Journal of Cardiovascular Translational Research

, Volume 3, Issue 6, pp 652–662

The Paracrine Effect: Pivotal Mechanism in Cell-Based Cardiac Repair

  • Simon Maltais
  • Jacques P. Tremblay
  • Louis P. Perrault
  • Hung Q. Ly


Cardiac cell therapy has emerged as a controversial yet promising therapeutic strategy. Both experimental data and clinical applications in this field have shown modest but tangible benefits on cardiac structure and function and underscore that transplanted stem–progenitor cells can attenuate the postinfarct microenvironment. The paracrine factors secreted by these cells represent a pivotal mechanism underlying the benefits of cell-mediated cardiac repair. This article reviews key studies behind the paracrine effect related to the cardiac reparative effects of cardiac cell therapy.


Paracrine Effect Cardiac Repair Stem–Progenitor Cells Therapy 


  1. 1.
    Antman, E. M., Hand, M., Armstrong, P. W., Bates, E. R., Green, L. A., et al. (2008). 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 writing group to review new evidence and update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation, 117, 296–329.PubMedCrossRefGoogle Scholar
  2. 2.
    Jessup, M., & Brozena, S. (2003). Heart failure. The New England Journal of Medicine, 348, 2007–2018.PubMedCrossRefGoogle Scholar
  3. 3.
    Hunt, S. A., Abraham, W. T., Chin, M. H., Feldman, A. M., Francis, G. S., et al. (2005). ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation, 112, e154–e235.PubMedCrossRefGoogle Scholar
  4. 4.
    Dimmeler, S., Zeiher, A. M., & Schneider, M. D. (2005). Unchain my heart: The scientific foundations of cardiac repair. Journal of Clinical Investigation, 115, 572–583.PubMedGoogle Scholar
  5. 5.
    Segers, V. F., & Lee, R. T. (2008). Stem-cell therapy for cardiac disease. Nature, 451, 937–942.PubMedCrossRefGoogle Scholar
  6. 6.
    Wagers, A. J., & Weissman, I. L. (2004). Plasticity of adult stem cells. Cell, 116, 639–648.PubMedCrossRefGoogle Scholar
  7. 7.
    Hristov, M., & Weber, C. (2006). The therapeutic potential of progenitor cells in ischemic heart disease—past, present and future. Basic Research in Cardiology, 101, 1–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Leri, A., Kajstura, J., & Anversa, P. (2005). Cardiac stem cells and mechanisms of myocardial regeneration. Physiological Reviews, 85, 1373–1416.PubMedCrossRefGoogle Scholar
  9. 9.
    Fraser, J. K., Schreiber, R. E., Zuk, P. A., & Hedrick, M. H. (2004). Adult stem cell therapy for the heart. The International Journal of Biochemistry & Cell Biology, 36, 658–666.CrossRefGoogle Scholar
  10. 10.
    Muller, P., Beltrami, A. P., Cesselli, D., Pfeiffer, P., Kazakov, A., et al. (2005). Myocardial regeneration by endogenous adult progenitor cells. Journal of Molecular and Cellular Cardiology, 39, 377–387.PubMedCrossRefGoogle Scholar
  11. 11.
    Caplice, N. M., Gersh, B. J., & Alegria, J. R. (2005). Cell therapy for cardiovascular disease: What cells, what diseases and for whom? Nature Clinical Practice. Cardiovascular Medicine, 2, 37–43.PubMedCrossRefGoogle Scholar
  12. 12.
    Fukuda, K., & Yuasa, S. (2006). Stem cells as a source of regenerative cardiomyocytes. Circulation Research, 98, 1002–1013.PubMedCrossRefGoogle Scholar
  13. 13.
    Gepstein, L. (2006). Cardiovascular therapeutic aspects of cell therapy and stem cells. Annals of the New York Academy of Sciences, 1080, 415–425.PubMedCrossRefGoogle Scholar
  14. 14.
    Anversa, P., Kajstura, J., Leri, A., & Bolli, R. (2006). Life and death of cardiac stem cells: A paradigm shift in cardiac biology. Circulation, 113, 1451–1463.PubMedCrossRefGoogle Scholar
  15. 15.
    Wang, Q. D., & Sjoquist, P. O. (2006). Myocardial regeneration with stem cells: Pharmacological possibilities for efficacy enhancement. Pharmacological Research, 53, 331–340.PubMedCrossRefGoogle Scholar
  16. 16.
    Beltrami, A. P., Urbanek, K., Kajstura, J., Yan, S. M., Finato, N., et al. (2001). Evidence that human cardiac myocytes divide after myocardial infarction. The New England Journal of Medicine, 344, 1750–1757.PubMedCrossRefGoogle Scholar
  17. 17.
