axis determines cell-cell integrity of self-renewing pluripotent stem cells. PLoS One, 3(8), e3001. doi: 10.1371/journal.pone.0003001.PubMedGoogle Scholar
  9. 9.
    Mahlstedt, M. M., Anderson, D., Sharp, J. S., McGilvray, R., Munoz, M. D., Buttery, L. D., et al. (2009). Maintenance of pluripotency in human embryonic stem cells cultured on a synthetic substrate in conditioned medium. Biotechnology and Bioengineering, 105(1), 130–140. doi: 10.1002/bit.22520.Google Scholar
  10. 10.
    Desbordes, S. C., Placantonakis, D. G., Ciro, A., Socci, N. D., Lee, G., Djaballah, H., et al. (2008). High-throughput screening assay for the identification of compounds regulating self-renewal and differentiation in human embryonic stem cells. Cell Stem Cell, 2(6), 602–612. doi: 10.1016/j.stem.2008.05.010.PubMedGoogle Scholar
  11. 11.
    Krawetz, R., Taiani, J. T., Liu, S., Meng, G., Li, X., Kallos, M. S., et al. (2009). Large-scale expansion of pluripotent human embryonic stem cells in stirred-suspension bioreactors. Tissue Engineering. Part C, Methods, 16(4), 573–582. doi: 10.1089/ten.TEC.2009.0228.Google Scholar
  12. 12.
    Li, Y., Powell, S., Brunette, E., Lebkowski, J., & Mandalam, R. (2005). Expansion of human embryonic stem cells in defined serum-free medium devoid of animal-derived products. Biotechnology and Bioengineering, 91(6), 688–698. doi: 10.1002/bit.20536.PubMedGoogle Scholar
  13. 13.
    Ludwig, T. E., Bergendahl, V., Levenstein, M. E., Yu, J., Probasco, M. D., & Thomson, J. A. (2006). Feeder-independent culture of human embryonic stem cells. Nature Methods, 3(8), 637–646. doi: 10.1038/nmeth902.PubMedGoogle Scholar
  14. 14.
    Wang, L., Schulz, T. C., Sherrer, E. S., Dauphin, D. S., Shin, S., Nelson, A. M., et al. (2007). Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Blood, 110(12), 4111–4119. doi: 10.1182/blood-2007-03-082586.PubMedGoogle Scholar
  15. 15.
    Chen, G., Gulbranson, D. R., Hou, Z., Bolin, J. M., Ruotti, V., Probasco, M. D., et al. (2011). Chemically defined conditions for human iPSC derivation and culture. Nature Methods, 8(5), 424–429. doi: 10.1038/nmeth.1593.PubMedGoogle Scholar
  16. 16.
    Thomas, R. J., Anderson, D., Chandra, A., Smith, N. M., Young, L. E., Williams, D., et al. (2009). Automated, scalable culture of human embryonic stem cells in feeder-free conditions. Biotechnology and Bioengineering, 102(6), 1636–1644. doi: 10.1002/bit.22187.PubMedGoogle Scholar
  17. 17.
    Moore, J. C., van Laake, L. W., Braam, S. R., Xue, T., Tsang, S. Y., Ward, D., et al. (2005). Human embryonic stem cells: Genetic manipulation on the way to cardiac cell therapies. Reproductive Toxicology, 20(3), 377–391. doi: 10.1016/j.reprotox.2005.04.012.PubMedGoogle Scholar
  18. 18.
    Gropp, M., Itsykson, P., Singer, O., Ben-Hur, T., Reinhartz, E., Galun, E., et al. (2003). Stable genetic modification of human embryonic stem cells by lentiviral vectors. Molecular Therapy, 7(2), 281–287.PubMedGoogle Scholar
  19. 19.
    Vallier, L., Rugg-Gunn, P. J., Bouhon, I. A., Andersson, F. K., Sadler, A. J., & Pedersen, R. A. (2004). Enhancing and diminishing gene function in human embryonic stem cells. Stem Cells, 22(1), 2–11. doi: 10.1634/stemcells.22-1-2.PubMedGoogle Scholar
  20. 20.
