Skip to main content

Inducing Embryonic Stem Cells to Become Cardiomyocytes

  • Chapter
  • First Online:
Book cover Regenerating the Heart

Abstract

Many forms of heart disease are associated with a decrease in the ­number of functional cardiomyocytes. These include congenital defects (e.g. ­hypoplastic and noncompaction syndromes) as well as acquired injuries (e.g. expo­sure to cardiotoxic agents or injuries resulting from coronary artery disease, hypertension, or surgical interventions). Although the adult mammalian heart retains some capacity for cardiomyocyte renewal (resulting from cardiomyocyte proliferation and/or cardiomyogenic stem cell activity), the magnitude of this regenerative process is insufficient to effect repair of substantively damaged hearts. It has become clear that exogenous cardiomyocytes transplanted into adult hearts are able to structurally and functionally integrate. It has also become clear that embryonic stem cells (ESCs), as well as induced progenitors with ESC-like characteristics, are able to generate bona fide cardiomyocytes in vitro and in vivo. These cells thus constitute a potential source of donor cardiomyocytes for therapeutic interventions in damaged hearts. This chapter reviews spontaneous cardiomyogenic ­differentiation in ESCs, methods used to generate enriched populations of ESC-derived cardiomyocytes, and current results obtained after engraftment of ESC-derived cardiomyocytes or cardiomyogenic precursors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bergmann, O., Bhardwaj, R.D., Bernard, S., et al. (2009) Evidence for cardiomyocyte renewal in humans. Science, 324, 98–102

    PubMed  CAS  Google Scholar 

  2. Soonpaa, M.H. and Field, L.J. (1997) Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Physiol, 272, H220–6

    PubMed  CAS  Google Scholar 

  3. Hsieh, P.C., Segers, V.F., Davis, M.E., et al. (2007) Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med, 13, 970–74

    PubMed  CAS  Google Scholar 

  4. Koh, G.Y., Soonpaa, M.H., Klug, M.G., et al. (1995) Stable fetal cardiomyocyte grafts in the hearts of dystrophic mice and dogs. J Clin Invest, 96, 2034–42

    PubMed  CAS  Google Scholar 

  5. Soonpaa, M.H., Koh, G.Y., Klug, M.G., et al. (1994) Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. Science, 264, 98–101

    PubMed  CAS  Google Scholar 

  6. Rubart, M., Pasumarthi, K.B., Nakajima, H., et al. (2003) Physiological coupling of donor and host cardiomyocytes after cellular transplantation. Circ Res, 92, 1217–24

    Google Scholar 

  7. Muller-Ehmsen, J., Whittaker, P., Kloner, R.A., et al. (2002b) Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. J Mol Cell Cardiol, 34, 107–16

    PubMed  Google Scholar 

  8. Li, R.K., Jia, Z.Q., Weisel, R.D., et al. (1996) Cardiomyocyte transplantation improves heart function. Ann Thorac Surg, 62, 654–60; discussion 660–1

    PubMed  CAS  Google Scholar 

  9. Muller-Ehmsen, J., Peterson, K.L., Kedes, L., et al. (2002a) Rebuilding a damaged heart: long-term survival of transplanted neonatal rat cardiomyocytes after myocardial infarction and effect on cardiac function. Circulation, 105, 1720–6

    PubMed  Google Scholar 

  10. Sakai, T., Li, R.K., Weisel, R.D., et al. (1999) Fetal cell transplantation: a comparison of three cell types. J Thorac Cardiovasc Surg, 118, 715–24

    PubMed  CAS  Google Scholar 

  11. Alvarez-Dolado, M., Pardal, R., Garcia-Verdugo, J.M., et al. (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature, 425, 968–73

    PubMed  CAS  Google Scholar 

  12. Doetschman, T.C., Eistetter, H., Katz, M., et al. (1985) The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol, 87, 27–45

    PubMed  CAS  Google Scholar 

  13. Evans, M.J. and Kaufman, M.H. (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154–56

    PubMed  CAS  Google Scholar 

  14. Martin, G.R. (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A, 78, 7634–8

    PubMed  CAS  Google Scholar 

  15. Maltsev, V.A., Rohwedel, J., Hescheler, J., et al. (1993) Embryonic stem cells differentiate in vitro into cardiomyocytes representing sinusnodal, atrial and ventricular cell types. Mech Dev, 44, 41–50