    Beltrami, A. P., Barlucchi, L., Torella, D., Baker, M., Limana, F., et al. (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell, 114, 763–776.PubMedCrossRefGoogle Scholar
  18. 18.
    Oh, H., Bradfute, S. B., Gallardo, T. D., Nakamura, T., Gaussin, V., et al. (2003). Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction. Proceedings of the National Academy of Sciences of the United States of America, 100, 12313–12318.PubMedCrossRefGoogle Scholar
  19. 19.
    Matsuura, K., Nagai, T., Nishigaki, N., Oyama, T., Nishi, J., et al. (2004). Adult cardiac Sca-1-positive cells differentiate into beating cardiomyocytes. The Journal of Biological Chemistry, 279, 11384–11391.PubMedCrossRefGoogle Scholar
  20. 20.
    Martin, C. M., Meeson, A. P., Robertson, S. M., Hawke, T. J., Richardson, J. A., et al. (2004). Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Developmental Biology, 265, 262–275.PubMedCrossRefGoogle Scholar
  21. 21.
    Pfister, O., Mouquet, F., Jain, M., Summer, R., Helmes, M., et al. (2005). CD31− but not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circulation Research, 97, 52–61.PubMedCrossRefGoogle Scholar
  22. 22.
    Lipinski, M. J., Biondi-Zoccai, G. G., Abbate, A., Khianey, R., Sheiban, I., et al. (2007). Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: A collaborative systematic review and meta-analysis of controlled clinical trials. Journal of the American College of Cardiology, 50, 1761–1767.PubMedCrossRefGoogle Scholar
  23. 23.
    Abdel-Latif, A., Bolli, R., Tleyjeh, I. M., Montori, V. M., Perin, E. C., et al. (2007). Adult bone marrow-derived cells for cardiac repair: A systematic review and meta-analysis. Archives of Internal Medicine, 167, 989–997.PubMedCrossRefGoogle Scholar
  24. 24.
    Schachinger, V., Erbs, S., Elsasser, A., Haberbosch, W., Hambrecht, R., et al. (2006). Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: Final 1-year results of the REPAIR-AMI trial. European Heart Journal, 28, 638.Google Scholar
  25. 25.
    Wollert, K. C., Meyer, G. P., Lotz, J., Ringes-Lichtenberg, S., Lippolt, P., et al. (2004). Intracoronary autologous bone-marrow cell transfer after myocardial infarction: The BOOST randomised controlled clinical trial. Lancet, 364, 141–148.PubMedCrossRefGoogle Scholar
  26. 26.
    Janssens, S., Dubois, C., Bogaert, J., Theunissen, K., Deroose, C., et al. (2006). Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: Double-blind, randomised controlled trial. Lancet, 367, 113–121.PubMedCrossRefGoogle Scholar
  27. 27.
    Oettgen, P., Boyle, A. J., Schulman, S. P., & Hare, J. M. (2006). Controversies in cardiovascular medicine. Circulation, 114, 353–358.PubMedCrossRefGoogle Scholar
  28. 28.
    Murry, C. E., Field, L. J., & Menasche, P. (2005). Cell-based cardiac repair: Reflections at the 10-year point. Circulation, 112, 3174–3183.PubMedCrossRefGoogle Scholar
  29. 29.
    Boyle, A. J., Schulman, S. P., Hare, J. M., & Oettgen, P. (2006). Controversies in cardiovascular medicine: Ready for the next step. Circulation, 114, 339–352.PubMedCrossRefGoogle Scholar
  30. 30.
    Charwat, S., Gyongyosi, M., Lang, I., Graf, S., Beran, G., et al. (2008). Role of adult bone marrow stem cells in the repair of ischemic myocardium: Current state of the art. Experimental Hematology, 36, 672–680.PubMedCrossRefGoogle Scholar
  31. 31.
    Burt, R. K., Loh, Y., Pearce, W., Beohar, N., Barr, W. G., et al. (2008). Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. JAMA, 299, 925–936.PubMedCrossRefGoogle Scholar
  32. 32.
    Sussman, M. A., & Murry, C. E. (2008). Bones of contention: Marrow-derived cells in myocardial regeneration. Journal of Molecular and Cellular Cardiology, 44, 950–953.PubMedCrossRefGoogle Scholar
  33. 33.
    Rosenzweig, A. (2006). Cardiac cell therapy—mixed results from mixed cells. The New England Journal of Medicine, 355, 1274–1277.PubMedCrossRefGoogle Scholar
  34. 34.
