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Embryonic Template-Based Generation and Purification of Pluripotent Stem Cell-Derived Cardiomyocytes for Heart Repair

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Abstract

Cardiovascular disease remains a leading cause of death in Western countries. Many types of cardiovascular diseases are due to a loss of functional cardiomyocytes, which can result in irreversible cardiac failure. Since the adult human heart has limited regenerative potential, cardiac transplantation is still the only effective therapy to address this cardiomyocyte loss. However, drawbacks, such as immune rejection and insufficient donor availability, are limiting this last-resort solution. Recent developments in the stem cell biology field have improved the potential of cardiac regeneration. Improvements in reprogramming strategies of differentiated adult cells into induced pluripotent stem cells, together with increased efficiency of directed differentiation of pluripotent stem cells toward cardiac myocytes, have brought cell-based heart muscle regeneration a few steps closer to the clinic. In this review, we outline the status of research on cardiac regeneration with a focus on directed differentiation of pluripotent stem cells toward the cardiac lineage.

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References

  1. Eefting, F., et al. (2004). Role of apoptosis in reperfusion injury. Cardiovascular Research, 61(3), 414–426.

    Article  PubMed  CAS  Google Scholar 

  2. Laflamme, M. A., et al. (2005). Formation of human myocardium in the rat heart from human embryonic stem cells. The American Journal of Pathology, 167(3), 663–671.

    Article  PubMed  CAS  Google Scholar 

  3. Roger, V. L., et al. (2011). Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation, 123(4), e18–e209.

    Article  PubMed  Google Scholar 

  4. Beltrami, A. P., et al. (2001). Evidence that human cardiac myocytes divide after myocardial infarction. The New England Journal of Medicine, 344(23), 1750–1757.

    Article  PubMed  CAS  Google Scholar 

  5. Urbanek, K., et al. (2005). Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proceedings of the National Academy of Sciences of the United States of America, 102(24), 8692–8697.

    Article  PubMed  CAS  Google Scholar 

  6. Anversa, P., Leri, A., & Kajstura, J. (2006). Cardiac regeneration. Journal of the American College of Cardiology, 47(9), 1769–1776.

    Article  PubMed  Google Scholar 

  7. Beltrami, A. P., et al. (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell, 114(6), 763–776.

    Article  PubMed  CAS  Google Scholar 

  8. Bergmann, O., et al. (2009). Evidence for cardiomyocyte renewal in humans. Science, 324(5923), 98–102.

    Article  PubMed  CAS  Google Scholar 

  9. Raikwar, S. P., Mueller, T., & Zavazava, N. (2006). Strategies for developing therapeutic application of human embryonic stem cells. Physiology (Bethesda), 21, 19–28.

    Article  CAS  Google Scholar 

  10. Goumans, M. J., et al. (2007). TGF-beta1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Research, 1(2), 138–149.

    Article  PubMed  CAS  Google Scholar 

  11. Bollini, S., Smart, N., & Riley, P. R. (2011). Resident cardiac progenitor cells: at the heart of regeneration. Journal of Molecular and Cellular Cardiology, 50(2), 296–303.

    Article  PubMed  CAS  Google Scholar 

  12. Steinhauser, M. L., & Lee, R. T. (2011). Regeneration of the heart. EMBO Molecular Medicine, 3(12), 701–712.

    Article  PubMed  CAS  Google Scholar 

  13. Vidarsson, H., Hyllner, J., & Sartipy, P. (2010). Differentiation of human embryonic stem cells to cardiomyocytes for in vitro and in vivo applications. Stem Cell Reviews, 6(1), 108–120.

    Article  PubMed  Google Scholar 

  14. Kattman, S. J., 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.

    Article  PubMed  CAS  Google Scholar 

  15. Burridge, P. W., 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.

    Article  PubMed  CAS  Google Scholar 

  16. Willems, E., et al. (2011). A chemical biology approach to myocardial regeneration. Journal of Cardiovascular Translational Research, 4(3), 340–350.

    Article  PubMed  Google Scholar 

  17. Laflamme, M. A., et al. (2007). Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nature Biotechnology, 25(9), 1015–1024.

    Article  PubMed  CAS  Google Scholar 

  18. Uosaki, H., et al. (2011). Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface expression. PLoS One, 6(8), e23657.

    Article  PubMed  CAS  Google Scholar 

  19. Elliott, D. A., et al. (2011). NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nature Methods, 8, 1037–1040.

    Article  PubMed  CAS  Google Scholar 

  20. Hudson, J., et al. (2012). Primitive cardiac cells from human embryonic stem cells. Stem Cells Development, 21(9), 1513–1523.

    Article  CAS  Google Scholar 

  21. Passier, R., van Laake, L. W., & Mummery, C. L. (2008). Stem-cell-based therapy and lessons from the heart. Nature, 453(7193), 322–329.

    Article  PubMed  CAS  Google Scholar 

  22. van Laake, L. W., et al. (2008). Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circulation Research, 102(9), 1008–1010.

