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

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Abstract

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.

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References

  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.

    Article  PubMed  Google Scholar 

  2. Jessup, M., & Brozena, S. (2003). Heart failure. The New England Journal of Medicine, 348, 2007–2018.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  5. Segers, V. F., & Lee, R. T. (2008). Stem-cell therapy for cardiac disease. Nature, 451, 937–942.

    Article  PubMed  CAS  Google Scholar 

  6. Wagers, A. J., & Weissman, I. L. (2004). Plasticity of adult stem cells. Cell, 116, 639–648.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  8. Leri, A., Kajstura, J., & Anversa, P. (2005). Cardiac stem cells and mechanisms of myocardial regeneration. Physiological Reviews, 85, 1373–1416.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  12. Fukuda, K., & Yuasa, S. (2006). Stem cells as a source of regenerative cardiomyocytes. Circulation Research, 98, 1002–1013.

    Article  PubMed  CAS  Google Scholar 

  13. Gepstein, L. (2006). Cardiovascular therapeutic aspects of cell therapy and stem cells. Annals of the New York Academy of Sciences, 1080, 415–425.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  15. Wang, Q. D., & Sjoquist, P. O. (2006). Myocardial regeneration with stem cells: Pharmacological possibilities for efficacy enhancement. Pharmacological Research, 53, 331–340.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  27. Oettgen, P., Boyle, A. J., Schulman, S. P., & Hare, J. M. (2006). Controversies in cardiovascular medicine. Circulation, 114, 353–358.

    Article  PubMed  Google Scholar 

  28. Murry, C. E., Field, L. J., & Menasche, P. (2005). Cell-based cardiac repair: Reflections at the 10-year point. Circulation, 112, 3174–3183.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  33. Rosenzweig, A. (2006). Cardiac cell therapy—mixed results from mixed cells. The New England Journal of Medicine, 355, 1274–1277.

    Article  PubMed  CAS  Google Scholar 

  34. Gersh, B. J., & Simari, R. D. (2006). Cardiac cell-repair therapy: Clinical issues. Nature Clinical Practice. Cardiovascular Medicine, 3(Suppl 1), S105–S109.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  37. Rosen, M. R. (2006). Are stem cells drugs? The regulation of stem cell research and development. Circulation, 114, 1992–2000.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  49. Frangogiannis, N. G., Smith, C. W., & Entman, M. L. (2002). The inflammatory response in myocardial infarction. Cardiovascular Research, 53, 31–47.

    Article  PubMed  CAS  Google Scholar 

  50. Mann, D. L. (2002). Inflammatory mediators and the failing heart: Past, present, and the foreseeable future. Circulation Research, 91, 988–998.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  67. Lapidot, T., Dar, A., & Kollet, O. (2005). How do stem cells find their way home? Blood, 106, 1901–1910.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  94. Luster, A. D. (1998). Chemokines–chemotactic cytokines that mediate inflammation. The New England Journal of Medicine, 338, 436–445.

    Article  PubMed  CAS  Google Scholar 

  95. Murphy, P. M. (2001). Chemokines and the molecular basis of cancer metastasis. The New England Journal of Medicine, 345, 833–835.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  104. Raines, E. W. (2004). PDGF and cardiovascular disease. Cytokine & Growth Factor Reviews, 15, 237–254.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  116. Kardami, E. (1990). Stimulation and inhibition of cardiac myocyte proliferation in vitro. Molecular and Cellular Biochemistry, 92, 129–135.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  125. Border, W. A., & Noble, N. A. (1994). Transforming growth factor beta in tissue fibrosis. The New England Journal of Medicine, 331, 1286–1292.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  134. Dimmeler, S., & Leri, A. (2008). Aging and disease as modifiers of efficacy of cell therapy. Circulation Research, 102, 1319–1330.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  139. Chien, K. R., Domian, I. J., & Parker, K. K. (2008). Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science, 322, 1494–1497.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by funding from Fonds de Recherche en Santé du Québec, Heart and Stroke Foundation of Quebec, and the Montreal Heart Institute Foundation (H.Q.L.; L.P.P., S.M.).

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Authors and Affiliations

  1. Department of Cardiac Surgery, Montreal Heart Institute, Université de Montréal, Montréal, QC, Canada

    Simon Maltais & Louis P. Perrault

  2. Department of Human Genetics, CHUQ-CHUL, Laval University, Ste-Foy, QC, Canada

    Jacques P. Tremblay

  3. Department of Medicine, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. (East), Montreal, QC, Canada, H1T 1C8

    Hung Q. Ly

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  1. Simon Maltais
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Correspondence to Hung Q. Ly.

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Maltais, S., Tremblay, J.P., Perrault, L.P. et al. The Paracrine Effect: Pivotal Mechanism in Cell-Based Cardiac Repair. J. of Cardiovasc. Trans. Res. 3, 652–662 (2010). https://doi.org/10.1007/s12265-010-9198-2

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