    Gersh, B. J., & Simari, R. D. (2006). Cardiac cell-repair therapy: Clinical issues. Nature Clinical Practice. Cardiovascular Medicine, 3(Suppl 1), S105–S109.PubMedCrossRefGoogle Scholar
  35. 35.
    Murry, C. E., Reinecke, H., & Pabon, L. M. (2006). Regeneration gaps: Observations on stem cells and cardiac repair. Journal of the American College of Cardiology, 47, 1777–1785.PubMedCrossRefGoogle Scholar
  36. 36.
    Ott, H. C., McCue, J., & Taylor, D. A. (2005). Cell-based cardiovascular repair—the hurdles and the opportunities. Basic Research in Cardiology, 100, 504–517.PubMedCrossRefGoogle Scholar
  37. 37.
    Rosen, M. R. (2006). Are stem cells drugs? The regulation of stem cell research and development. Circulation, 114, 1992–2000.PubMedCrossRefGoogle Scholar
  38. 38.
    Anversa, P., Leri, A., & Kajstura, J. (2006). Cardiac regeneration. Journal of the American College of Cardiology, 47, 1769–1776.PubMedCrossRefGoogle Scholar
  39. 39.
    Hou, D., Youssef, E. A., Brinton, T. J., Zhang, P., Rogers, P., et al. (2005). Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: Implications for current clinical trials. Circulation, 112, I150–I156.PubMedGoogle Scholar
  40. 40.
    Ly, H. Q., Hoshino, K., Pomerantseva, I., Kawase, Y., Yoneyama, R., et al. (2009). In vivo myocardial distribution of multipotent progenitor cells following intracoronary delivery in a swine model of myocardial infarction. European Heart Journal, 30, 2861–2868.PubMedCrossRefGoogle Scholar
  41. 41.
    Schachinger, V., Aicher, A., Dobert, N., Rover, R., Diener, J., et al. (2008). Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium. Circulation, 118, 1425–1432.PubMedCrossRefGoogle Scholar
  42. 42.
    Hofmann, M., Wollert, K. C., Meyer, G. P., Menke, A., Arseniev, L., et al. (2005). Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation, 111, 2198–2202.PubMedCrossRefGoogle Scholar
  43. 43.
    Beeres, S. L., Bengel, F. M., Bartunek, J., Atsma, D. E., Hill, J. M., et al. (2007). Role of imaging in cardiac stem cell therapy. Journal of the American College of Cardiology, 49, 1137–1148.PubMedCrossRefGoogle Scholar
  44. 44.
    Yau, T. M., Kim, C., Li, G., Zhang, Y., Weisel, R. D., et al. (2005). Maximizing ventricular function with multimodal cell-based gene therapy. Circulation, 112, I123–I128.PubMedCrossRefGoogle Scholar
  45. 45.
    Jain, M., DerSimonian, H., Brenner, D. A., Ngoy, S., Teller, P., et al. (2001). Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction. Circulation, 103, 1920–1927.PubMedGoogle Scholar
  46. 46.
    Lapidot, T., & Petit, I. (2002). Current understanding of stem cell mobilization: The roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Experimental Hematology, 30, 973–981.PubMedCrossRefGoogle Scholar
  47. 47.
    Thum, T., Bauersachs, J., Poole-Wilson, P. A., Volk, H. D., & Anker, S. D. (2005). The dying stem cell hypothesis: Immune modulation as a novel mechanism for progenitor cell therapy in cardiac muscle. Journal of the American College of Cardiology, 46, 1799–1802.PubMedCrossRefGoogle Scholar
  48. 48.
    Heil, M., Ziegelhoeffer, T., Mees, B., & Schaper, W. (2004). A different outlook on the role of bone marrow stem cells in vascular growth: Bone marrow delivers software not hardware. Circulation Research, 94, 573–574.PubMedCrossRefGoogle Scholar
  49. 49.
    Frangogiannis, N. G., Smith, C. W., & Entman, M. L. (2002). The inflammatory response in myocardial infarction. Cardiovascular Research, 53, 31–47.PubMedCrossRefGoogle Scholar
  50. 50.
    Mann, D. L. (2002). Inflammatory mediators and the failing heart: Past, present, and the foreseeable future. Circulation Research, 91, 988–998.PubMedCrossRefGoogle Scholar
  51. 51.
    Riese, U., Brenner, S., Docke, W. D., Prosch, S., Reinke, P., et al. (2000). Catecholamines induce IL-10 release in patients suffering from acute myocardial infarction by transactivating its promoter in monocytic but not in T-cells. Molecular and Cellular Biochemistry, 212, 45–50.PubMedCrossRefGoogle Scholar
  52. 52.