    Liu, Y. P., Dovzhenko, O. V., Garthwaite, M. A., Dambaeva, S. V., Durning, M., Pollastrini, L. M., et al. (2004). Maintenance of pluripotency in human embryonic stem cells stably over-expressing enhanced green fluorescent protein. Stem Cells and Development, 13(6), 636–645. doi: 10.1089/scd.2004.13.636.PubMedGoogle Scholar
  21. 21.
    Eiges, R., Schuldiner, M., Drukker, M., Yanuka, O., Itskovitz-Eldor, J., & Benvenisty, N. (2001). Establishment of human embryonic stem cell-transfected clones carrying a marker for undifferentiated cells. Current Biology, 11(7), 514–518.PubMedGoogle Scholar
  22. 22.
    Gerrard, L., Zhao, D., Clark, A. J., & Cui, W. (2005). Stably transfected human embryonic stem cell clones express OCT4-specific green fluorescent protein and maintain self-renewal and pluripotency. Stem Cells, 23(1), 124–133. doi: 10.1634/stemcells.2004-0102.PubMedGoogle Scholar
  23. 23.
    Braam, S. R., Denning, C., Matsa, E., Young, L. E., Passier, R., & Mummery, C. L. (2008). Feeder-free culture of human embryonic stem cells in conditioned medium for efficient genetic modification. Nature Protocols, 3(9), 1435–1443. doi: 10.1038/nprot.2008.140.PubMedGoogle Scholar
  24. 24.
    Chang, T., Zheng, W., Tsark, W., Bates, S., Huang, H., Lin, R. J., et al. (2011). Brief report: Phenotypic rescue of induced pluripotent stem cell-derived motoneurons of a spinal muscular atrophy patient. Stem Cells, 29(12), 2090–2093. doi: 10.1002/stem.749.PubMedGoogle Scholar
  25. 25.
    Hay, D. C., Sutherland, L., Clark, J., & Burdon, T. (2004). Oct-4 knockdown induces similar patterns of endoderm and trophoblast differentiation markers in human and mouse embryonic stem cells. Stem Cells, 22(2), 225–235. doi: 10.1634/stemcells.22-2-225.PubMedGoogle Scholar
  26. 26.
    Liu, G. H., Barkho, B. Z., Ruiz, S., Diep, D., Qu, J., Yang, S. L., et al. (2011). Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome. Nature, 472(7342), 221–225. doi: 10.1038/nature09879.PubMedGoogle Scholar
  27. 27.
    Costa, M., Dottori, M., Sourris, K., Jamshidi, P., Hatzistavrou, T., Davis, R., et al. (2007). A method for genetic modification of human embryonic stem cells using electroporation. Nature Protocols, 2(4), 792–796. doi: 10.1038/nprot.2007.105.PubMedGoogle Scholar
  28. 28.
    Hockemeyer, D., Wang, H., Kiani, S., Lai, C. S., Gao, Q., Cassady, J. P., et al. (2011). Genetic engineering of human pluripotent cells using TALE nucleases. Nature Biotechnology, 29(8), 731–734. doi: 10.1038/nbt.1927.PubMedGoogle Scholar
  29. 29.
    Zwaka, T. P., & Thomson, J. A. (2003). Homologous recombination in human embryonic stem cells. Nature Biotechnology, 21(3), 319–321. doi: 10.1038/nbt788.PubMedGoogle Scholar
  30. 30.
    Elliott, D. A., Braam, S. R., Koutsis, K., Ng, E. S., Jenny, R., Lagerqvist, E. L., et al. (2011). NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nature Methods, 8(12), 1037–1040. doi: 10.1038/nmeth.1740.PubMedGoogle Scholar
  31. 31.
    Davis RP, Grandela C, Sourris K, Hatzistavrou T, Dottori M, Elefanty AG, Stanley EG, Costa M (2009) Generation of human embryonic stem cell reporter knock-in lines by homologous recombination. Curr Protoc Stem Cell Biol Chapter 5:Unit 5B 1 1 1–34. doi: 10.1002/9780470151808.sc05b01s11
  32. 32.
