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Regenerative Strategies for Cardiac Disease

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Stem Cells & Regenerative Medicine

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Current treatments for ischemic heart disease (IHD) are generally limited to palliative measures and do not halt or reverse the loss of cardiac muscle cells, the defining characteristic of the disease. Recent findings in the stem cell and developmental biology fields have suggested the possibility of generating new heart muscle using cells derived from a variety of sources. These include adult autologous stem cells found in bone marrow or skeletal muscle, autologous ­cardiac progenitor cells, embryonic stem cells, and induced pluripotent stem cells or other types of reprogrammed cells. Beating cardiomyocytes have been successfully obtained from a number of these different cell types in both murine and human models, but significant technical challenges remain before cell-based cardiac regeneration is a viable therapy. Nevertheless, a large research effort is underway to address these challenges, and the outlook for revolutionizing the treatment of IHD is optimistic.

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References

  1. National Center for Health Statistics. (2009) Health, United States, 2008, with Chartbook. National Center for Health Statistics. Hyattsville, MD.

    Google Scholar 

  2. Mackay, J. and Mensah, G. (2004) The Atlas of Heart Disease and Stroke. World Health Organization. Geneva, Switzerland.

    Google Scholar 

  3. Ahuja, P., Sdek, P., and MacLellan W.R. (2007) Cardiac myocyte cell cycle control in ­development, disease, and regeneration. Physiol. Rev. 87, 521-544.

    Article  PubMed  CAS  Google Scholar 

  4. Rubart, M. and Field, L.J. (2006) Cardiac regeneration: repopulating the heart. Annu. Rev. Physiol. 68, 29-49.

    Article  PubMed  CAS  Google Scholar 

  5. Okabe, M., Tsukahara, Y., Tanaka, M., et al. (2009) Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver. Development 136, 1951-1960.

    Article  PubMed  CAS  Google Scholar 

  6. Sherwood, R.I., Christensen, J.L., Conboy, I.M., et al. (2004) Isolation of adult mouse ­myogenic progenitors: functional heterogeneity of cells within and engrafting skeletal muscle. Cell 119, 543-554.

    Article  PubMed  CAS  Google Scholar 

  7. Li, A., Pouliot, N., Redvers, R., et al. (2004) Extensive tissue-regenerative capacity of neonatal human keratinocyte stem cells and their progeny. J. Clin. Invest. 113, 390-400.

    PubMed  CAS  Google Scholar 

  8. Baum, C.M., Weissman, I.L., Tsukamoto, A.S., et al. (1992) Isolation of a candidate human hematopoietic stem-cell population. Proc. Natl. Acad. Sci. U. S. A. 89, 2804-2808.

    Article  CAS  Google Scholar 

  9. Beltrami, A.P., Barlucchi, L., Torella, D., et al. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763-776.

    Article  PubMed  CAS  Google Scholar 

  10. Laugwitz, K.L., Moretti, A., Lam, J., et al. (2005) Postnatal isl1+ cardioblasts enter fully ­differentiated cardiomyocyte lineages. Nature 433, 647-653.

    Article  PubMed  CAS  Google Scholar 

  11. Martin, C.M., Meeson, A.P., Robertson, S.M., et al. (2004) Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev. Biol. 265, 262-275.

    Article  PubMed  CAS  Google Scholar 

  12. Oh, H., Bradfute, S.B., Gallardo, T.D., et al. (2003) Cardiac progenitor cells from adult ­myocardium: homing, differentiation, and fusion after infarction. Proc. Natl. Acad. Sci. U. S. A. 100, 12313-12318.

    Article  CAS  Google Scholar 

  13. Segers, V. and Lee, R.T. (2008) Stem-cell therapy for cardiac disease. Nature 451, 937-942.

    Article  PubMed  CAS  Google Scholar 

  14. Yoon, P.D., Kao, R.L., and Magovern, G.J. (1995) Myocardial regeneration. Transplanting satellite cells into damaged myocardium. Tex. Heart Inst. J. 22, 119-125.

    PubMed  CAS  Google Scholar 

  15. Taylor, D.A., Atkins, B.Z., Hungspreugs, P., et al. (1998) Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat. Med. 4, 929-933.

    Article  PubMed  CAS  Google Scholar 

  16. Iijima, Y., Nagai, T., Mizukami, M., et al. (2003) Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes. FASEB J. 17, 1361-1363.

    PubMed  CAS  Google Scholar 

  17. Winitsky, S.O., Gopal, T.V., Hassanzadeh, S., et al. (2005) Adult murine skeletal muscle ­contains cells that can differentiate into beating cardiomyocytes in vitro. PLOS Biol. 3, e87.

    Article  PubMed  CAS  Google Scholar 

  18. Gavira, J.J., Perez-Ilzarbe, M., Abizanda, G., et al. (2006) A comparison between percutaneous and surgical transplantation of autologous skeletal myoblasts in a swine model of chronic myocardial infarction. Cardiovasc. Res. 71, 744-753.