    Kranz, A., Rau, C., Kochs, M., & Waltenberger, J. (2000). Elevation of vascular endothelial growth factor-A serum levels following acute myocardial infarction. Evidence for its origin and functional significance. Journal of Molecular and Cellular Cardiology, 32, 65–72.PubMedCrossRefGoogle Scholar
  53. 53.
    Ziegelhoeffer, T., Fernandez, B., Kostin, S., Heil, M., Voswinckel, R., et al. (2004). Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circulation Research, 94, 230–238.PubMedCrossRefGoogle Scholar
  54. 54.
    Kinnaird, T., Stabile, E., Burnett, M. S., Shou, M., Lee, C. W., et al. (2004). Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation, 109, 1543–1549.PubMedCrossRefGoogle Scholar
  55. 55.
    Kinnaird, T., Stabile, E., Burnett, M. S., Lee, C. W., Barr, S., et al. (2004). Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation Research, 94, 678–685.PubMedCrossRefGoogle Scholar
  56. 56.
    Uemura, R., Xu, M., Ahmad, N., & Ashraf, M. (2006). Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circulation Research, 98, 1414–1421.PubMedCrossRefGoogle Scholar
  57. 57.
    Gnecchi, M., He, H., Liang, O. D., Melo, L. G., Morello, F., et al. (2005). Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Natural Medicines, 11, 367–368.CrossRefGoogle Scholar
  58. 58.
    Gnecchi, M., He, H., Noiseux, N., Liang, O. D., Zhang, L., et al. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. The FASEB Journal, 20, 661–669.PubMedCrossRefGoogle Scholar
  59. 59.
    Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., Zhang, L., Solomon, S. D., et al. (2006). Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy, 14, 840–850.PubMedCrossRefGoogle Scholar
  60. 60.
    Mirotsou, M., Zhang, Z., Deb, A., Zhang, L., Gnecchi, M., et al. (2007). Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proceedings of the National Academy of Sciences of the United States of America, 104, 1643–1648.PubMedCrossRefGoogle Scholar
  61. 61.
    Fazel, S., Cimini, M., Chen, L., Li, S., Angoulvant, D., et al. (2006). Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. Journal of Clinical Investigation, 116, 1865–1877.PubMedCrossRefGoogle Scholar
  62. 62.
    Brogi, E., Schatteman, G., Wu, T., Kim, E. A., Varticovski, L., et al. (1996). Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. Journal of Clinical Investigation, 97, 469–476.PubMedCrossRefGoogle Scholar
  63. 63.
    Murtuza, B., Suzuki, K., Bou-Gharios, G., Beauchamp, J. R., Smolenski, R. T., et al. (2004). Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium. Proceedings of the National Academy of Sciences of the United States of America, 101, 4216–4221.PubMedCrossRefGoogle Scholar
  64. 64.
    Formigli, L., Perna, A. M., Meacci, E., Cinci, L., Margheri, M., et al. (2007). Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodelling. Journal of Cellular and Molecular Medicine, 11, 1087–1100.PubMedCrossRefGoogle Scholar
  65. 65.
    Perez-Ilzarbe, M., Agbulut, O., Pelacho, B., Ciorba, C., San Jose-Eneriz, E., et al. (2008). Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium. European Journal of Heart Failure, 10, 1065–1072.PubMedCrossRefGoogle Scholar
  66. 66.
    Rehman, J., Traktuev, D., Li, J., Merfeld-Clauss, S., Temm-Grove, C. J., et al. (2004). Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation, 109, 1292–1298.PubMedCrossRefGoogle Scholar
  67. 67.
    Lapidot, T., Dar, A., & Kollet, O. (2005). How do stem cells find their way home? Blood, 106, 1901–1910.PubMedCrossRefGoogle Scholar
  68. 68.
    Tilling, L., Chowienczyk, P., & Clapp, B. (2009). Progenitors in motion: Mechanisms of mobilization of endothelial progenitor cells. British Journal of Clinical Pharmacology, 68, 484–492.PubMedCrossRefGoogle Scholar
  69. 69.
    Tashiro, K., Tada, H., Heilker, R., Shirozu, M., Nakano, T., et al. (1993). Signal sequence trap: A cloning strategy for secreted proteins and type I membrane proteins. Science, 261, 600–603.PubMedCrossRefGoogle Scholar
  70. 70.
    Levesque, J. P., Hendy, J., Takamatsu, Y., Simmons, P. J., & Bendall, L. J. (2003). Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. Journal of Clinical Investigation, 111, 187–196.PubMedGoogle Scholar
  71. 71.