    Article  PubMed  CAS  Google Scholar 

  23. Kattman, S. J., et al. (2011). Stem cells and their derivatives: a renaissance in cardiovascular translational research. Journal of Cardiovascular Translational Research, 4(1), 66–72.

    Article  PubMed  Google Scholar 

  24. Davis, R. P., et al. (2011). Pluripotent stem cell models of cardiac disease and their implication for drug discovery and development. Trends in Molecular Medicine, 17(9), 475–484.

    Article  PubMed  CAS  Google Scholar 

  25. Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819), 154–156.

    Article  PubMed  CAS  Google Scholar 

  26. Martin, G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proceedings of the National Academy of Sciences of the United States of America, 78(12), 7634–7638.

    Article  PubMed  CAS  Google Scholar 

  27. Thomson, J. A., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.

    Article  PubMed  CAS  Google Scholar 

  28. Mummery, C., et al. (2003). Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation, 107(21), 2733–2740.

    Article  PubMed  CAS  Google Scholar 

  29. Kehat, I., et al. (2001). Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. The Journal of Clinical Investigation, 108(3), 407–414.

    PubMed  CAS  Google Scholar 

  30. Gai, H., et al. (2009). Generation and characterization of functional cardiomyocytes using induced pluripotent stem cells derived from human fibroblasts. Cell Biology International, 33(11), 1184–1193.

    Article  PubMed  CAS  Google Scholar 

  31. Xu, C., et al. (2002). Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circulation Research, 91(6), 501–508.

    Article  PubMed  CAS  Google Scholar 

  32. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.

    Article  PubMed  CAS  Google Scholar 

  33. Takahashi, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872.

    Article  PubMed  CAS  Google Scholar 

  34. Kim, K., et al. (2011). Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nature Biotechnology, 29(12), 1117–1119.

    Article  PubMed  CAS  Google Scholar 

  35. Cherry, A. B., & Daley, G. Q. (2012). Reprogramming cellular identity for regenerative medicine. Cell, 148(6), 1110–1122.

    Article  PubMed  CAS  Google Scholar 

  36. Schenke-Layland, K., et al. (2008). Reprogrammed mouse fibroblasts differentiate into cells of the cardiovascular and hematopoietic lineages. Stem Cells, 26(6), 1537–1546.

    Article  PubMed  CAS  Google Scholar 

  37. Narazaki, G., et al. (2008). Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation, 118(5), 498–506.

    Article  PubMed  Google Scholar 

  38. Zhang, J., et al. (2009). Functional cardiomyocytes derived from human induced pluripotent stem cells. Circulation Research, 104(4), e30–e41.

    Article  PubMed  CAS  Google Scholar 

  39. Nelson, T. J., et al. (2009). Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation, 120(5), 408–416.

    Article  PubMed  Google Scholar 

  40. Zhao, T., et al. (2011). Immunogenicity of induced pluripotent stem cells. Nature, 474(7350), 212–215.

    PubMed  CAS  Google Scholar 

  41. Okita, K., Nagata, N., & Yamanaka, S. (2011). Immunogenicity of induced pluripotent stem cells. Circulation Research, 109(7), 720–721.

    Article  PubMed  CAS  Google Scholar 

  42. Moriguchi, H., Chung, R. T., & Sato, C. (2010). Tumorigenicity of human induced pluripotent stem cells depends on the balance of gene expression between p21 and p53. Hepatology, 51(3), 1088–1089.

    Article  PubMed  Google Scholar 

  43. Ghosh, Z., et al. (2011). Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells. Cancer Research, 71(14), 5030–5039.

    Article  PubMed  CAS  Google Scholar 

  44. Lin, S. L., et al. (2010). MicroRNA miR-302 inhibits the tumorigenecity of human pluripotent stem cells by coordinate suppression of the CDK2 and CDK4/6 cell cycle pathways. Cancer Research, 70(22), 9473–9482.

    Article  PubMed  CAS  Google Scholar 

  45. Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151), 313–317.

    Article  PubMed  CAS  Google Scholar 

  46. Okita, K., et al. (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science, 322(5903), 949–953.

    Article  PubMed  CAS  Google Scholar 

  47. Stadtfeld, M., et al. (2008). Induced pluripotent stem cells generated without viral integration. Science, 322(5903), 945–949.

    Article  PubMed  CAS  Google Scholar 

  48. Yu, J., et al. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science, 324(5928), 797–801.

    Article  PubMed  CAS  Google Scholar 

  49. Jia, F., et al. (2010). A nonviral minicircle vector for deriving human iPS cells. Nature Methods, 7(3), 197–199.

    Article  PubMed  CAS  Google Scholar 

  50. Narsinh, K. H., et al. (2011). Generation of adult human induced pluripotent stem cells using nonviral minicircle DNA vectors. Nature Protocols, 6(1), 78–88.