    Article  PubMed  CAS  Google Scholar 

  19. Gavira, J.J., Herreros, J., Perez, A., et al. (2006) Autologous skeletal myoblast transplantation in patients with nonacute myocardial infarction: 1-year follow-up. J. Thorac. Cardiovasc. Surg. 131, 799-804.

    Article  PubMed  Google Scholar 

  20. Menasche, P., Hagege, A.A., Scorsin, M., et al. (2001) Myoblast transplantation for heart failure. Lancet 357, 279-280.

    Article  PubMed  CAS  Google Scholar 

  21. Perez-Ilzarbe, M., Agbulut, O., Pelacho, B., et al. (2008) Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium. Eur. J. Heart Fail. 10, 1065-1072.

    Article  PubMed  CAS  Google Scholar 

  22. Laflamme, M.A. and Murry, C.E. (2005) Regenerating the heart. Nat. Biotechnol. 23, 845-856.

    Article  PubMed  CAS  Google Scholar 

  23. Leobon, B., Garcin, I., Menasche, P., et al. (2003) Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc. Natl. Acad. Sci. U. S. A. 100, 7808-7811.

    Google Scholar 

  24. Menasche, P., Hagege, A.A., Vilquin, J.T., et al. (2003) Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J. Am. Coll. Cardiol. 41, 1078-1083.

    Article  PubMed  Google Scholar 

  25. Hocht-Zeisberg, E., Kahnert, H., Guan, K., et al. (2004) Cellular repopulation of myocardial infarction in patients with sex-mismatched heart transplantation. Eur. Heart J. 25, 749−758.

    Article  PubMed  CAS  Google Scholar 

  26. Glaser, R., Lu, M.M., Narula, N., Epstein, J.A. (2002) Smooth muscle cells, but not myocytes, of host origin in transplanted human hearts. Circulation 106, 17−19.

    Article  PubMed  Google Scholar 

  27. Deb, A., Wang, S., Skelding, K.A., et al. (2003) Bone marrow-derived cardiomyocytes are present in adult human heart: a study of gender-mismatched bone marrow transplantation patients. Circulation 107, 1247−1249.

    Article  PubMed  Google Scholar 

  28. Bittner, R.E., Schofer, C., Weipoltshammer, K., et al. (1999) Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat. Embryol. (Berl) 199, 391−396.

    Article  CAS  Google Scholar 

  29. Erbs, S., Linke, A., Schachinger, V., et al. (2007) Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. Circulation 116, 366-374.

    Article  PubMed  Google Scholar 

  30. Wollert, K.C., Meyer, G.P., Lotz, J., et al. (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364, 141−148.

    Article  PubMed  Google Scholar 

  31. Laflamme, M.A., Myerson, D., Saffitz, J.E., et al. (2002) Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ. Res. 90, 634−640.

    Article  PubMed  CAS  Google Scholar 

  32. Zhou, Q. and Melton, D.A. (2008) Extreme makeover: converting one cell into another. Cell Stem Cell 3, 382-388.

    Article  PubMed  CAS  Google Scholar 

  33. Amit, M., Carpenter, M.K., Inokuma, M.S., et al. (2000) Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev. Biol. 227, 271−278.

    Article  PubMed  CAS  Google Scholar 

  34. 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 

  35. Xu, C., Police, S., Rao, N., Carpenter, M.K. (2002) Characterization and enrichment of ­cardiomyocytes derived from human embryonic stem cells. Circ. Res. 91, 501−508.

    Article  PubMed  CAS  Google Scholar 

  36. Fijnvandraat, A.C., van Ginneken, A.C., de Boer, P.A., et al. (2003) Cardiomyocytes derived from embryonic stem cells resemble cardiomyocytes of the embryonic heart tube. Cardiovasc. Res. 58, 399−409.

    Article  PubMed  CAS  Google Scholar 

  37. 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, 1345-1357.

    Article  PubMed  CAS  Google Scholar 

  38. 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−H479.

    Article  PubMed  CAS  Google Scholar 

  39. Klug, M.G., Soonpaa, M.H., Koh, G.Y., et al. (1996) Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J. Clin. Invest. 98, 216−224.

    Article  PubMed  CAS  Google Scholar 

  40. 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, 1525−1539.

    Article  PubMed  CAS  Google Scholar 

  41. Takahashi, T., Lord, B., Schulze, P.C., et al. (2003) Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 107, 1912−1916.

    Article  PubMed  CAS  Google Scholar 

  42. Kawai, T., Takahashi, T., Esaki, M., et al. (2004) Efficient cardiomyogenic differentiation of embryonic stem cell by fibroblast growth factor 2 and bone morphogenetic protein 2. Circ. J. 68, 691−702.

    Article  PubMed  CAS  Google Scholar 

  43. Terami, H., Hidaka, K., Katsumata, T., et al. (2004) Wnt11 facilitates embryonic stem cell differentiation to Nkx2.5-positive cardiomyocytes. Biochem. Biophys. Res. Commun. 325, 968−975.

    Article  PubMed  CAS  Google Scholar 

  44. Semb, H. (2006) Human embryonic stem cells: origin, properties and applications. APMIS 113, 743-750.

    Article  Google Scholar 

  45. Zou, K., Yuan, Z., Yang, Z., et al. (2009) Production of offspring from a germline stem cell line derived from neonatal ovaries. Nat. Cell Biol. 11, 631-636.