    De Falco, E., Porcelli, D., Torella, A. R., Straino, S., Iachininoto, M. G., et al. (2004). SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood, 104, 3472–3482.PubMedCrossRefGoogle Scholar
  72. 72.
    Burns, J. M., Summers, B. C., Wang, Y., Melikian, A., Berahovich, R., et al. (2006). A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. The Journal of Experimental Medicine, 203, 2201–2213.PubMedCrossRefGoogle Scholar
  73. 73.
    Peichev, M., Naiyer, A. J., Pereira, D., Zhu, Z., Lane, W. J., et al. (2000). Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood, 95, 952–958.PubMedGoogle Scholar
  74. 74.
    Ceradini, D. J., & Gurtner, G. C. (2005). Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends in Cardiovascular Medicine, 15, 57–63.PubMedCrossRefGoogle Scholar
  75. 75.
    Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., et al. (2002). Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell, 109, 625–637.PubMedCrossRefGoogle Scholar
  76. 76.
    Petit, I., Jin, D., & Rafii, S. (2007). The SDF-1-CXCR4 signaling pathway: A molecular hub modulating neo-angiogenesis. Trends in Immunology, 28, 299–307.PubMedCrossRefGoogle Scholar
  77. 77.
    Massa, M., Rosti, V., Ferrario, M., Campanelli, R., Ramajoli, I., et al. (2005). Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood, 105, 199–206.PubMedCrossRefGoogle Scholar
  78. 78.
    Isner, J. M. (2000). Tissue responses to ischemia: Local and remote responses for preserving perfusion of ischemic muscle. Journal of Clinical Investigation, 106, 615–619.PubMedCrossRefGoogle Scholar
  79. 79.
    Tepper, O. M., Capla, J. M., Galiano, R. D., Ceradini, D. J., Callaghan, M. J., et al. (2005). Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood, 105, 1068–1077.PubMedCrossRefGoogle Scholar
  80. 80.
    Minchenko, A., Salceda, S., Bauer, T., & Caro, J. (1994). Hypoxia regulatory elements of the human vascular endothelial growth factor gene. Cellular & Molecular Biology Research, 40, 35–39.Google Scholar
  81. 81.
    Laterveer, L., Zijlmans, J. M., Lindley, I. J., Hamilton, M. S., Willemze, R., et al. (1996). Improved survival of lethally irradiated recipient mice transplanted with circulating progenitor cells mobilized by IL-8 after pretreatment with stem cell factor. Experimental Hematology, 24, 1387–1393.PubMedGoogle Scholar
  82. 82.
    King, A. G., Horowitz, D., Dillon, S. B., Levin, R., Farese, A. M., et al. (2001). Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta. Blood, 97, 1534–1542.PubMedCrossRefGoogle Scholar
  83. 83.
    Discher, D. E., Mooney, D. J., & Zandstra, P. W. (2009). Growth factors, matrices, and forces combine and control stem cells. Science, 324, 1673–1677.PubMedCrossRefGoogle Scholar
  84. 84.
    Yla-Herttuala, S., Rissanen, T. T., Vajanto, I., & Hartikainen, J. (2007). Vascular endothelial growth factors: Biology and current status of clinical applications in cardiovascular medicine. Journal of the American College of Cardiology, 49, 1015–1026.PubMedCrossRefGoogle Scholar
  85. 85.
    Hattori, K., Dias, S., Heissig, B., Hackett, N. R., Lyden, D., et al. (2001). Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. The Journal of Experimental Medicine, 193, 1005–1014.PubMedCrossRefGoogle Scholar
  86. 86.
    Hiasa, K., Egashira, K., Kitamoto, S., Ishibashi, M., Inoue, S., et al. (2004). Bone marrow mononuclear cell therapy limits myocardial infarct size through vascular endothelial growth factor. Basic Research in Cardiology, 99, 165–172.PubMedCrossRefGoogle Scholar
  87. 87.
    Laguens, R., Cabeza Meckert, P., Vera Janavel, G., Del Valle, H., Lascano, E., et al. (2002). Entrance in mitosis of adult cardiomyocytes in ischemic pig hearts after plasmid-mediated rhVEGF165 gene transfer. Gene Therapy, 9, 1676–1681.PubMedCrossRefGoogle Scholar
  88. 88.
    Zarnegar, R., & Michalopoulos, G. K. (1995). The many faces of hepatocyte growth factor: From hepatopoiesis to hematopoiesis. The Journal of Cell Biology, 129, 1177–1180.PubMedCrossRefGoogle Scholar
  89. 89.