    Nieminen, M., Tuuri, T., & Savilahti, H. (2010). Genetic recombination pathways and their application for genome modification of human embryonic stem cells. Experimental Cell Research, 316(16), 2578–2586. doi: 10.1016/j.yexcr.2010.06.004.PubMedGoogle Scholar
  33. 33.
    Tolar, J., Xia, L., Riddle, M. J., Lees, C. J., Eide, C. R., McElmurry, R. T., et al. (2011). Induced pluripotent stem cells from individuals with recessive dystrophic epidermolysis bullosa. The Journal of Investigative Dermatology, 131(4), 848–856. doi: 10.1038/jid.2010.346.PubMedGoogle Scholar
  34. 34.
    Sebastiano, V., Maeder, M. L., Angstman, J. F., Haddad, B., Khayter, C., Yeo, D. T., et al. (2011). In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Stem Cells, 29(11), 1717–1726. doi: 10.1002/stem.718.PubMedGoogle Scholar
  35. 35.
    Wang, Y., Zheng, C. G., Jiang, Y., Zhang, J., Chen, J., Yao, C., et al. (2012). Genetic correction of beta-thalassemia patient-specific iPS cells and its use in improving hemoglobin production in irradiated SCID mice. Cell Research. doi: 10.1038/cr.2012.23.
  36. 36.
    Narsinh, K., Narsinh, K. H., & Wu, J. C. (2011). Derivation of human induced pluripotent stem cells for cardiovascular disease modeling. Circulation Research, 108(9), 1146–1156. doi: 10.1161/CIRCRESAHA.111.240374.PubMedGoogle Scholar
  37. 37.
    Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y. H., Li, H., Lau, F., et al. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, 7(5), 618–630. doi: 10.1016/j.stem.2010.08.012.PubMedGoogle Scholar
  38. 38.
    Onder, T. T., Kara, N., Cherry, A., Sinha, A. U., Zhu, N., Bernt, K. M., et al. (2012). Chromatin-modifying enzymes as modulators of reprogramming. Nature. doi: 10.1038/nature10953.
  39. 39.
    Hanna, J., Markoulaki, S., Schorderet, P., Carey, B. W., Beard, C., Wernig, M., et al. (2008). Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell, 133(2), 250–264. doi: 10.1016/j.cell.2008.03.028.PubMedGoogle Scholar
  40. 40.
    Aoi, T., Yae, K., Nakagawa, M., Ichisaka, T., Okita, K., Takahashi, K., Chiba, T., & Yamanaka, S. (2008). Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science, 321(5889), 699–702. doi: 10.1126/science.1154884 PubMedGoogle Scholar
  41. 41.
    Haase, A., Olmer, R., Schwanke, K., Wunderlich, S., Merkert, S., Hess, C., et al. (2009). Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell, 5(4), 434–441. doi: 10.1016/j.stem.2009.08.021.PubMedGoogle Scholar
  42. 42.
    Ghosh, Z., Wilson, K. D., Wu, Y., Hu, S., Quertermous, T., & Wu, J. C. (2010). Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS One, 5(2), e8975. doi: 10.1371/journal.pone.0008975.PubMedGoogle Scholar
  43. 43.
    Burridge, P. W., Anderson, D., Priddle, H., Barbadillo Munoz, M. D., Chamberlain, S., Allegrucci, C., et al. (2007). Improved human embryonic stem cell embryoid body homogeneity and cardiomyocyte differentiation from a novel V-96 plate aggregation system highlights interline variability. Stem Cells, 25(4), 929–938. doi: 10.1634/stemcells.2006-0598.PubMedGoogle Scholar
  44. 44.
    Burridge, P. W., Keller, G., Gold, J. D., & Wu, J. C. (2012). Production of de novo cardiomyocytes: Human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell, 10(1), 16–28. doi: 10.1016/j.stem.2011.12.013.PubMedGoogle Scholar
  45. 45.