    PubMed  CAS  Google Scholar 

  16. Zweigerdt, R., Burg, M., Willbold, E., et al. (2003) Generation of confluent cardiomyocyte monolayers derived from embryonic stem cells in suspension: a cell source for new therapies and screening strategies. Cytotherapy, 5, 399–413

    PubMed  CAS  Google Scholar 

  17. Schroeder, M., Niebruegge, S., Werner, A., et al. (2005) Differentiation and lineage selection of mouse embryonic stem cells in a stirred bench scale bioreactor with automated process control. Biotechnol Bioeng, 92, 920–33

    PubMed  CAS  Google Scholar 

  18. Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–47

    PubMed  CAS  Google Scholar 

  19. Kehat, I., Kenyagin-Karsenti, D., Snir, M., et al. (2001) Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest, 108, 407–14

    PubMed  CAS  Google Scholar 

  20. Wobus, A.M., Kaomei, G., Shan, J., et al. (1997) Retinoic acid accelerates embryonic stem cell-derived cardiac differentiation and enhances development of ventricular cardiomyocytes. J Mol Cell Cardiol, 29, 1525–39

    PubMed  CAS  Google Scholar 

  21. Guan, K., Furst, D.O. and Wobus, A.M. (1999) Modulation of sarcomere organization during embryonic stem cell-derived cardiomyocyte differentiation. Eur J Cell Biol, 78, 813–23

    PubMed  CAS  Google Scholar 

  22. Bader, A., Al-Dubai, H. and Weitzer, G. (2000) Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions. Circ Res, 86, 787–94

    PubMed  CAS  Google Scholar 

  23. Buggisch, M., Ateghang, B., Ruhe, C., et al. (2007) Stimulation of ES-cell-derived cardiomyogenesis and neonatal cardiac cell proliferation by reactive oxygen species and NADPH oxidase. J Cell Sci, 120, 885–94

    PubMed  CAS  Google Scholar 

  24. Sauer, H., Rahimi, G., Hescheler, J., et al. (2000) Role of reactive oxygen species and phosphatidylinositol 3-kinase in cardiomyocyte differentiation of embryonic stem cells. FEBS Lett, 476, 218–23

    PubMed  CAS  Google Scholar 

  25. Sharifpanah, F., Wartenberg, M., Hannig, M., et al. (2008) Peroxisome proliferator-activated receptor alpha agonists enhance cardiomyogenesis of mouse ES cells by utilization of a reactive oxygen species-dependent mechanism. Stem Cells, 26, 64–71

    PubMed  CAS  Google Scholar 

  26. Wo, Y.B., Zhu, D.Y., Hu, Y., et al. (2008) Reactive oxygen species involved in prenylflavonoids, icariin and icaritin, initiating cardiac differentiation of mouse embryonic stem cells. J Cell Biochem, 103, 1536–50

    PubMed  CAS  Google Scholar 

  27. Bader, A., Gruss, A., Hollrigl, A., et al. (2001) Paracrine promotion of cardiomyogenesis in embryoid bodies by LIF modulated endoderm. Differentiation, 68, 31–43

    PubMed  CAS  Google Scholar 

  28. Rudy-Reil, D. and Lough, J. (2004) Avian precardiac endoderm/mesoderm induces cardiac myocyte differentiation in murine embryonic stem cells. Circ Res, 94, e107–16

    PubMed  Google Scholar 

  29. Behfar, A., Zingman, L.V., Hodgson, D.M., et al. (2002) Stem cell differentiation requires a paracrine pathway in the heart. Faseb J, 16, 1558–66

    PubMed  Google Scholar 

  30. Kim, H.S., Cho, J.W., Hidaka, K., et al. (2007) Activation of MEK-ERK by heregulin-beta1 promotes the development of cardiomyocytes derived from ES cells. Biochem Biophys Res Commun, 361, 732–38