    Article  PubMed  CAS  Google Scholar 

  51. Warren, L., 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.

    Article  PubMed  CAS  Google Scholar 

  52. Anokye-Danso, F., et al. (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell, 8(4), 376–388.

    Article  PubMed  CAS  Google Scholar 

  53. Woltjen, K., et al. (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature, 458(7239), 766–770.

    Article  PubMed  CAS  Google Scholar 

  54. Hu, K., et al. (2011). Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood, 117(14), e109–e119.

    Article  PubMed  CAS  Google Scholar 

  55. Seki, T., Yuasa, S., & Fukuda, K. (2012). Generation of induced pluripotent stem cells from a small amount of human peripheral blood using a combination of activated T cells and Sendai virus. Nature Protocols, 7(4), 718–728.

    Article  PubMed  CAS  Google Scholar 

  56. Ban, H., et al. (2011). Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proceedings of the National Academy of Sciences of the United States of America, 108(34), 14234–14239.

    Article  PubMed  CAS  Google Scholar 

  57. Fusaki, N., et al. (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.

    Article  PubMed  CAS  Google Scholar 

  58. Rao, M. S., & Malik, N. (2012). Assessing iPSC reprogramming methods for their suitability in translational medicine. Journal of Cell Biochemistry. doi:10.1002/jcb.24183.

  59. Lai, M. I., et al. (2011). Advancements in reprogramming strategies for the generation of induced pluripotent stem cells. Journal of Assisted Reproduction and Genetics, 28(4), 291–301.

    Article  PubMed  Google Scholar 

  60. Okita, K., & Yamanaka, S. (2011). Induced pluripotent stem cells: opportunities and challenges. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 366(1575), 2198–2207.

    Article  PubMed  CAS  Google Scholar 

  61. Stadtfeld, M., & Hochedlinger, K. (2010). Induced pluripotency: history, mechanisms, and applications. Genes & Development, 24(20), 2239–2263.

    Article  CAS  Google Scholar 

  62. Lawson, K. A., Meneses, J. J., & Pedersen, R. A. (1991). Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development, 113(3), 891–911.

    PubMed  CAS  Google Scholar 

  63. Willems, E., Bushway, P. J., & Mercola, M. (2009). Natural and synthetic regulators of embryonic stem cell cardiogenesis. Pediatric Cardiology, 30(5), 635–642.

    Article  PubMed  Google Scholar 

  64. Mercola, M., Ruiz-Lozano, P., & Schneider, M. D. (2011). Cardiac muscle regeneration: lessons from development. Genes & Development, 25(4), 299–309.

    Article  CAS  Google Scholar 

  65. Burridge, P. W., et al. (2012). Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell, 10(1), 16–28.

    Article  PubMed  CAS  Google Scholar 

  66. Bondue, A., et al. (2008). Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell, 3(1), 69–84.

    Article  PubMed  CAS  Google Scholar 

  67. Bondue, A., & Blanpain, C. (2010). Mesp1: a key regulator of cardiovascular lineage commitment. Circulation Research, 107(12), 1414–1427.

    Article  PubMed  CAS  Google Scholar 

  68. David, R., et al. (2008). MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nature Cell Biology, 10(3), 338–345.

    Article  PubMed  CAS  Google Scholar 

  69. Lindsley, R. C., et al. (2008). Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ESCs. Cell Stem Cell, 3(1), 55–68.

    Article  PubMed  CAS  Google Scholar 

  70. Hiroi, Y., et al. (2001). Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nature Genetics, 28(3), 276–280.

    Article  PubMed  CAS  Google Scholar 

  71. Plageman, T. F., Jr., & Yutzey, K. E. (2004). Differential expression and function of Tbx5 and Tbx20 in cardiac development. Journal of Biological Chemistry, 279(18), 19026–19034.

    Article  PubMed  CAS  Google Scholar 

  72. Riley, P., Anson-Cartwright, L., & Cross, J. C. (1998). The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis. Nature Genetics, 18(3), 271–275.

    Article  PubMed  CAS  Google Scholar 

  73. Buckingham, M., Meilhac, S., & Zaffran, S. (2005). Building the mammalian heart from two sources of myocardial cells. Nature Reviews Genetics, 6(11), 826–835.

    Article  PubMed  CAS  Google Scholar 

  74. Klaus, A., et al. (2007). Distinct roles of Wnt/beta-catenin and Bmp signaling during early cardiogenesis. Proceedings of the National Academy of Sciences of the United States of America, 104(47), 18531–18536.

    Article  PubMed  CAS  Google Scholar 

  75. Cai, C. L., et al. (2003). Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Developmental Cell, 5(6), 877–889.

    Article  PubMed  CAS  Google Scholar 

  76. Ilagan, R., et al. (2006). Fgf8 is required for anterior heart field development. Development, 133(12), 2435–2445.

    Article  PubMed  CAS  Google Scholar 

  77. Kelly, R. G., Brown, N. A., & Buckingham, M. E. (2001). The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Developmental Cell, 1(3), 435–440.

