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Stem Cell Reviews and Reports

, Volume 9, Issue 3, pp 266–280 | Cite as

Cardiac Cell Therapy: Boosting Mesenchymal Stem Cells Effects

  • E. Samper
  • A. Diez-Juan
  • J. A. Montero
  • P. SepúlvedaEmail author
Article

Abstract

Acute myocardial infarction is a major problem of world public health and available treatments have limited efficacy. Cardiac cell therapy is a new therapeutic strategy focused on regeneration and repair of the injured cardiac muscle. Among different cell types used, mesenchymal stem cells (MSC) have been widely tested in preclinical studies and several clinical trials have evaluated their clinical efficacy in myocardial infarction. However, the beneficial effects of MSC in humans are limited due to poor engraftment and survival of these cells, therefore ways to overcome these obstacles should improve efficacy. Different strategies have been used, such as genetically modifying MSC, or preconditioning the cells with factors that potentiate their survival and therapeutic mechanisms. In this review we compile the most relevant approaches used to improve MSC therapeutic capacity and to understand the molecular mechanisms involved in MSC mediated cardiac repair.

Keywords

Myocardial infarction Cardiac regeneration Cell therapy Mesenchymal stem cells Genetic engineering Adult stem cells 

Notes

Acknowledgments

This work was supported by grants from Instituto de Salud Carlos III (CP08/80 and PI07/784) and from Obra Social Kutxa. P. Sepúlveda is the recipient of a contract from the Instituto de Salud Carlos III. E. Samper is a predoctoral fellow from the Centro de Investigación Príncipe Felipe.

Conflicts of interest

The authors declare no potential conflicts of interest.