    PubMed  CAS  Google Scholar 

  31. Sachinidis, A., Schwengberg, S., Hippler-Altenburg, R., et al. (2006) Identification of small signalling molecules promoting cardiac-specific differentiation of mouse embryonic stem cells. Cell Physiol Biochem, 18, 303–14

    PubMed  CAS  Google Scholar 

  32. Xu, C., Police, S., Rao, N., et al. (2002) Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res, 91, 501–508

    PubMed  CAS  Google Scholar 

  33. Mummery, C., Ward-van Oostwaard, D., Doevendans, P., et al. (2003) Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation, 107, 2733–40

    PubMed  CAS  Google Scholar 

  34. Mummery, C.L., Ward, D. and Passier, R. (2007) Differentiation of human embryonic stem cells to cardiomyocytes by coculture with endoderm in serum-free medium. Curr Protoc Stem Cell Biol, Chapter 1, Unit 1F 2

    Google Scholar 

  35. Takahashi, T., Lord, B., Schulze, P.C., et al. (2003) Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation, 107, 1912–16

    PubMed  CAS  Google Scholar 

  36. Laflamme, M.A., Chen, K.Y., Naumova, A.V., et al. (2007) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol, 25, 1015–24

    PubMed  CAS  Google Scholar 

  37. Klug, M.G., Soonpaa, M.H., Koh, G.Y., et al. (1996) Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest, 98, 216–24

    PubMed  CAS  Google Scholar 

  38. Zandstra, P.W., Bauwens, C., Yin, T., et al. (2003a) Scalable production of embryonic stem cell-derived cardiomyocytes. Tissue Eng, 9:4

    Google Scholar 

  39. Muller, M., Fleischmann, B.K., Selbert, S., et al. (2000) Selection of ventricular-like cardiomyocytes from ES cells in vitro. Faseb J, 14, 2540–8

    PubMed  CAS  Google Scholar 

  40. Sudou, A., Muramatsu, H., Kaname, T., et al. (1997) Le(X) structure enhances myocardial differentiation from embryonic stem cells. Cell Struct Funct, 22, 247–51

    PubMed  CAS  Google Scholar 

  41. Pasumarthi, K.B., Tsai, S.C. and Field, L.J. (2001) Coexpression of mutant p53 and p193 renders embryonic stem cell-derived cardiomyocytes responsive to the growth-promoting activities of adenoviral E1A. Circ Res, 88, 1004–11

    PubMed  CAS  Google Scholar 

  42. Huh, N.E., Pasumarthi, K.B., Soonpaa, M.H., et al. (2001) Functional abrogation of p53 is required for T-Ag induced proliferation in cardiomyocytes. J Mol Cell Cardiol, 33, 1405–19

    PubMed  CAS  Google Scholar 

  43. Singh, A.M., Li, F.Q., Hamazaki, T., et al. (2007) Chibby, an antagonist of the Wnt/beta-catenin pathway, facilitates cardiomyocyte differentiation of murine embryonic stem cells. Circulation, 115, 617–26

    PubMed  CAS  Google Scholar 

  44. Anderson, D., Self, T., Mellor, I.R., et al. (2007) Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Mol Ther, 15, 2027–36

    PubMed  CAS  Google Scholar 

  45. Xu, X.Q., Zweigerdt, R., Soo, S.Y., et al. (2008) Highly enriched cardiomyocytes from human embryonic stem cells. Cytotherapy, 10, 376–89

    PubMed  Google Scholar 

  46. Sauer, H., Rahimi, G., Hescheler, J., et al. (1999) Effects of electrical fields on cardiomyocyte differentiation of embryonic stem cells. J Cell Biochem, 75, 710–23

    PubMed  CAS  Google Scholar 

  47. Gwak, S.J., Bhang, S.H., Kim, I.K., et al. (2008) The effect of cyclic strain on embryonic stem cell-derived cardiomyocytes. Biomaterials, 29, 844–56

    PubMed  CAS  Google Scholar 

  48. Shimko, V.F. and Claycomb, W.C. (2008) Effect of mechanical loading on three-dimensional cultures of embryonic stem cell-derived cardiomyocytes. Tissue Eng Part A, 14, 49–58