    Article  PubMed  CAS  Google Scholar 

  78. Xu, H., et al. (2004). Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development, 131(13), 3217–3227.

    Article  PubMed  CAS  Google Scholar 

  79. Meilhac, S. M., et al. (2004). The clonal origin of myocardial cells in different regions of the embryonic mouse heart. Developmental Cell, 6(5), 685–698.

    Article  PubMed  CAS  Google Scholar 

  80. Waldo, K. L., et al. (2001). Conotruncal myocardium arises from a secondary heart field. Development, 128(16), 3179–3188.

    PubMed  CAS  Google Scholar 

  81. Mjaatvedt, C. H., et al. (2001). The outflow tract of the heart is recruited from a novel heart-forming field. Developmental Biology, 238(1), 97–109.

    Article  PubMed  CAS  Google Scholar 

  82. Dyer, L. A., & Kirby, M. L. (2009). Sonic hedgehog maintains proliferation in secondary heart field progenitors and is required for normal arterial pole formation. Developmental Biology, 330(2), 305–317.

    Article  PubMed  CAS  Google Scholar 

  83. Goddeeris, M. M., et al. (2008). Intracardiac septation requires hedgehog-dependent cellular contributions from outside the heart. Development, 135(10), 1887–1895.

    Article  PubMed  CAS  Google Scholar 

  84. Kwon, C., et al. (2007). Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. Proceedings of the National Academy of Sciences of the United States of America, 104(26), 10894–10899.

    Article  PubMed  CAS  Google Scholar 

  85. Ai, D., et al. (2007). Canonical Wnt signaling functions in second heart field to promote right ventricular growth. Proceedings of the National Academy of Sciences of the United States of America, 104(22), 9319–9324.

    Article  PubMed  CAS  Google Scholar 

  86. Cohen, E. D., et al. (2007). Wnt/beta-catenin signaling promotes expansion of Isl-1-positive cardiac progenitor cells through regulation of FGF signaling. The Journal of Clinical Investigation, 117(7), 1794–1804.

    Article  PubMed  CAS  Google Scholar 

  87. Grego-Bessa, J., et al. (2007). Notch signaling is essential for ventricular chamber development. Developmental Cell, 12(3), 415–429.

    Article  PubMed  CAS  Google Scholar 

  88. Watanabe, Y., et al. (2006). Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse. Development, 133(9), 1625–1634.

    Article  PubMed  CAS  Google Scholar 

  89. Lavine, K. J., et al. (2005). Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo. Developmental Cell, 8(1), 85–95.

    Article  PubMed  CAS  Google Scholar 

  90. Brade, T., et al. (2011). Retinoic acid stimulates myocardial expansion by induction of hepatic erythropoietin which activates epicardial Igf2. Development, 138(1), 139–148.

    Article  PubMed  CAS  Google Scholar 

  91. Phillips, H. M., et al. (2005). Vangl2 acts via RhoA signaling to regulate polarized cell movements during development of the proximal outflow tract. Circulation Research, 96(3), 292–299.

    Article  PubMed  CAS  Google Scholar 

  92. Zhou, W., et al. (2007). Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2. Nature Genetics, 39(10), 1225–1234.

    Article  PubMed  CAS  Google Scholar 

  93. Shi, Y., et al. (2000). BMP signaling is required for heart formation in vertebrates. Developmental Biology, 224(2), 226–237.

    Article  PubMed  CAS  Google Scholar 

  94. Walters, M. J., Wayman, G. A., & Christian, J. L. (2001). Bone morphogenetic protein function is required for terminal differentiation of the heart but not for early expression of cardiac marker genes. Mechanisms of Development, 100(2), 263–273.

    Article  PubMed  CAS  Google Scholar 

  95. Zhao, Y., Samal, E., & Srivastava, D. (2005). Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature, 436(7048), 214–220.

    Article  PubMed  CAS  Google Scholar 

  96. Chen, J. F., et al. (2006). The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nature Genetics, 38(2), 228–233.

    Article  PubMed  CAS  Google Scholar 

  97. Evans-Anderson, H. J., Alfieri, C. M., & Yutzey, K. E. (2008). Regulation of cardiomyocyte proliferation and myocardial growth during development by FOXO transcription factors. Circulation Research, 102(6), 686–694.

    Article  PubMed  CAS  Google Scholar 

  98. Synnergren, J., et al. (2008). Molecular signature of cardiomyocyte clusters derived from human embryonic stem cells. Stem Cells, 26(7), 1831–1840.

    Article  PubMed  CAS  Google Scholar 

  99. Cao, F., et al. (2008). Transcriptional and functional profiling of human embryonic stem cell-derived cardiomyocytes. PLoS One, 3(10), e3474.

    Article  PubMed  CAS  Google Scholar 

  100. Xu, X. Q., et al. (2009). Global expression profile of highly enriched cardiomyocytes derived from human embryonic stem cells. Stem Cells, 27(9), 2163–2174.