References

  1. 1.
    Mackay, J., & Mensah, G. (2004). Atlas of heart disease and stroke. World Health Organization.Google Scholar
  2. 2.
    Andersen, H. R., Nielsen, T. T., Rasmussen, K., et al. (2003). A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. The New England Journal of Medicine, 349(8), 733–742.PubMedCrossRefGoogle Scholar
  3. 3.
    Costanzo, M. R., Augustine, S., Bourge, R., et al. (1995). Selection and treatment of candidates for heart transplantation. A statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation, 92(12), 3593–3612.PubMedCrossRefGoogle Scholar
  4. 4.
    Kajstura, J., Cheng, W., Reiss, K., et al. (1996). Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Laboratory Investigation, 74(1), 86–107.PubMedGoogle Scholar
  5. 5.
    Sun, Y., Zhang, J. Q., Zhang, J., & Lamparter, S. (2000). Cardiac remodeling by fibrous tissue after infarction in rats. The Journal of Laboratory and Clinical Medicine, 135(4), 316–323.PubMedCrossRefGoogle Scholar
  6. 6.
    Sutton, M. G., & Sharpe, N. (2000). Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation, 101(25), 2981–2988.PubMedCrossRefGoogle Scholar
  7. 7.
    Segers, V. F., & Lee, R. T. (2008). Stem-cell therapy for cardiac disease. Nature, 451(7181), 937–942.PubMedCrossRefGoogle Scholar
  8. 8.
    Tongers, J., Losordo, D. W., & Landmesser, U. (2011). Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges. European Heart Journal, 32(10), 1197–1206.PubMedCrossRefGoogle Scholar
  9. 9.
    Janssens, S. (2010). Stem cells in the treatment of heart disease. Annual Review of Medicine, 61, 287–300.PubMedCrossRefGoogle Scholar
  10. 10.
    Arminan, A., Gandia, C., Garcia-Verdugo, J. M., et al. (2010). Mesenchymal stem cells provide better results than hematopoietic precursors for the treatment of myocardial infarction. Journal of the American College of Cardiology, 55(20), 2244–2253.PubMedCrossRefGoogle Scholar
  11. 11.
    Martinez, E. C., & Kofidis, T. (2011). Adult stem cells for cardiac tissue engineering. Journal of Molecular and Cellular Cardiology, 50(2), 312–319.PubMedCrossRefGoogle Scholar
  12. 12.
    Herrmann, J. L., Abarbanell, A. M., Weil, B. R., et al. (2011). Optimizing stem cell function for the treatment of ischemic heart disease. Journal of Surgical Research, 166(1), 138–145.PubMedCrossRefGoogle Scholar
  13. 13.
    Haider, H., & Ashraf, M. (2010). Preconditioning and stem cell survival. Journal of Cardiovascular Translational Research, 3(2), 89–102.PubMedCrossRefGoogle Scholar
  14. 14.
    Menasche, P. (2011). Cardiac cell therapy: lessons from clinical trials. Journal of Molecular and Cellular Cardiology, 50(2), 258–265.PubMedCrossRefGoogle Scholar
  15. 15.
    Rosenzweig, A. (2006). Cardiac cell therapy–mixed results from mixed cells. The New England Journal of Medicine, 355(12), 1274–1277.PubMedCrossRefGoogle Scholar
  16. 16.
    Passier, R., van Laake, L. W., & Mummery, C. L. (2008). Stem-cell-based therapy and lessons from the heart. Nature, 453(7193), 322–329.PubMedCrossRefGoogle Scholar
  17. 17.
    Fouts, K., Fernandes, B., Mal, N., Liu, J., & Laurita, K. R. (2006). Electrophysiological consequence of skeletal myoblast transplantation in normal and infarcted canine myocardium. Heart Rhythm, 3(4), 452–461.PubMedCrossRefGoogle Scholar
  18. 18.
    Hagege, A. A., Marolleau, J. P., Vilquin, J. T., et al. (2006). Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients. Circulation, 114(1 Suppl), I108–I113.PubMedGoogle Scholar
  19. 19.
    Fernandes, S., Amirault, J. C., Lande, G., et al. (2006). Autologous myoblast transplantation after myocardial infarction increases the inducibility of ventricular arrhythmias. Cardiovascular Research, 69(2), 348–358.PubMedCrossRefGoogle Scholar
  20. 20.
    Jeong, J. O., Han, J. W., Kim, J. M., et al. (2011). Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circulation Research, 108(11), 1340–1347.PubMedCrossRefGoogle Scholar
  21. 21.
    Hatzistergos, K. E., Blum, A., Ince, T., Grichnik, J. M., & Hare, J. M. (2011). What is the oncologic risk of stem cell treatment for heart disease? Circulation Research, 108(11), 1300–1303.PubMedCrossRefGoogle Scholar
  22. 22.
    Wollert, K. C., & Drexler, H. (2010). Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nature Reviews Cardiology, 7(4), 204–215.PubMedCrossRefGoogle Scholar