    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(21), 2733–2740. doi: 10.1161/01.CIR.0000068356.38592.68.PubMedGoogle Scholar
  46. 46.
    Burridge, P. W., Thompson, S., Millrod, M. A., 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(4), e18293. doi: 10.1371/journal.pone.0018293.PubMedGoogle Scholar
  47. 47.
    Kattman, S. J., Witty, A. D., Gagliardi, M., Dubois, N. C., 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(2), 228–240. doi: 10.1016/j.stem.2010.12.008.PubMedGoogle Scholar
  48. 48.
    Yu, P., Pan, G., Yu, J., & Thomson, J. A. (2011). FGF2 sustains NANOG and switches the outcome of BMP4-induced human embryonic stem cell differentiation. Cell Stem Cell, 8(3), 326–334. doi: 10.1016/j.stem.2011.01.001.PubMedGoogle Scholar
  49. 49.
    Paige, S. L., Osugi, T., Afanasiev, O. K., Pabon, L., Reinecke, H., & Murry, C. E. (2010). Endogenous Wnt/beta-catenin signaling is required for cardiac differentiation in human embryonic stem cells. PLoS One, 5(6), e11134. doi: 10.1371/journal.pone. 0011134.PubMedGoogle Scholar
  50. 50.
    Martinez-Fernandez, A., Nelson, T. J., Ikeda, Y., & Terzic, A. (2010). c-MYC independent nuclear reprogramming favors cardiogenic potential of induced pluripotent stem cells. Journal of Cardiovascular Translational Research, 3(1), 13–23. doi: 10.1007/s12265-009-9150-5.PubMedGoogle Scholar
  51. 51.
    Anderson, D., Self, T., Mellor, I. R., Goh, G., Hill, S. J., & Denning, C. (2007). Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Molecular Therapy, 15(11), 2027–2036. doi: 10.1038/sj.mt.6300303.PubMedGoogle Scholar
  52. 52.
    Huber, I., Itzhaki, I., Caspi, O., Arbel, G., Tzukerman, M., Gepstein, A., et al. (2007). Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. The FASEB Journal, 21(10), 2551–2563. doi: 10.1096/fj.05-5711com.Google Scholar
  53. 53.
    Dubois, N. C., Craft, A. M., Sharma, P., Elliott, D. A., Stanley, E. G., Elefanty, A. G., et al. (2011). SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nature Biotechnology, 29(11), 1011–1018. doi: 10.1038/nbt.2005.PubMedGoogle Scholar
  54. 54.
    Van Hoof, D., Dormeyer, W., Braam, S. R., Passier, R., Monshouwer-Kloots, J., Ward-van Oostwaard, D., et al. (2010). Identification of cell surface proteins for antibody-based selection of human embryonic stem cell-derived cardiomyocytes. Journal of Proteome Research, 9(3), 1610–1618. doi: 10.1021/pr901138a.PubMedGoogle Scholar
  55. 55.
    Chan, J. W., Lieu, D. K., Huser, T., & Li, R. A. (2009). Label-free separation of human embryonic stem cells and their cardiac derivatives using Raman spectroscopy. Analytical Chemistry, 81(4), 1324–1331. doi: 10.1021/ac801665m.PubMedGoogle Scholar
  56. 56.
    Pascut, F. C., Goh, H. T., George, V., Denning, C., & Notingher, I. (2011). Toward label-free Raman-activated cell sorting of cardiomyocytes derived from human embryonic stem cells. Journal of Biomedical Optics, 16(4), 045002. doi: 10.1117/1.3570302.PubMedGoogle Scholar
  57. 57.
    Zhang, J., Wilson, G. F., Soerens, A. G., Koonce, C. H., Yu, J., Palecek, S. P., et al. (2009). Functional cardiomyocytes derived from human induced pluripotent stem cells. Circulation Research, 104(4), e30–e41. doi: 10.1161/CIRCRESAHA.108.192237.PubMedGoogle Scholar
  58. 58.