    Nakamura, T., Mizuno, S., Matsumoto, K., Sawa, Y., & Matsuda, H. (2000). Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. Journal of Clinical Investigation, 106, 1511–1519.PubMedCrossRefGoogle Scholar
  90. 90.
    Niagara, M. I., Haider, H., Jiang, S., & Ashraf, M. (2007). Pharmacologically preconditioned skeletal myoblasts are resistant to oxidative stress and promote angiomyogenesis via release of paracrine factors in the infarcted heart. Circulation Research, 100, 545–555.PubMedCrossRefGoogle Scholar
  91. 91.
    Miyagawa, S., Sawa, Y., Taketani, S., Kawaguchi, N., Nakamura, T., et al. (2002). Myocardial regeneration therapy for heart failure: Hepatocyte growth factor enhances the effect of cellular cardiomyoplasty. Circulation, 105, 2556–2561.PubMedCrossRefGoogle Scholar
  92. 92.
    Duan, H. F., Wu, C. T., Wu, D. L., Lu, Y., Liu, H. J., et al. (2003). Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Molecular Therapy, 8, 467–474.PubMedCrossRefGoogle Scholar
  93. 93.
    Urbanek, K., Torella, D., Sheikh, F., De Angelis, A., Nurzynska, D., 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, 8692–8697.PubMedCrossRefGoogle Scholar
  94. 94.
    Luster, A. D. (1998). Chemokines–chemotactic cytokines that mediate inflammation. The New England Journal of Medicine, 338, 436–445.PubMedCrossRefGoogle Scholar
  95. 95.
    Murphy, P. M. (2001). Chemokines and the molecular basis of cancer metastasis. The New England Journal of Medicine, 345, 833–835.PubMedCrossRefGoogle Scholar
  96. 96.
    Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., et al. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121, 335–348.PubMedCrossRefGoogle Scholar
  97. 97.
    Staller, P., Sulitkova, J., Lisztwan, J., Moch, H., Oakeley, E. J., et al. (2003). Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature, 425, 307–311.PubMedCrossRefGoogle Scholar
  98. 98.
    Schutyser, E., Su, Y., Yu, Y., Gouwy, M., Zaja-Milatovic, S., et al. (2007). Hypoxia enhances CXCR4 expression in human microvascular endothelial cells and human melanoma cells. European Cytokine Network, 18, 59–70.PubMedGoogle Scholar
  99. 99.
    Abbott, J. D., Huang, Y., Liu, D., Hickey, R., Krause, D. S., et al. (2004). Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation, 110, 3300–3305.PubMedCrossRefGoogle Scholar
  100. 100.
    Askari, A. T., Unzek, S., Popovic, Z. B., Goldman, C. K., Forudi, F., et al. (2003). Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet, 362, 697–703.PubMedCrossRefGoogle Scholar
  101. 101.
    Yamaguchi, J., Kusano, K. F., Masuo, O., Kawamoto, A., Silver, M., et al. (2003). Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation, 107, 1322–1328.PubMedCrossRefGoogle Scholar
  102. 102.
    Heldin, C. H., Westermark, B., & Wasteson, A. (1981). Platelet-derived growth factor. Isolation by a large-scale procedure and analysis of subunit composition. Biochemical Journal, 193, 907–913.PubMedGoogle Scholar
  103. 103.
    Raines, E. W., & Ross, R. (1982). Platelet-derived growth factor. I. High yield purification and evidence for multiple forms. Journal of Biological Chemistry, 257, 5154–5160.PubMedGoogle Scholar
  104. 104.
    Raines, E. W. (2004). PDGF and cardiovascular disease. Cytokine & Growth Factor Reviews, 15, 237–254.CrossRefGoogle Scholar
  105. 105.
    Sarzani, R., Arnaldi, G., & Chobanian, A. V. (1991). Hypertension-induced changes of platelet-derived growth factor receptor expression in rat aorta and heart. Hypertension, 17, 888–895.PubMedGoogle Scholar
  106. 106.
    Edelberg, J. M., Lee, S. H., Kaur, M., Tang, L., Feirt, N. M., et al. (2002). Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: Feasibility of restoring impaired angiogenic capacity in the aging heart. Circulation, 105, 608–613.PubMedCrossRefGoogle Scholar
  107. 107.
    Zheng, J., Shin, J. H., Xaymardan, M., Chin, A., Duignan, I., et al. (2004). Platelet-derived growth factor improves cardiac function in a rodent myocardial infarction model. Coronary Artery Disease, 15, 59–64.PubMedCrossRefGoogle Scholar
  108. 108.
    Xaymardan, M., Tang, L., Zagreda, L., Pallante, B., Zheng, J., et al. (2004). Platelet-derived growth factor-AB promotes the generation of adult bone marrow-derived cardiac myocytes. Circulation Research, 94, E39–E45.PubMedCrossRefGoogle Scholar
  109. 109.