  23. 23.
    Giordano, A., Galderisi, U., & Marino, I. R. (2007). From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. Journal of Cellular Physiology, 211(1), 27–35.PubMedCrossRefGoogle Scholar
  24. 24.
    Hare, J. M., Traverse, J. H., Henry, T. D., et al. (2009). A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. Journal of the American College of Cardiology, 54(24), 2277–2286.PubMedCrossRefGoogle Scholar
  25. 25.
    Trachtenberg, B., Velazquez, D. L., Williams, A. R., et al. (2011). Rationale and design of the Transendocardial Injection of Autologous Human Cells (bone marrow or mesenchymal) in Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction (TAC-HFT) trial: A randomized, double-blind, placebo-controlled study of safety and efficacy. American Heart Journal, 161(3), 487–493.CrossRefGoogle Scholar
  26. 26.
    Williams, A. R., Trachtenberg, B., Velazquez, D. L., et al. (2011). Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circulation Research, 108(7), 792–796.CrossRefGoogle Scholar
  27. 27.
    Friedenstein, A. J., Deriglasova, U. F., Kulagina, N. N., et al. (1974). Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Experimental Hematology, 2(2), 83–92.PubMedGoogle Scholar
  28. 28.
    Pittenger, M. F., Mackay, A. M., Beck, S. C., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284(5411), 143–147.PubMedCrossRefGoogle Scholar
  29. 29.
    Pereira, R. F., Halford, K. W., O’Hara, M. D., et al. (1995). Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proceedings of the National Academy of Sciences of the United States of America, 92(11), 4857–4861.PubMedCrossRefGoogle Scholar
  30. 30.
    Sekiya, I., Vuoristo, J. T., Larson, B. L., & Prockop, D. J. (2002). In vitro cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis. Proceedings of the National Academy of Sciences of the United States of America, 99(7), 4397–4402.PubMedCrossRefGoogle Scholar
  31. 31.
    Prockop, D. J. (1997). Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276(5309), 71–74.PubMedCrossRefGoogle Scholar
  32. 32.
    Liechty, K. W., MacKenzie, T. C., Shaaban, A. F., et al. (2000). Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nature Medicine, 6(11), 1282–1286.PubMedCrossRefGoogle Scholar
  33. 33.
    Sakaguchi, Y., Sekiya, I., Yagishita, K., & Muneta, T. (2005). Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis and Rheumatism, 52(8), 2521–2529.PubMedCrossRefGoogle Scholar
  34. 34.
    Luria, E. A., Panasyuk, A. F., & Friedenstein, A. Y. (1971). Fibroblast colony formation from monolayer cultures of blood cells. Transfusion, 11(6), 345–349.PubMedCrossRefGoogle Scholar
  35. 35.
    Kuznetsov, S. A., Mankani, M. H., Gronthos, S., Satomura, K., Bianco, P., & Robey, P. G. (2001). Circulating skeletal stem cells. The Journal of Cell Biology, 153(5), 1133–1140.PubMedCrossRefGoogle Scholar
  36. 36.
    Zuk, P. A., Zhu, M., Mizuno, H., et al. (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering, 7(2), 211–228.PubMedCrossRefGoogle Scholar
  37. 37.
    Toma, J. G., Akhavan, M., Fernandes, K. J., et al. (2001). Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nature Cell Biology, 3(9), 778–784.PubMedCrossRefGoogle Scholar
  38. 38.
    Gronthos, S., Mankani, M., Brahim, J., Robey, P. G., & Shi, S. (2000). Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 97(25), 13625–13630.PubMedCrossRefGoogle Scholar
  39. 39.
    Najimi, M., Khuu, D. N., Lysy, P. A., et al. (2007). Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes? Cell Transplantation, 16(7), 717–728.PubMedGoogle Scholar
  40. 40.
    De Bari, C., Dell’Accio, F., Tylzanowski, P., & Luyten, F. P. (2001). Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis and Rheumatism, 44(8), 1928–1942.PubMedCrossRefGoogle Scholar
  41. 41.
    Williams, J. T., Southerland, S. S., Souza, J., Calcutt, A. F., & Cartledge, R. G. (1999). Cells isolated from adult human skeletal muscle capable of differentiating into multiple mesodermal phenotypes. American Surgeon, 65(1), 22–26.PubMedGoogle Scholar
  42. 42.
    Lama, V. N., Smith, L., Badri, L., et al. (2007). Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. The Journal of Clinical Investigation, 117(4), 989–996.PubMedCrossRefGoogle Scholar