    PubMed  CAS  Google Scholar 

  49. Kattman, S.J., Huber, T.L. and Keller, G.M. (2006) Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev Cell, 11, 723–32

    PubMed  CAS  Google Scholar 

  50. Xu, C., Police, S., Hassanipour, M., et al. (2006) Cardiac bodies: a novel culture method for enrichment of cardiomyocytes derived from human embryonic stem cells. Stem Cells Dev, 15, 631–9

    PubMed  CAS  Google Scholar 

  51. Yang, L., Soonpaa, M.H., Adler, E.D., et al. (2008) Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature, 453, 524–28

    PubMed  CAS  Google Scholar 

  52. Zandstra, P.W., Bauwens, C., Yin, T., et al. (2003b) Scalable production of embryonic stem cell-derived cardiomyocytes. Tissue Eng, 9, 767–78

    PubMed  CAS  Google Scholar 

  53. Huber, I., Itzhaki, I., Caspi, O., et al. (2007) Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. Faseb J, 21, 2551–63

    PubMed  CAS  Google Scholar 

  54. Nussbaum, J., Minami, E., Laflamme, M.A., et al. (2007) Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. Faseb J, 21, 1345–57

    PubMed  CAS  Google Scholar 

  55. Wang, J.F., Yang, Y., Wang, G., et al. (2002) Embryonic stem cells attenuate viral myocarditis in murine model. Cell Transplant, 11, 753–58

    PubMed  Google Scholar 

  56. Yang, Y., Min, J.Y., Rana, J.S., et al. (2002) VEGF enhances functional improvement of postinfarcted hearts by transplantation of ESC-differentiated cells. J Appl Physiol, 93, 1140–51

    PubMed  CAS  Google Scholar 

  57. Kofidis, T., de Bruin, J.L., Yamane, T., et al. (2004) Insulin-like growth factor promotes engraftment, differentiation, and functional improvement after transfer of embryonic stem cells for myocardial restoration. Stem Cells, 22, 1239–45

    PubMed  CAS  Google Scholar 

  58. Kofidis, T., de Bruin, J.L., Yamane, T., et al. (2005b) Stimulation of paracrine pathways with growth factors enhances embryonic stem cell engraftment and host-specific differentiation in the heart after ischemic myocardial injury. Circulation, 111, 2486–93

    PubMed  CAS  Google Scholar 

  59. Ke, Q., Yang, Y., Rana, J.S., et al. (2005) Embryonic stem cells cultured in biodegradable scaffold repair infarcted myocardium in mice. Sheng Li Xue Bao, 57, 673–81

    PubMed  CAS  Google Scholar 

  60. Kofidis, T., deBruin, J.L., Tanaka, M., et al. (2005c) They are not stealthy in the heart: embryonic stem cells trigger cell infiltration, humoral and T-lymphocyte-based host immune response. Eur J Cardiothorac Surg, 28, 461–66

    PubMed  Google Scholar 

  61. Swijnenburg, R.J., Tanaka, M., Vogel, H., et al. (2005) Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium. Circulation, 112, I166–72

    PubMed  Google Scholar 

  62. Kofidis, T., Lebl, D.R., Martinez, E.C., et al. (2005d) Novel injectable bioartificial tissue facilitates targeted, less invasive, large-scale tissue restoration on the beating heart after myocardial injury. Circulation, 112, I173–77

    PubMed  Google Scholar 

  63. Kolossov, E., Bostani, T., Roell, W., et al. (2006) Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med, 203, 2315–27

    PubMed  CAS  Google Scholar 

  64. Nelson, T.J., Ge, Z.D., Van Orman, J., et al. (2006) Improved cardiac function in infarcted mice after treatment with pluripotent embryonic stem cells. Anat Rec A Discov Mol Cell Evol Biol, 288, 1216–24

    PubMed  Google Scholar 

  65. Singla, D.K., Hacker, T.A., Ma, L., et al. (2006) Transplantation of embryonic stem cells into the infarcted mouse heart: formation of multiple cell types. J Mol Cell Cardiol, 40, 195–200