    Article  PubMed  CAS  Google Scholar 

  101. Passier, R., et al. (2005). Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures. Stem Cells, 23(6), 772–780.

    Article  PubMed  CAS  Google Scholar 

  102. Freund, C., et al. (2008). Insulin redirects differentiation from cardiogenic mesoderm and endoderm to neuroectoderm in differentiating human embryonic stem cells. Stem Cells, 26(3), 724–733.

    Article  PubMed  CAS  Google Scholar 

  103. Graichen, R., et al. (2008). Enhanced cardiomyogenesis of human embryonic stem cells by a small molecular inhibitor of p38 MAPK. Differentiation, 76(4), 357–370.

    Article  PubMed  CAS  Google Scholar 

  104. Gaur, M., et al. (2010). Timed inhibition of p38MAPK directs accelerated differentiation of human embryonic stem cells into cardiomyocytes. Cytotherapy, 12(6), 807–817.

    Article  PubMed  CAS  Google Scholar 

  105. Xu, X. Q., et al. (2008). Chemically defined medium supporting cardiomyocyte differentiation of human embryonic stem cells. Differentiation, 76(9), 958–970.

    PubMed  CAS  Google Scholar 

  106. Fujiwara, M., et al. (2011). Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-A. PLoS One, 6(2), e16734.

    Article  PubMed  CAS  Google Scholar 

  107. Itskovitz-Eldor, J., et al. (2000). Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Molecular Medicine, 6(2), 88–95.

    PubMed  CAS  Google Scholar 

  108. Desbaillets, I., et al. (2000). Embryoid bodies: an in vitro model of mouse embryogenesis. Experimental Physiology, 85(6), 645–651.

    Article  PubMed  CAS  Google Scholar 

  109. Doetschman, T. C., et al. (1985). The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. Journal of Embryology and Experimental Morphology, 87, 27–45.

    PubMed  CAS  Google Scholar 

  110. Tran, T. H., et al. (2009). Wnt3a-induced mesoderm formation and cardiomyogenesis in human embryonic stem cells. Stem Cells, 27(8), 1869–1878.

    Article  PubMed  CAS  Google Scholar 

  111. He, J. Q., et al. (2003). Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circulation Research, 93(1), 32–39.

    Article  PubMed  CAS  Google Scholar 

  112. Bu, L., et al. (2009). Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature, 460(7251), 113–117.

    Article  PubMed  CAS  Google Scholar 

  113. Cao, N., et al. (2012). Ascorbic acid enhances the cardiac differentiation of induced pluripotent stem cells promoting the proliferation of cardiac progenitor cells. Cell Research, 22(1), 219–36.

    Article  PubMed  CAS  Google Scholar 

  114. McDevitt, T. C., Laflamme, M. A., & Murry, C. E. (2005). Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway. Journal of Molecular and Cellular Cardiology, 39(6), 865–873.

    Article  PubMed  CAS  Google Scholar 

  115. Tseng, A. S., Engel, F. B., & Keating, M. T. (2006). The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chemical Biology, 13(9), 957–963.

    Article  CAS  Google Scholar 

  116. Ng, E. S., et al. (2005). Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood, 106(5), 1601–1603.

    Article  PubMed  CAS  Google Scholar 

  117. Rajala, K., Pekkanen-Mattila, M., & Aalto-Setala, K. (2011). Cardiac differentiation of pluripotent stem cells. Stem Cells International, 2011, 383709.

    Article  PubMed  CAS  Google Scholar 

  118. Sugi, Y., & Lough, J. (1995). Activin-A and FGF-2 mimic the inductive effects of anterior endoderm on terminal cardiac myogenesis in vitro. Developmental Biology, 168(2), 567–574.

    Article  PubMed  CAS  Google Scholar 

  119. Shiba, Y., Hauch, K. D., & Laflamme, M. A. (2009). Cardiac applications for human pluripotent stem cells. Current Pharmaceutical Design, 15(24), 2791–2806.

    Article  PubMed  CAS  Google Scholar 

  120. Paige, S. L., et al. (2010). Endogenous Wnt/beta-catenin signaling is required for cardiac differentiation in human embryonic stem cells. PLoS One, 5(6), e11134.

    Article  PubMed  CAS  Google Scholar 

  121. Filipczyk, A. A., et al. (2007). Regulation of cardiomyocyte differentiation of embryonic stem cells by extracellular signalling. Cellular and Molecular Life Sciences, 64(6), 704–718.

    Article  PubMed  CAS  Google Scholar 

  122. Yang, L., et al. (2008). Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature, 453(7194), 524–528.

    Article  PubMed  CAS  Google Scholar 

  123. Willems, E., & Mercola, M. (2011). What your heart doth know. Cell Stem Cell, 8(2), 124–126.

    Article  PubMed  CAS  Google Scholar 

  124. David, R., et al. (2009). Forward programming of pluripotent stem cells towards distinct cardiovascular cell types. Cardiovascular Research, 84(2), 263–272.

    Article  PubMed  CAS  Google Scholar 

  125. Dambrot, C., et al. (2011). Cardiomyocyte differentiation of pluripotent stem cells and their use as cardiac disease models. Biochemical Journal, 434(1), 25–35.