  43. 43.
    Erices, A., Conget, P., & Minguell, J. J. (2000). Mesenchymal progenitor cells in human umbilical cord blood. British Journal of Haematology, 109(1), 235–242.PubMedCrossRefGoogle Scholar
  44. 44.
    In ’t Anker, P. S., Scherjon, S. A., Kleijburg-van der Keur, C., et al. (2003). Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood, 102(4), 1548–1549.Google Scholar
  45. 45.
    In ’t Anker, P. S., Scherjon, S. A., Kleijburg-van der Keur, C., et al. (2004). Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells, 22(7), 1338–1345.Google Scholar
  46. 46.
    Hass, R., Kasper, C., Bohm, S., & Jacobs, R. (2011). Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Communication and Signaling, 9, 12.PubMedCrossRefGoogle Scholar
  47. 47.
    Garcia-Castro, J., Trigueros, C., Madrenas, J., Perez-Simon, J. A., Rodriguez, R., & Menendez, P. (2008). Mesenchymal stem cells and their use as cell replacement therapy and disease modelling tool. Journal of Cellular and Molecular Medicine, 12(6B), 2552–2565.PubMedCrossRefGoogle Scholar
  48. 48.
    Wagner, W., Wein, F., Seckinger, A., et al. (2005). Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Experimental Hematology, 33(11), 1402–1416.PubMedCrossRefGoogle Scholar
  49. 49.
    Simonsen, J. L., Rosada, C., Serakinci, N., et al. (2002). Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nature Biotechnology, 20(6), 592–596.PubMedCrossRefGoogle Scholar
  50. 50.
    Asumda, F. Z., & Chase, P. B. (2011). Age-related changes in rat bone-marrow mesenchymal stem cell plasticity. BMC Cell Biology, 12, 44.CrossRefGoogle Scholar
  51. 51.
    Ryan, J. M., Barry, F. P., Murphy, J. M., & Mahon, B. P. (2005). Mesenchymal stem cells avoid allogeneic rejection. Journal of Inflammation (London), 2, 8.CrossRefGoogle Scholar
  52. 52.
    Beyth, S., Borovsky, Z., Mevorach, D., et al. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood, 105(5), 2214–2219.PubMedCrossRefGoogle Scholar
  53. 53.
    Rasmusson, I. (2006). Immune modulation by mesenchymal stem cells. Experimental Cell Research, 312(12), 2169–2179.PubMedCrossRefGoogle Scholar
  54. 54.
    Jones, B. J., & McTaggart, S. J. (2008). Immunosuppression by mesenchymal stromal cells: from culture to clinic. Experimental Hematology, 36(6), 733–741.PubMedCrossRefGoogle Scholar
  55. 55.
    Eliopoulos, N., Stagg, J., Lejeune, L., Pommey, S., & Galipeau, J. (2005). Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood, 106(13), 4057–4065.PubMedCrossRefGoogle Scholar
  56. 56.
    Nauta, A. J., Westerhuis, G., Kruisselbrink, A. B., Lurvink, E. G., Willemze, R., & Fibbe, W. E. (2006). Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood, 108(6), 2114–2120.PubMedCrossRefGoogle Scholar
  57. 57.
    Mirotsou, M., Jayawardena, T. M., Schmeckpeper, J., Gnecchi, M., & Dzau, V. J. (2011). Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. Journal of Molecular and Cellular Cardiology, 50(2), 280–289.PubMedCrossRefGoogle Scholar
  58. 58.
    Wen, Z., Zheng, S., Zhou, C., Wang, J., & Wang, T. (2011). Repair mechanisms of bone marrow mesenchymal stem cells in myocardial infarction. Journal of Cellular and Molecular Medicine, 15(5), 1032–1043.PubMedCrossRefGoogle Scholar
  59. 59.
    Chen, S., Liu, Z., Tian, N., et al. (2006). Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery. The Journal of Invasive Cardiology, 18(11), 552–556.PubMedGoogle Scholar
  60. 60.
    Frangogiannis, N. G., Smith, C. W., & Entman, M. L. (2002). The inflammatory response in myocardial infarction. Cardiovascular Research, 53(1), 31–47.PubMedCrossRefGoogle Scholar
  61. 61.
    Bonvini, R. F., Hendiri, T., & Camenzind, E. (2005). Inflammatory response post-myocardial infarction and reperfusion: a new therapeutic target? European Heart Journal Supplements, 7(suppl I), I27–I36.CrossRefGoogle Scholar
  62. 62.
    Arslan, F., de Kleijn, D. P., & Pasterkamp, G. (2011). Innate immune signaling in cardiac ischemia. Nature Reviews Cardiology, 8(5), 292–300.PubMedCrossRefGoogle Scholar
  63. 63.
    Nian, M., Lee, P., Khaper, N., & Liu, P. (2004). Inflammatory cytokines and postmyocardial infarction remodeling. Circulation Research, 94(12), 1543–1553.PubMedCrossRefGoogle Scholar
  64. 64.