    Hao, X., Mansson-Broberg, A., Blomberg, P., Dellgren, G., Siddiqui, A. J., et al. (2004). Angiogenic and cardiac functional effects of dual gene transfer of VEGF-A165 and PDGF-BB after myocardial infarction. Biochemical and Biophysical Research Communications, 322, 292–296.PubMedCrossRefGoogle Scholar
  110. 110.
    Hao, X., Mansson-Broberg, A., Gustafsson, T., Grinnemo, K. H., Blomberg, P., et al. (2004). Angiogenic effects of dual gene transfer of bFGF and PDGF-BB after myocardial infarction. Biochemical and Biophysical Research Communications, 315, 1058–1063.PubMedCrossRefGoogle Scholar
  111. 111.
    Schweigerer, L., Neufeld, G., Friedman, J., Abraham, J. A., Fiddes, J. C., et al. (1987). Capillary endothelial cells express basic fibroblast growth factor, a mitogen that promotes their own growth. Nature, 325, 257–259.PubMedCrossRefGoogle Scholar
  112. 112.
    Schumacher, B., Pecher, P., von Specht, B. U., & Stegmann, T. (1998). Induction of neoangiogenesis in ischemic myocardium by human growth factors: First clinical results of a new treatment of coronary heart disease. Circulation, 97, 645–650.PubMedGoogle Scholar
  113. 113.
    Henry, T. D., Grines, C. L., Watkins, M. W., Dib, N., Barbeau, G., et al. (2007). Effects of Ad5FGF-4 in patients with angina: An analysis of pooled data from the AGENT-3 and AGENT-4 trials. Journal of the American College of Cardiology, 50, 1038–1046.PubMedCrossRefGoogle Scholar
  114. 114.
    Lu, H., Xu, X., Zhang, M., Cao, R., Brakenhielm, E., et al. (2007). Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs. Proceedings of the National Academy of Sciences of the United States of America, 104, 12140–12145.PubMedCrossRefGoogle Scholar
  115. 115.
    Padua, R. R., & Kardami, E. (1993). Increased basic fibroblast growth factor (bFGF) accumulation and distinct patterns of localization in isoproterenol-induced cardiomyocyte injury. Growth Factors, 8, 291–306.PubMedCrossRefGoogle Scholar
  116. 116.
    Kardami, E. (1990). Stimulation and inhibition of cardiac myocyte proliferation in vitro. Molecular and Cellular Biochemistry, 92, 129–135.PubMedCrossRefGoogle Scholar
  117. 117.
    Sakakibara, Y., Nishimura, K., Tambara, K., Yamamoto, M., Lu, F., et al. (2002). Prevascularization with gelatin microspheres containing basic fibroblast growth factor enhances the benefits of cardiomyocyte transplantation. The Journal of Thoracic and Cardiovascular Surgery, 124, 50–56.PubMedCrossRefGoogle Scholar
  118. 118.
    Baker, J., Liu, J. P., Robertson, E. J., & Efstratiadis, A. (1993). Role of insulin-like growth factors in embryonic and postnatal growth. Cell, 75, 73–82.PubMedGoogle Scholar
  119. 119.
    Le Roith, D. (1997). Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. New England Journal of Medicine, 336, 633–640.PubMedCrossRefGoogle Scholar
  120. 120.
    Werner, H., & Le Roith, D. (1997). The insulin-like growth factor-I receptor signaling pathways are important for tumorigenesis and inhibition of apoptosis. Critical Reviews in Oncogenesis, 8, 71–92.PubMedGoogle Scholar
  121. 121.
    Ishii, D. N., & Lupien, S. B. (1995). Insulin-like growth factors protect against diabetic neuropathy: Effects on sensory nerve regeneration in rats. Journal of Neuroscience Research, 40, 138–144.PubMedCrossRefGoogle Scholar
  122. 122.
    Arsenijevic, Y., Weiss, S., Schneider, B., & Aebischer, P. (2001). Insulin-like growth factor-I is necessary for neural stem cell proliferation and demonstrates distinct actions of epidermal growth factor and fibroblast growth factor-2. The Journal of Neuroscience, 21, 7194–7202.PubMedGoogle Scholar
  123. 123.
    de Pablo, F., & de la Rosa, E. J. (1995). The developing CNS: A scenario for the action of proinsulin, insulin and insulin-like growth factors. Trends in Neurosciences, 18, 143–150.PubMedCrossRefGoogle Scholar
  124. 124.