    Fu, J.-D., H-f, T., Siu, C.-W., Moore, J. C., Lieu, D. K., Liao, S.-Y., et al. (2008). Driven maturation of embryonic stem cell-derived cardiomyocytes confers post-transplantation safety. Cell Research, 18(S1), S132.Google Scholar
  59. 59.
    Otsuji, T. G., Minami, I., Kurose, Y., Yamauchi, K., Tada, M., & Nakatsuji, N. (2010). Progressive maturation in contracting cardiomyocytes derived from human embryonic stem cells: Qualitative effects on electrophysiological responses to drugs. Stem Cell Research, 4(3), 201–213. doi: 10.1016/j.scr.2010.01.002.PubMedGoogle Scholar
  60. 60.
    Rajala, K., Pekkanen-Mattila, M., & Aalto-Setala, K. (2011). Cardiac differentiation of pluripotent stem cells. Stem Cells International, 2011, 383709. doi: 10.4061/2011/383709.PubMedGoogle Scholar
  61. 61.
    Beqqali, A., Kloots, J., Ward-van Oostwaard, D., Mummery, C., & Passier, R. (2006). Genome-wide transcriptional profiling of human embryonic stem cells differentiating to cardiomyocytes. Stem Cells, 24(8), 1956–1967. doi: 10.1634/stemcells.2006-0054.PubMedGoogle Scholar
  62. 62.
    Bu, L., Jiang, X., Martin-Puig, S., Caron, L., Zhu, S., Shao, Y., et al. (2009). Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature, 460(7251), 113–117. doi: 10.1038/nature08191.PubMedGoogle Scholar
  63. 63.
    Xu, H., Yi, B. A., & Chien, K. R. (2011). Shortcuts to making cardiomyocytes. Nature Cell Biology, 13(3), 191–193. doi: 10.1038/ncb0311-191.PubMedGoogle Scholar
  64. 64.
    Hudson, J. E., & Zimmermann, W. H. (2011). Tuning Wnt-signaling to enhance cardiomyogenesis in human embryonic and induced pluripotent stem cells. Journal of Molecular and Cellular Cardiology, 51(3), 277–279. doi: 10.1016/j.yjmcc.2011.06.011.PubMedGoogle Scholar
  65. 65.
    Dickson, M., & Gagnon, J. P. (2004). Key factors in the rising cost of new drug discovery and development. Nature Reviews. Drug Discovery, 3(5), 417–429.PubMedGoogle Scholar
  66. 66.
    Terrar, D. A., Wilson, C. M., Graham, S. G., Bryant, S. M., & Heath, B. M. (2007). Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization. Journal of Pharmacological and Toxicological Methods, 56(2), 171–185. doi: 10.1016/j.vascn.2007.04.005.PubMedGoogle Scholar
  67. 67.
    Pouton, C. W., & Haynes, J. M. (2007). Embryonic stem cells as a source of models for drug discovery. Nature Reviews. Drug Discovery, 6(8), 605–616. doi: 10.1038/nrd2194.PubMedGoogle Scholar
  68. 68.
    Fermini, B., & Fossa, A. A. (2003). The impact of drug-induced QT interval prolongation on drug discovery and development. Nature Reviews. Drug Discovery, 2(6), 439–447. doi: 10.1038/nrd1108.PubMedGoogle Scholar
  69. 69.
    Dick, E., Rajamohan, D., Ronksley, J., & Denning, C. (2010). Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening. Biochemical Society Transactions, 38(4), 1037–1045. doi: 10.1042/BST0381037.PubMedGoogle Scholar
  70. 70.
    Ma, J., Guo, L., Fiene, S. J., Anson, B. D., Thomson, J. A., Kamp, T. J., et al. (2011). High purity human-induced pluripotent stem cell-derived cardiomyocytes: Electrophysiological properties of action potentials and ionic currents. American Journal of Physiology—Heart and Circulatory Physiology, 301(5), H2006–H2017. doi: 10.1152/ajpheart.00694.2011.PubMedGoogle Scholar
  71. 71.