    PubMed  CAS  Google Scholar 

  66. Behfar, A., Perez-Terzic, C., Faustino, R.S., et al. (2007) Cardiopoietic programming of embryonic stem cells for tumor-free heart repair. J Exp Med, 204, 405–20

    PubMed  CAS  Google Scholar 

  67. Ebelt, H., Jungblut, M., Zhang, Y., et al. (2007) Cellular cardiomyoplasty: improvement of left ventricular function correlates with the release of cardioactive cytokines. Stem Cells, 25, 236–44

    PubMed  CAS  Google Scholar 

  68. Ebert, S.N., Taylor, D.G., Nguyen, H.L., et al. (2007) Noninvasive tracking of cardiac embryonic stem cells in vivo using magnetic resonance imaging techniques. Stem Cells, 25, 2936–44

    PubMed  Google Scholar 

  69. Singla, D.K., Lyons, G.E. and Kamp, T.J. (2007) Transplanted embryonic stem cells following mouse myocardial infarction inhibit apoptosis and cardiac remodeling. Am J Physiol Heart Circ Physiol, 293, H1308–14

    PubMed  CAS  Google Scholar 

  70. Min, J.Y., Yang, Y., Converso, K.L., et al. (2002) Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. J Appl Physiol, 92, 288–96

    PubMed  Google Scholar 

  71. Hodgson, D.M., Behfar, A., Zingman, L.V., et al. (2004) Stable benefit of embryonic stem cell therapy in myocardial infarction. Am J Physiol Heart Circ Physiol, 287, H471–9

    PubMed  CAS  Google Scholar 

  72. Naito, H., Nishizaki, K., Yoshikawa, M., et al. (2004) Xenogeneic embryonic stem cell-derived cardiomyocyte transplantation. Transplant Proc, 36, 2507–508

    PubMed  CAS  Google Scholar 

  73. Kofidis, T., de Bruin, J.L., Hoyt, G., et al. (2005a) Myocardial restoration with embryonic stem cell bioartificial tissue transplantation. J Heart Lung Transplant, 24, 737–44

    PubMed  Google Scholar 

  74. Min, J.Y., Chen, Y., Malek, S., et al. (2005) Stem cell therapy in the aging hearts of Fisher 344 rats: synergistic effects on myogenesis and angiogenesis. J Thorac Cardiovasc Surg, 130, 547–53

    PubMed  Google Scholar 

  75. Cho, S.W., Gwak, S.J., Kim, I.K., et al. (2006) Granulocyte colony-stimulating factor treatment enhances the efficacy of cellular cardiomyoplasty with transplantation of embryonic stem cell-derived cardiomyocytes in infarcted myocardium. Biochem Biophys Res Commun, 340, 573–82

    PubMed  CAS  Google Scholar 

  76. Min, J.Y., Huang, X., Xiang, M., et al. (2006) Homing of intravenously infused embryonic stem cell-derived cells to injured hearts after myocardial infarction. J Thorac Cardiovasc Surg, 131, 889–97

    PubMed  Google Scholar 

  77. He, Q., Trindade, P.T., Stumm, M., et al. (2008) Fate of undifferentiated mouse embryonic stem cells within the rat heart: role of myocardial infarction and immune suppression. J Cell Mol Med, 13(1), 188–201

    PubMed  Google Scholar 

  78. Lu, W.N., Lu, S.H., Wang, H.B., et al. (2008) Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Eng Part A, 15, 1437–47

    Google Scholar 

  79. Cai, J., Yi, F.F., Yang, X.C., et al. (2007) Transplantation of embryonic stem cell-derived cardiomyocytes improves cardiac function in infarcted rat hearts. Cytotherapy, 9, 283–91

    PubMed  CAS  Google Scholar 

  80. Menard, C., Hagege, A.A., Agbulut, O., et al. (2005) Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study. Lancet, 366, 1005–12

    PubMed  Google Scholar 

  81. Kofidis, T., Lebl, D.R., Swijnenburg, R.J., et al. (2006) Allopurinol/uricase and ibuprofen enhance engraftment of cardiomyocyte-enriched human embryonic stem cells and improve cardiac function following myocardial injury. Eur J Cardiothorac Surg, 29, 50–55