    Article  PubMed  CAS  Google Scholar 

  126. Nussbaum, J., et al. (2007). Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. The FASEB Journal, 21(7), 1345–1357.

    Article  CAS  Google Scholar 

  127. Behfar, A., et al. (2007). Cardiopoietic programming of embryonic stem cells for tumor-free heart repair. The Journal of Experimental Medicine, 204(2), 405–420.

    Article  PubMed  CAS  Google Scholar 

  128. Braam, S. R., Passier, R., & Mummery, C. L. (2009). Cardiomyocytes from human pluripotent stem cells in regenerative medicine and drug discovery. Trends in Pharmacological Sciences, 30(10), 536–545.

    Article  PubMed  CAS  Google Scholar 

  129. Kolossov, E., et al. (2006). Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. The Journal of Experimental Medicine, 203(10), 2315–2327.

    Article  PubMed  CAS  Google Scholar 

  130. Miura, K., et al. (2009). Variation in the safety of induced pluripotent stem cell lines. Nature Biotechnology, 27(8), 743–745.

    Article  PubMed  CAS  Google Scholar 

  131. Christoforou, N., et al. (2010). Implantation of mouse embryonic stem cell-derived cardiac progenitor cells preserves function of infarcted murine hearts. PLoS One, 5(7), e11536.

    Article  PubMed  CAS  Google Scholar 

  132. Adler, E. D., et al. (2010). The cardiomyocyte lineage is critical for optimization of stem cell therapy in a mouse model of myocardial infarction. The FASEB Journal, 24(4), 1073–1081.

    Article  CAS  Google Scholar 

  133. Caspi, O., et al. (2007). Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. Journal of the American College of Cardiology, 50(19), 1884–1893.

    Article  PubMed  Google Scholar 

  134. Fernandes, S., et al. (2010). Human embryonic stem cell-derived cardiomyocytes engraft but do not alter cardiac remodeling after chronic infarction in rats. Journal of Molecular and Cellular Cardiology, 49(6), 941–949.

    Article  PubMed  CAS  Google Scholar 

  135. van Laake, L. W., et al. (2009). Improvement of mouse cardiac function by hESC-derived cardiomyocytes correlates with vascularity but not graft size. Stem Cell Research, 3(2–3), 106–112.

    Article  PubMed  Google Scholar 

  136. Lu, W. N., et al. (2009). Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Engineering. Part A, 15(6), 1437–1447.

    Article  PubMed  CAS  Google Scholar 

  137. Fujimoto, K. L., et al. (2009). Naive rat amnion-derived cell transplantation improved left ventricular function and reduced myocardial scar of postinfarcted heart. Cell Transplantation, 18(4), 477–486.

    Article  PubMed  Google Scholar 

  138. Xu, C., et al. (2006). Cardiac bodies: a novel culture method for enrichment of cardiomyocytes derived from human embryonic stem cells. Stem Cells and Development, 15(5), 631–639.

    Article  PubMed  CAS  Google Scholar 

  139. Murry, C. E., & Keller, G. (2008). Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell, 132(4), 661–680.

    Article  PubMed  CAS  Google Scholar 

  140. Hattori, F., et al. (2010). Nongenetic method for purifying stem cell-derived cardiomyocytes. Nature Methods, 7(1), 61–66.

    Article  PubMed  CAS  Google Scholar 

  141. Dubois, N. C., 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.

    Article  PubMed  CAS  Google Scholar 

  142. Awasthi, S., et al. (2012). Label-free identification and characterization of human pluripotent stem cell-derived cardiomyocytes using second harmonic generation (SHG) microscopy. Journal of Biophotonics, 5(1), 57–66.

    Article  PubMed  CAS  Google Scholar 

  143. Doevendans, P. A., et al. (1996). The utility of fluorescent in vivo reporter genes in molecular cardiology. Biochemical and Biophysical Research Communications, 222(2), 352–358.

    Article  PubMed  CAS  Google Scholar 

  144. Anderson, D., et al. (2007). Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Molecular Therapy, 15(11), 2027–2036.

    Article  PubMed  CAS  Google Scholar 

  145. Ritner, C., et al. (2011). An engineered cardiac reporter cell line identifies human embryonic stem cell-derived myocardial precursors. PLoS One, 6(1), e16004.

    Article  PubMed  CAS  Google Scholar 

  146. Huber, I., et al. (2007). Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. The FASEB Journal, 21(10), 2551–2563.

    Article  CAS  Google Scholar 

  147. Fu, J. D., et al. (2010). Na+/Ca2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes. Stem Cells and Development, 19(6), 773–782.

    Article  PubMed  CAS  Google Scholar 

  148. van Laake, L. W., et al. (2010). Reporter-based isolation of induced pluripotent stem cell- and embryonic stem cell-derived cardiac progenitors reveals limited gene expression variance. Circulation Research, 107(3), 340–347.