    Urbanek, K., Rota, M., Cascapera, S., Bearzi, C., Nascimbene, A., et al. (2005). Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circulation Research, 97, 663–673.PubMedCrossRefGoogle Scholar
  125. 125.
    Border, W. A., & Noble, N. A. (1994). Transforming growth factor beta in tissue fibrosis. The New England Journal of Medicine, 331, 1286–1292.PubMedCrossRefGoogle Scholar
  126. 126.
    Blobe, G. C., Schiemann, W. P., & Lodish, H. F. (2000). Role of transforming growth factor beta in human disease. The New England Journal of Medicine, 342, 1350–1358.PubMedCrossRefGoogle Scholar
  127. 127.
    Dickson, M. C., Martin, J. S., Cousins, F. M., Kulkarni, A. B., Karlsson, S., et al. (1995). Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development, 121, 1845–1854.PubMedGoogle Scholar
  128. 128.
    Oshima, M., Oshima, H., & Taketo, M. M. (1996). TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Developmental Biology, 179, 297–302.PubMedCrossRefGoogle Scholar
  129. 129.
    Burrows, F. J., Derbyshire, E. J., Tazzari, P. L., Amlot, P., Gazdar, A. F., et al. (1995). Up-regulation of endoglin on vascular endothelial cells in human solid tumors: Implications for diagnosis and therapy. Clinical Cancer Research, 1, 1623–1634.PubMedGoogle Scholar
  130. 130.
    Bartram, U., Molin, D. G., Wisse, L. J., Mohamad, A., Sanford, L. P., et al. (2001). Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-beta(2)-knockout mice. Circulation, 103, 2745–2752.PubMedGoogle Scholar
  131. 131.
    Goumans, M. J., Valdimarsdottir, G., Itoh, S., Rosendahl, A., Sideras, P., et al. (2002). Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. The EMBO Journal, 21, 1743–1753.PubMedCrossRefGoogle Scholar
  132. 132.
    Li, J., Hampton, T., Morgan, J. P., & Simons, M. (1997). Stretch-induced VEGF expression in the heart. Journal of Clinical Investigation, 100, 18–24.PubMedCrossRefGoogle Scholar
  133. 133.
    Li, T. S., Hayashi, M., Ito, H., Furutani, A., Murata, T., et al. (2005). Regeneration of infarcted myocardium by intramyocardial implantation of ex vivo transforming growth factor-beta-preprogrammed bone marrow stem cells. Circulation, 111, 2438–2445.PubMedCrossRefGoogle Scholar
  134. 134.
    Dimmeler, S., & Leri, A. (2008). Aging and disease as modifiers of efficacy of cell therapy. Circulation Research, 102, 1319–1330.PubMedCrossRefGoogle Scholar
  135. 135.
    Valgimigli, M., Rigolin, G. M., Fucili, A., Porta, M. D., Soukhomovskaia, O., et al. (2004). CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation, 110, 1209–1212.PubMedCrossRefGoogle Scholar
  136. 136.
    Seeger, F. H., Tonn, T., Krzossok, N., Zeiher, A. M., & Dimmeler, S. (2007). Cell isolation procedures matter: A comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. European Heart Journal, 28, 766–772.PubMedCrossRefGoogle Scholar
  137. 137.
    Woo, Y. J., Panlilio, C. M., Cheng, R. K., Liao, G. P., Atluri, P., et al. (2006). Therapeutic delivery of cyclin A2 induces myocardial regeneration and enhances cardiac function in ischemic heart failure. Circulation, 114, I206–I213.PubMedCrossRefGoogle Scholar
  138. 138.
    Kuhn, B., del Monte, F., Hajjar, R. J., Chang, Y. S., Lebeche, D., et al. (2007). Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Natural Medicines, 13, 962–969.CrossRefGoogle Scholar
  139. 139.
    Chien, K. R., Domian, I. J., & Parker, K. K. (2008). Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science, 322, 1494–1497.PubMedCrossRefGoogle Scholar
  140. 140.
    Bursac, N. (2007). Stem cell therapies for heart disease: Why do we need bioengineers? IEEE Engineering in Medicine and Biology Magazine, 26, 76–79.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Simon Maltais
    • 1
  • Jacques P. Tremblay
    • 2
  • Louis P. Perrault
    • 1
  • Hung Q. Ly
    • 3
  1. 1.Department of Cardiac Surgery, Montreal Heart InstituteUniversité de MontréalMontréalCanada
  2. 2.Department of Human Genetics, CHUQ-CHULLaval UniversitySte-FoyCanada
  3. 3.Department of Medicine, Montreal Heart InstituteUniversité de MontréalMontrealCanada

Personalised recommendations