    PubMed  Google Scholar 

  82. van Laake, L.W., Passier, R., Doevendans, P.A., et al. (2008) Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circ Res, 102, 1008–10

    PubMed  Google Scholar 

  83. van Laake, L.W., Passier, R., Monshouwer-Kloots, J., 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 Res, 1, 9–24

    PubMed  Google Scholar 

  84. Tallheden, T., Nannmark, U., Lorentzon, M., et al. (2006) In vivo MR imaging of magnetically labeled human embryonic stem cells. Life Sci, 79, 999–1006

    PubMed  CAS  Google Scholar 

  85. Caspi, O., Huber, I., Kehat, I., et al. (2007) Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol, 50, 1884–93

    PubMed  Google Scholar 

  86. Dai, W., Field, L.J., Rubart, M., et al. (2007) Survival and maturation of human embryonic stem cell-derived cardiomyocytes in rat hearts. J Mol Cell Cardiol, 43, 504–16

    PubMed  CAS  Google Scholar 

  87. Leor, J., Gerecht, S., Cohen, S., et al. (2007) Human embryonic stem cell transplantation to repair the infarcted myocardium. Heart, 93, 1278–84

    PubMed  Google Scholar 

  88. Tomescot, A., Leschik, J., Bellamy, V., et al. (2007) Differentiation in vivo of cardiac committed human embryonic stem cells in postmyocardial infarcted rats. Stem Cells, 25, 2200–5

    PubMed  CAS  Google Scholar 

  89. Xie, C.Q., Zhang, J., Xiao, Y., et al. (2007) Transplantation of human undifferentiated embryonic stem cells into a myocardial infarction rat model. Stem Cells Dev, 16, 25–29

    PubMed  CAS  Google Scholar 

  90. Laflamme, M.A., Gold, J., Xu, C., et al. (2005) Formation of human myocardium in the rat heart from human embryonic stem cells. Am J Pathol, 167, 663–71

    PubMed  CAS  Google Scholar 

  91. Xue, T., Cho, H.C., Akar, F.G., et al. (2005) Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation, 111, 11–20

    PubMed  Google Scholar 

  92. Kehat, I., Khimovich, L., Caspi, O., et al. (2004) Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol, 22, 1282–89

    PubMed  CAS  Google Scholar 

  93. Gnecchi, M., He, H., Liang, O.D., et al. (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med, 11, 367–68

    PubMed  CAS  Google Scholar 

  94. Gnecchi, M., He, H., Noiseux, N., et al. (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. Faseb J, 20, 661–69

    PubMed  CAS  Google Scholar 

  95. Mangi, A.A., Noiseux, N., Kong, D., et al. (2003) Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med, 9, 1195–201

    PubMed  CAS  Google Scholar 

  96. Mirotsou, M., Zhang, Z., Deb, A., et al. (2007) Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci U S A, 104, 1643–48

    PubMed  CAS  Google Scholar 

  97. Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., et al. (2006) Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther, 14(6), 840–50

    PubMed  CAS  Google Scholar 

  98. Kaab, S., Nuss, H.B., Chiamvimonvat, N., et al. (1996) Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res, 78, 262–73

    PubMed  CAS  Google Scholar 

  99. Kang, P.M. and Izumo, S. (2003) Apoptosis in heart: basic mechanisms and implications in cardiovascular diseases. Trends Mol Med, 9, 177–82

    PubMed  CAS  Google Scholar 

  100. Lafontant, P.J., Field, L.J. (2007) “Myocardial regeneration via cell cycle activation”, in Rebuilding the infarcted heart, K.C. Wollert and L.J. Field, Eds., Informa Healthcare, London, UK., 41–54

    Google Scholar 

  101. Pasumarthi, K.B. and Field, L.J. (2002) Cardiomyocyte cell cycle regulation. Circ Res, 90, 1044–54

    PubMed  CAS  Google Scholar 

  102. Bersell, K., Arab, S., Haring, B., et al. (2009) Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell, 138, 257–70

    PubMed  CAS  Google Scholar 

  103. Engel, F.B., Schebesta, M., Duong, M.T., et al. (2005) p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev, 19, 1175–87