    Article  PubMed  CAS  Google Scholar 

  149. Gassanov, N., et al. (2004). Endothelin induces differentiation of ANP-EGFP expressing embryonic stem cells towards a pacemaker phenotype. The FASEB Journal, 18(14), 1710–1712.

    CAS  Google Scholar 

  150. Ma, 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.

    Article  PubMed  CAS  Google Scholar 

  151. Xu, X. Q., et al. (2008). Highly enriched cardiomyocytes from human embryonic stem cells. Cytotherapy, 10(4), 376–389.

    Article  PubMed  CAS  Google Scholar 

  152. Recchia, A., et al. (2006). Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proceedings of the National Academy of Sciences of the United States of America, 103(5), 1457–1462.

    Article  PubMed  CAS  Google Scholar 

  153. Tsukahara, T., et al. (2006). Murine leukemia virus vector integration favors promoter regions and regional hot spots in a human T-cell line. Biochemical and Biophysical Research Communications, 345(3), 1099–1107.

    Article  PubMed  CAS  Google Scholar 

  154. Woods, N. B., et al. (2003). Lentiviral vector transduction of NOD/SCID repopulating cells results in multiple vector integrations per transduced cell: risk of insertional mutagenesis. Blood, 101(4), 1284–1289.

    Article  PubMed  CAS  Google Scholar 

  155. Gropp, M., & Reubinoff, B. (2006). Lentiviral vector-mediated gene delivery into human embryonic stem cells. Methods in Enzymology, 420, 64–81.

    Article  PubMed  CAS  Google Scholar 

  156. Nelson, T. J., et al. (2008). CXCR4+/FLK-1+ biomarkers select a cardiopoietic lineage from embryonic stem cells. Stem Cells, 26(6), 1464–1473.

    Article  PubMed  CAS  Google Scholar 

  157. Yamashita, J. K., et al. (2005). Prospective identification of cardiac progenitors by a novel single cell-based cardiomyocyte induction. The FASEB Journal, 19(11), 1534–1536.

    CAS  Google Scholar 

  158. Hidaka, K., et al. (2010). The cellular prion protein identifies bipotential cardiomyogenic progenitors. Circulation Research, 106(1), 111–119.

    Article  PubMed  CAS  Google Scholar 

  159. Rust, W., Balakrishnan, T., & Zweigerdt, R. (2009). Cardiomyocyte enrichment from human embryonic stem cell cultures by selection of ALCAM surface expression. Regenerative Medicine, 4(2), 225–237.

    Article  PubMed  CAS  Google Scholar 

  160. Van Hoof, 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.

    Article  PubMed  CAS  Google Scholar 

  161. Snir, M., et al. (2003). Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. American Journal of Physiology-Heart and Circulatory Physiology, 285(6), H2355–H2363.

    PubMed  CAS  Google Scholar 

  162. Satin, J., et al. (2004). Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. The Journal of Physiology, 559(Pt 2), 479–496.

    Article  PubMed  CAS  Google Scholar 

  163. Dolnikov, K., et al. (2005). Functional properties of human embryonic stem cell-derived cardiomyocytes. Annals of the New York Academy of Sciences, 1047, 66–75.

    Article  PubMed  CAS  Google Scholar 

  164. Sartiani, L., et al. (2007). Developmental changes in cardiomyocytes differentiated from human embryonic stem cells: a molecular and electrophysiological approach. Stem Cells, 25(5), 1136–1144.

    Article  PubMed  CAS  Google Scholar 

  165. Liu, J., et al. (2007). Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation. Stem Cells, 25(12), 3038–3044.

    Article  PubMed  CAS  Google Scholar 

  166. Binah, O., et al. (2007). Functional and developmental properties of human embryonic stem cells-derived cardiomyocytes. Journal of Electrocardiology, 40(6 Suppl), S192–S196.

    Article  PubMed  Google Scholar 

  167. Norstrom, A., et al. (2006). Molecular and pharmacological properties of human embryonic stem cell-derived cardiomyocytes. Experimental Biology and Medicine (Maywood), 231(11), 1753–1762.

    Google Scholar 

  168. Otsuji, T. G., et al. (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.

    Article  PubMed  CAS  Google Scholar 

  169. Brito-Martins, M., Harding, S. E., & Ali, N. N. (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. British Journal of Pharmacology, 153(4), 751–759.

    Article  PubMed  CAS  Google Scholar 

  170. Beqqali, A., et al. (2006). Genome-wide transcriptional profiling of human embryonic stem cells differentiating to cardiomyocytes. Stem Cells, 24(8), 1956–1967.

    Article  PubMed  CAS  Google Scholar 

  171. Kehat, I., et al. (2004). Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nature Biotechnology, 22(10), 1282–1289.

    Article  PubMed  CAS  Google Scholar 

  172. Synnergren, J., et al. (2008). Cardiomyogenic gene expression profiling of differentiating human embryonic stem cells. Journal of Biotechnology, 134(1–2), 162–170.

    Article  PubMed  CAS  Google Scholar 

  173. Kehat, I., et al. (2002). High-resolution electrophysiological assessment of human embryonic stem cell-derived cardiomyocytes: a novel in vitro model for the study of conduction. Circulation Research, 91(8), 659–661.