    Mehta, A., Chung, Y. Y., Ng, A., Iskandar, F., Atan, S., Wei, H., et al. (2011). Pharmacological response of human cardiomyocytes derived from virus-free induced pluripotent stem cells. Cardiovascular Research, 91(4), 577–586. doi: 10.1093/cvr/cvr132.PubMedGoogle Scholar
  72. 72.
    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. Biochemical and Biophysical Research Communications, 387(3), 482–488. doi: 10.1016/j.bbrc.2009.07.052.PubMedGoogle Scholar
  73. 73.
    Braam, S. R., Tertoolen, L., van de Stolpe, A., Meyer, T., Passier, R., & Mummery, C. L. (2010). Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Research, 4(2), 107–116. doi: 10.1016/j.scr.2009.11.004.PubMedGoogle Scholar
  74. 74.
    Mummery, C. L., Davis, R. P., & Krieger, J. E. (2010). Challenges in using stem cells for cardiac repair. Science Translational Medicine, 2(27), 27ps17. doi: 10.1126/scitranslmed.3000558.PubMedGoogle Scholar
  75. 75.
    Foldes, G., Mioulane, M., Wright, J. S., Liu, A. Q., Novak, P., Merkely, B., et al. (2011). Modulation of human embryonic stem cell-derived cardiomyocyte growth: A testbed for studying human cardiac hypertrophy? Journal of Molecular and Cellular Cardiology, 50(2), 367–376. doi: 10.1016/j.yjmcc.2010.10.029.PubMedGoogle Scholar
  76. 76.
    Tropel, P., Tournois, J., Come, J., Varela, C., Moutou, C., Fragner, P., et al. (2010). High-efficiency derivation of human embryonic stem cell lines following pre-implantation genetic diagnosis. In Vitro Cellular & Developmental Biology—Animal, 46(3–4), 376–385. doi: 10.1007/s11626-010-9300-8.Google Scholar
  77. 77.
    Verlinsky, Y., Strelchenko, N., Kukharenko, V., Rechitsky, S., Verlinsky, O., Galat, V., et al. (2005). Human embryonic stem cell lines with genetic disorders. Reproductive Biomedicine Online, 10(1), 105–110.PubMedGoogle Scholar
  78. 78.
    Puri, M. C., & Nagy, A. (2012). Concise review: Embryonic stem cells versus induced pluripotent stem cells: The game is on. Stem Cells, 30(1), 10–14. doi: 10.1002/stem.788.PubMedGoogle Scholar
  79. 79.
    Wu, S. M., & Hochedlinger, K. (2011). Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nature Cell Biology, 13(5), 497–505.PubMedGoogle Scholar
  80. 80.
    Park, I. H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., Lensch, M. W., Cowan, C., Hochedlinger, K., & Daley, G. Q. (2008). Disease-specific induced pluripotent stem cells. Cell, 134(5), 877–886. doi: 10.1016/j.cell.2008.07.041 PubMedGoogle Scholar
  81. 81.
    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. European Heart Journal, 32(8), 952–962. doi: 10.1093/eurheartj/ehr073.PubMedGoogle Scholar
  82. 82.
    Kazuki, Y., Hiratsuka, M., Takiguchi, M., Osaki, M., Kajitani, N., Hoshiya, H., et al. (2010). Complete genetic correction of ips cells from Duchenne muscular dystrophy. Molecular Therapy, 18(2), 386–393. doi: 10.1038/mt.2009.274.PubMedGoogle Scholar
  83. 83.
    Bokil, N. J., Baisden, J. M., Radford, D. J., & Summers, K. M. (2010). Molecular genetics of long QT syndrome. Molecular Genetics and Metabolism, 101(1), 1–8. doi: 10.1016/j.ymgme.2010.05.011.PubMedGoogle Scholar
  84. 84.
    Hofman, N., van Lochem, L. T., & Wilde, A. A. (2010). Genetic basis of malignant channelopathies and ventricular fibrillation in the structurally normal heart. Future Cardiology, 6(3), 395–408. doi: 10.2217/fca.10.11.PubMedGoogle Scholar
  85. 85.