    PubMed  CAS  Google Scholar 

  104. Tseng, A.S., Engel, F.B. and Keating, M.T. (2006) The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem Biol, 13, 957–63

    PubMed  CAS  Google Scholar 

  105. Yildirim, Y., Naito, H., Didie, M., et al. (2007) Development of a biological ventricular assist device: preliminary data from a small animal model. Circulation, 116, I16–23

    PubMed  Google Scholar 

  106. Zimmermann, W.H., Melnychenko, I., Wasmeier, G., et al. (2006) Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med, 12, 452–58

    PubMed  CAS  Google Scholar 

  107. Christoforou, N., Miller, R.A., Hill, C.M., et al. (2008) Mouse ES cell-derived cardiac precursor cells are multipotent and facilitate identification of novel cardiac genes. J Clin Invest, 118, 894–903

    PubMed  CAS  Google Scholar 

  108. Wu, S.M., Fujiwara, Y., Cibulsky, S.M., et al. (2006) Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell, 127, 1137–50

    PubMed  CAS  Google Scholar 

  109. Bu, L., Jiang, X., Martin-Puig, S., et al. (2009) Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature, 460, 113–17

    PubMed  CAS  Google Scholar 

  110. Moretti, A., Caron, L., Nakano, A., et al. (2006) Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell, 127, 1151–65

    PubMed  CAS  Google Scholar 

  111. David, R., Brenner, C., Stieber, J., et al. (2008) MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat Cell Biol, 10, 338–45

    PubMed  CAS  Google Scholar 

  112. Blin, G., Nury, D., Stefanovic, S., et al. (2010) A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. J Clin Invest, 120, 1125–39

    PubMed  CAS  Google Scholar 

  113. Moretti, A., Bellin, M., Jung, C.B., et al. (2010) Mouse and human induced pluripotent stem cells as a source for multipotent Isl1+ cardiovascular progenitors. FASEB J, 24, 700–11

    PubMed  CAS  Google Scholar 

  114. Shapiro, A.M., Lakey, J.R., Ryan, E.A., et al. (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med, 343, 230–38

    PubMed  CAS  Google Scholar 

  115. Lanza, R.P., Cibelli, J.B. and West, M.D. (1999) Human therapeutic cloning. Nat Med, 5, 975–77

    PubMed  CAS  Google Scholar 

  116. Guan, K., Nayernia, K., Maier, L.S., et al. (2006) Pluripotency of spermatogonial stem cells from adult mouse testis. Nature, 440, 1199–203

    PubMed  CAS  Google Scholar 

  117. Jiang, Y., Jahagirdar, B.N., Reinhardt, R.L., et al. (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 418, 41–49

    PubMed  CAS  Google Scholar 

  118. Lewitzky, M. and Yamanaka, S. (2007) Reprogramming somatic cells towards pluripotency by defined factors. Curr Opin Biotechnol, 18, 467–73

    PubMed  CAS  Google Scholar 

  119. Nakagawa, M., Koyanagi, M., Tanabe, K., et al. (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol, 26, 101–106

    PubMed  CAS  Google Scholar 

  120. Okita, K., Ichisaka, T. and Yamanaka, S. (2007) Generation of germline-competent induced pluripotent stem cells. Nature, 448, 313–37

    PubMed  CAS  Google Scholar 

  121. Takahashi, K., Tanabe, K., Ohnuki, M., et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–72

    PubMed  CAS  Google Scholar 

  122. Mauritz, C., Schwanke, K., Reppel, M., et al. (2008) Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation, 118, 507–17

    PubMed  Google Scholar 

  123. Zovoilis, A., Nolte, J., Drusenheimer, N., et al. (2008) Multipotent adult germline stem cells and embryonic stem cells have similar microRNA profiles. Mol Hum Reprod 14(9), 521–29

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Loren J. Field .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Becker, A.M., Rubart, M., Field, L.J. (2011). Inducing Embryonic Stem Cells to Become Cardiomyocytes. In: Cohen, I., Gaudette, G. (eds) Regenerating the Heart. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-61779-021-8_2

Download citation

Publish with us

Policies and ethics