    Article  PubMed  CAS  Google Scholar 

  174. Rugg-Gunn, P. J., et al. (2012). Cell-surface proteomics identifies lineage-specific markers of embryo-derived stem cells. Developmental Cell, 22(4), 887–901.

    Article  PubMed  CAS  Google Scholar 

  175. Denning, C., et al. (2006). Common culture conditions for maintenance and cardiomyocyte differentiation of the human embryonic stem cell lines, BG01 and HUES-7. The International Journal of Developmental Biology, 50(1), 27–37.

    Article  PubMed  CAS  Google Scholar 

  176. Xu, C., et al. (2001). Feeder-free growth of undifferentiated human embryonic stem cells. Nature Biotechnology, 19(10), 971–974.

    Article  PubMed  CAS  Google Scholar 

  177. Hodgetts, S. I., et al. (2000). Why do cultured transplanted myoblasts die in vivo? DNA quantification shows enhanced survival of donor male myoblasts in host mice depleted of CD4+ and CD8+ cells or Nk1.1+ cells. Cell Transplantation, 9(4), 489–502.

    PubMed  CAS  Google Scholar 

  178. van Laake, L. W., et al. (2007). Human embryonic stem cell-derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction. Stem Cell Research, 1(1), 9–24.

    Article  PubMed  Google Scholar 

  179. Niebruegge, S., et al. (2009). Generation of human embryonic stem cell-derived mesoderm and cardiac cells using size-specified aggregates in an oxygen-controlled bioreactor. Biotechnology and Bioengineering, 102(2), 493–507.

    Article  PubMed  CAS  Google Scholar 

  180. Stevens, K. R., et al. (2009). Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue. Proceedings of the National Academy of Sciences of the United States of America, 106(39), 16568–16573.

    Article  PubMed  CAS  Google Scholar 

  181. Stevens, K. R., et al. (2009). Scaffold-free human cardiac tissue patch created from embryonic stem cells. Tissue Engineering. Part A, 15(6), 1211–1222.

    Article  PubMed  CAS  Google Scholar 

  182. Ye, Z., et al. (2011). Myocardial regeneration: roles of stem cells and hydrogels. Advanced Drug Delivery Reviews, 63(8), 688–697.

    Article  PubMed  CAS  Google Scholar 

  183. Tulloch, N. L., et al. (2011). Growth of engineered human myocardium with mechanical loading and vascular coculture. Circulation Research, 109(1), 47–59.

    Article  PubMed  CAS  Google Scholar 

  184. Caspi, O., et al. (2007). Tissue engineering of vascularized cardiac muscle from human embryonic stem cells. Circulation Research, 100(2), 263–272.

    Article  PubMed  CAS  Google Scholar 

  185. Gaetani, R., et al. (2012). Cardiac tissue engineering using tissue printing technology and human cardiac progenitor cells. Biomaterials, 33(6), 1782–1790.

    Article  PubMed  CAS  Google Scholar 

  186. Nunes, S. S., et al. (2011). Stem cell-based cardiac tissue engineering. Journal of Cardiovascular Translational Research, 4(5), 592–602.

    Article  PubMed  Google Scholar 

  187. Vrijsen, K. R., et al. (2010). Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells. Journal of Cellular and Molecular Medicine, 14(5), 1064–1070.

    PubMed  CAS  Google Scholar 

  188. Lee, Y. K., et al. (2010). Triiodothyronine promotes cardiac differentiation and maturation of embryonic stem cells via the classical genomic pathway. Molecular Endocrinology, 24(9), 1728–1736.

    Article  PubMed  CAS  Google Scholar 

  189. Kim, C., et al. (2010). Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation. Stem Cells and Development, 19(6), 783–795.

    Article  PubMed  CAS  Google Scholar 

  190. Matsa, E., & Denning, C. (2012). In vitro uses of human pluripotent stem cell-derived cardiomyocytes. Journal of Cardiovascular and Translational Research (in press)

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Authors and Affiliations

  1. Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands

    Pieterjan Dierickx, Pieter A. Doevendans & Linda W. van Laake

  2. Hubrecht Institute-KNAW, Utrecht, The Netherlands

    Pieterjan Dierickx, Niels Geijsen & Linda W. van Laake

  3. Ghent University, Ghent, Belgium

    Pieterjan Dierickx

  4. ICIN, Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands

    Pieter A. Doevendans

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  1. Pieterjan Dierickx
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  2. Pieter A. Doevendans
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  4. Linda W. van Laake
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Correspondence to Pieterjan Dierickx.

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Dierickx, P., Doevendans, P.A., Geijsen, N. et al. Embryonic Template-Based Generation and Purification of Pluripotent Stem Cell-Derived Cardiomyocytes for Heart Repair. J. of Cardiovasc. Trans. Res. 5, 566–580 (2012). https://doi.org/10.1007/s12265-012-9391-6

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