    Article  PubMed  CAS  Google Scholar 

  46. Snir, M., Kehat, I., Gepstein, A., et al. (2003) Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 285, H2355−H2363.

    PubMed  CAS  Google Scholar 

  47. 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, 663-671.

    Article  PubMed  CAS  Google Scholar 

  48. 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, 1015-1024.

    Article  PubMed  CAS  Google Scholar 

  49. 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, 1008-1010.

    Article  PubMed  CAS  Google Scholar 

  50. Takahashi, K. and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 652-655.

    Article  CAS  Google Scholar 

  51. Mauritz, C., Schwanke, K., Reppel, M., et al. (2008) Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 118, 507-517.

    Article  PubMed  Google Scholar 

  52. Zhang, J., Wilson, G.F., Soerens, A.G., et al. (2009) Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ. Res. 104, e30-e41.

    Article  PubMed  CAS  Google Scholar 

  53. Yamanaka, S. (2009) A fresh look at iPS cells. Cell 137, 13-17.

    Article  PubMed  CAS  Google Scholar 

  54. Zhao, R. and Daley, G.Q. (2008) From fibroblasts to iPS cells: induced pluripotency by defined factors. J. Cell. Biochem. 105, 949-955.

    Article  PubMed  CAS  Google Scholar 

  55. Stadtfeld, M., Nagaya, M., Utikal, J., et al. (2008) Induced pluripotent stem cells generated without viral integration. Science 322, 945-949.

    Article  PubMed  CAS  Google Scholar 

  56. Kaji, K., Norrby, K., Paca, A., et al. (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458, 771-775.

    Article  PubMed  CAS  Google Scholar 

  57. Shi, Y., Desponts, C., Do, J.T., et al. (2008) Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3, 568-574.

    Article  PubMed  CAS  Google Scholar 

  58. Brockes, J.P. and Kumar, A. (2002) Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nat. Rev. Mol. Cell Biol. 3, 566-574.

    Article  PubMed  CAS  Google Scholar 

  59. Davis, R.L., Weintraub, H., and Lassar, A.B. (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987-1000.

    Article  PubMed  CAS  Google Scholar 

  60. Xie, H., Ye, M., Feng, R., et al. (2004) Stepwise reprogramming of B cells into macrophages. Cell 117, 663-676.

    Article  PubMed  CAS  Google Scholar 

  61. Zhou, Q., Brown, J., Kanarek, A., et al. (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627-632.

    Article  PubMed  CAS  Google Scholar 

  62. Martin-Puig, S., Wang, Z., and Chien, K.R. (2008) Lives of a heart cell: tracing the origins of cardiac progenitors. Cell Stem Cell 2, 320-331.

    Article  PubMed  CAS  Google Scholar 

  63. Takeuchi, J.K. and Bruneau, BG. (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459, 708-711.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  65. 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, 970-974.

    Article  PubMed  CAS  Google Scholar 

  66. Baker, D.E., Harrison, N.J., Maltby, E., et al. (2007) Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat. Biotechnol. 25, 207-215.

    Article  PubMed  CAS  Google Scholar 

  67. Kuhn, B., del Monte, F., Hajjar, R.J., et al. (2007) Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat. Med. 13, 962-969.

    Article  PubMed  CAS  Google Scholar 

  68. Tateishi, K., Takehara, N., Matsubara, H., et al. (2008) Stemming heart failure with cardiac- or reprogrammed-stem cells. J. Cell. Mol. Med. 12, 2217-2232.

    Article  PubMed  CAS  Google Scholar 

  69. Laugwitz, K.L., Moretti, A., Lam, J., et al. (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647−653.

    Article  PubMed  CAS  Google Scholar 

  70. Oh, H., Bradfute, S.B., Gallardo, T.D., et al. (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl. Acad. Sci. U. S. A. 100, 12313−12318.

    Article  PubMed  CAS  Google Scholar 

  71. Dawn, B., Stein, A.B., Urbanek, K., et al. (2005) Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc. Natl. Acad. Sci. U. S. A. 102, 3766-3771.

    Article  CAS  Google Scholar 

  72. Wu, S.M., Chien, K.R., Mummery, C. (2008) Origins and fates of cardiovascular progenitor cells. Cell. 132, 537–543.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Harvard Stem Cell Institute, Simches Building, CPZN 3224 185 Cambridge Street, Boston, MA, 02114, USA

    Sean M. Wu

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  1. Xiaojing Huang
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  2. James Oh
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  3. Sean M. Wu
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Correspondence to Sean M. Wu .

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  1. Gene Expression Systems, Inc., Waltham, Massachusetts, USA

    Krishnarao Appasani

  2. Student Science, Wyllys Ave 45, Middletown, 06459, Connecticut, USA

    Raghu K. Appasani

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Huang, X., Oh, J., Wu, S.M. (2011). Regenerative Strategies for Cardiac Disease. In: Appasani, K., Appasani, R. (eds) Stem Cells & Regenerative Medicine. Stem Cell Biology and Regenerative Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-860-7_35

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