    Moretti, A., Bellin, M., Welling, A., Jung, C. B., Lam, J. T., Bott-Flugel, L., et al. (2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. The New England Journal of Medicine, 363(15), 1397–1409. doi: 10.1056/NEJMoa0908679.PubMedGoogle Scholar
  86. 86.
    Robinton, D. A., & Daley, G. Q. (2012). The promise of induced pluripotent stem cells in research and therapy. Nature, 481(7381), 295–305. doi: 10.1038/nature10761.PubMedGoogle Scholar
  87. 87.
    Woodcock, J. (2007). The prospects for "personalized medicine" in drug development and drug therapy. Clinical Pharmacology and Therapeutics, 81(2), 164–169. doi: 10.1038/sj.clpt.6100063.PubMedGoogle Scholar
  88. 88.
    Han, Y., Miller, A., Mangada, J., Liu, Y., Swistowski, A., Zhan, M., et al. (2009). Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One, 4(9), e7155. doi: 10.1371/journal.pone.0007155.PubMedGoogle Scholar
  89. 89.
    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(5), 861–872.PubMedGoogle Scholar
  90. 90.
    Dimos, J. T., Rodolfa, K. T., Niakan, K. K., Weisenthal, L. M., Mitsumoto, H., Chung, W., et al. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321(5893), 1218–1221. doi: 10.1126/science.1158799.PubMedGoogle Scholar
  91. 91.
    Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., et al. (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26(11), 1269–1275.PubMedGoogle Scholar
  92. 92.
    Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., et al. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology, 26(1), 101–106.PubMedGoogle Scholar
  93. 93.
    Hester, M. E., Song, S., Miranda, C. J., Eagle, A., Schwartz, P. H., & Kaspar, B. K. (2009). Two factor reprogramming of human neural stem cells into pluripotency. PLoS One, 4(9), e7044. doi: 10.1371/journal.pone.0007044.PubMedGoogle Scholar
  94. 94.
    Kim, J. B., Greber, B., Arauzo-Bravo, M. J., Meyer, J., Park, K. I., Zaehres, H., et al. (2009). Direct reprogramming of human neural stem cells by OCT4. Nature, 461(7264), 643–649. doi: 10.1038/nature08436.Google Scholar
  95. 95.
    Ebert, A. D., Yu, J., Rose, F. F., Mattis, V. B., Lorson, C. L., Thomson, J. A., et al. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature, 457(7227), 277–280.PubMedGoogle Scholar
  96. 96.
    Carey, B. W., Markoulaki, S., Hanna, J., Saha, K., Gao, Q., Mitalipova, M., et al. (2009). Reprogramming of murine and human somatic cells using a single polycistronic vector. Proceedings of the National Academy of Sciences of the United States of America, 106(1), 157–162. doi: 10.1073/pnas.0811426106.PubMedGoogle Scholar
  97. 97.
    Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G. W., Cook, E. G., et al. (2009). Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136(5), 964–977. doi: 10.1016/j.cell.2009.02.013.PubMedGoogle Scholar
  98. 98.
    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(7239), 771–775. doi: 10.1038/nature07864.PubMedGoogle Scholar
  99. 99.
    Zhou, W., & Freed, C. R. (2009). Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells, 27(11), 2667–2674. doi: 10.1002/stem.201.PubMedGoogle Scholar
  100. 100.
    Si-Tayeb, K., Noto, F. K., Sepac, A., Sedlic, F., Bosnjak, Z. J., Lough, J. W., et al. (2010). Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Developmental Biology, 10, 81. doi: 10.1186/1471-213X-10-81.PubMedGoogle Scholar
  101. 101.
    Jia, F., Wilson, K. D., Sun, N., Gupta, D. M., Huang, M., Li, Z., et al. (2010). A nonviral minicircle vector for deriving human iPS cells. Nature Methods, 7(3), 197–199. doi: 10.1038/nmeth.1426.PubMedGoogle Scholar
  102. 102.
    Yu, J., Hu, K., Smuga-Otto, K., Tian, S., Stewart, R., Slukvin, I. I., et al. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science, 324(5928), 797–801. doi: 10.1126/science.1172482.PubMedGoogle Scholar
  103. 103.
    Kim, D., Kim, C.-H., Moon, J.-I., Chung, Y.-G., Chang, M.-Y., Han, B.-S., et al. (2009). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell, 4(6), 472–476.PubMedGoogle Scholar
  104. 104.
    Zhou, H., Wu, S., Joo, J. Y., Zhu, S., Han, D. W., Lin, T., et al. (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell, 4(5), 381–384. doi: 10.1016/j.stem.2009.04.005.PubMedGoogle Scholar
  105. 105.
    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. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 85(8), 348–362. doi: JST.JSTAGE/pjab/85.348.PubMedGoogle Scholar
  106. 106.
    Miyoshi, N., Ishii, H., Nagano, H., Haraguchi, N., Dewi, D. L., Kano, Y., et al. (2011). Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell, 8(6), 633–638. doi: 10.1016/j.stem.2011.05.001.PubMedGoogle Scholar
  107. 107.
    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. Biochemical and Biophysical Research Communications, 385(4), 497–502. doi: 10.1016/j.bbrc.2009.05.073.PubMedGoogle Scholar
  108. 108.
    Zwi, L., Caspi, O., Arbel, G., Huber, I., Gepstein, A., Park, I. H., et al. (2009). Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation, 120(15), 1513–1523. doi: 10.1161/CIRCULATIONAHA.109.868885.PubMedGoogle Scholar
  109. 109.
    Dick, E., Matsa, E., Bispham, J., Reza, M., Guglieri, M., Staniforth, A., et al. (2011). Two new protocols to enhance the production and isolation of human induced pluripotent stem cell lines. Stem Cell Research, 6(2), 158–167. doi: 10.1016/j.scr.2010.10.002.PubMedGoogle Scholar
  110. 110.
    Carvajal-Vergara, X., Sevilla, A., D'Souza, S. L., Ang, Y. S., Schaniel, C., Lee, D. F., et al. (2010). Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature, 465(7299), 808–812. doi: 10.1038/nature09005.PubMedGoogle Scholar
  111. 111.
    Itzhaki, I., Maizels, L., Huber, I., Zwi-Dantsis, L., Caspi, O., Winterstern, A., et al. (2011). Modelling the long QT syndrome with induced pluripotent stem cells. Nature, 471(7337), 225–229.PubMedGoogle Scholar
  112. 112.
    Lahti, A. L., Kujala, V. J., Chapman, H., Koivisto, A. P., Pekkanen-Mattila, M., Kerkela, E., et al. (2011). Human disease model for long QT syndrome type 2 using iPS cells demonstrates arrhythmogenic characteristics in cell culture. Disease Models & Mechanisms. doi: 10.1242/dmm.008409.
  113. 113.
    Fatima, A., Xu, G., Shao, K., Papadopoulos, S., Lehmann, M., Arnaiz-Cot, J. J., et al. (2011). In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells. Cellular Physiology and Biochemistry, 28(4), 579–592. doi: 10.1159/000335753.PubMedGoogle Scholar
  114. 114.
    Jung, C. B., Moretti, A., Schnitzler, M. M., Iop, L., Storch, U., Bellin, M., et al. (2011). Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Molecular Medicine. doi: 10.1002/emmm.201100194.
  115. 115.
    Yazawa, M., Hsueh, B., Jia, X., Pasca, A. M., Bernstein, J. A., Hallmayer, J., et al. (2011). Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature. doi: 10.1038/nature09855.
  116. 116.
    Pasca, S. P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A. M., et al. (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nature Medicine, 17(12), 1657–1662. doi: 10.1038/nm.2576.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Wolfson Centre for Stem Cells, Tissue Engineering & Modelling (STEM)University of NottinghamNottinghamUK

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