    Nah, D. Y., & Rhee, M. Y. (2009). The inflammatory response and cardiac repair after myocardial infarction. Korean Circulation Journal, 39(10), 393–398.PubMedCrossRefGoogle Scholar
  65. 65.
    Kollar, K., Cook, M. M., Atkinson, K., & Brooke, G. (2009). Molecular mechanisms involved in mesenchymal stem cell migration to the site of acute myocardial infarction. International Journal of Cell Biology, p. 904682.Google Scholar
  66. 66.
    Neuss, S., Becher, E., Woltje, M., Tietze, L., & Jahnen-Dechent, W. (2004). Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells, 22(3), 405–414.PubMedCrossRefGoogle Scholar
  67. 67.
    Kim, Y. S., Park, H. J., Hong, M. H., et al. (2009). TNF-alpha enhances engraftment of mesenchymal stem cells into infarcted myocardium. Frontiers in Bioscience, 14, 2845–2856.PubMedCrossRefGoogle Scholar
  68. 68.
    Ponte, A. L., Marais, E., Gallay, N., et al. (2007). The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells, 25(7), 1737–1745.PubMedCrossRefGoogle Scholar
  69. 69.
    Majumdar, M. K., Keane-Moore, M., Buyaner, D., et al. (2003). Characterization and functionality of cell surface molecules on human mesenchymal stem cells. Journal of Biomedical Science, 10(2), 228–241.PubMedCrossRefGoogle Scholar
  70. 70.
    Thankamony, S. P., & Sackstein, R. (2011). Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. Proceedings of the National Academy of Sciences of the United States of America, 108(6), 2258–2263.PubMedCrossRefGoogle Scholar
  71. 71.
    Steingen, C., Brenig, F., Baumgartner, L., Schmidt, J., Schmidt, A., & Bloch, W. (2008). Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells. Journal of Molecular and Cellular Cardiology, 44(6), 1072–1084.PubMedCrossRefGoogle Scholar
  72. 72.
    Segers, V. F., Van Riet, I., Andries, L. J., et al. (2006). Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms. American Journal of Physiology—Heart and Circulatory Physiology, 290(4), H1370–H1377.PubMedCrossRefGoogle Scholar
  73. 73.
    Toma, C., Pittenger, M. F., Cahill, K. S., Byrne, B. J., & Kessler, P. D. (2002). Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation, 105(1), 93–98.PubMedCrossRefGoogle Scholar
  74. 74.
    Grinnemo, K. H., Mansson, A., Dellgren, G., et al. (2004). Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. The Journal of Thoracic and Cardiovascular Surgery, 127(5), 1293–1300.PubMedCrossRefGoogle Scholar
  75. 75.
    Terrovitis, J., Stuber, M., Youssef, A., et al. (2008). Magnetic resonance imaging overestimates ferumoxide-labeled stem cell survival after transplantation in the heart. Circulation, 117(12), 1555–1562.PubMedCrossRefGoogle Scholar
  76. 76.
    Quevedo, H. C., Hatzistergos, K. E., Oskouei, B. N., et al. (2009). Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proceedings of the National Academy of Sciences of the United States of America, 106(33), 14022–14027.PubMedCrossRefGoogle Scholar
  77. 77.
    Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., et al. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research, 107(7), 913–922.PubMedCrossRefGoogle Scholar
  78. 78.
    Muller-Ehmsen, J., Krausgrill, B., Burst, V., et al. (2006). Effective engraftment but poor mid-term persistence of mononuclear and mesenchymal bone marrow cells in acute and chronic rat myocardial infarction. Journal of Molecular and Cellular Cardiology, 41(5), 876–884.PubMedCrossRefGoogle Scholar
  79. 79.
    Freyman, T., Polin, G., Osman, H., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal, 27(9), 1114–1122.PubMedCrossRefGoogle Scholar
  80. 80.
    Serda, R. E., Gu, J., Bhavane, R. C., et al. (2009). The association of silicon microparticles with endothelial cells in drug delivery to the vasculature. Biomaterials, 30(13), 2440–2448.PubMedCrossRefGoogle Scholar
  81. 81.
    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. Nature Biotechnology, 25(9), 1015–1024.PubMedCrossRefGoogle Scholar
  82. 82.
    Godier-Furnemont, A. F., Martens, T. P., Koeckert, M. S., et al. (2011). Composite scaffold provides a cell delivery platform for cardiovascular repair. Proceedings of the National Academy of Sciences of the United States of America, 108(19), 7974–7979.PubMedCrossRefGoogle Scholar
  83. 83.
    Trouche, E., Girod Fullana, S., Mias, C., et al. (2010). Evaluation of alginate microspheres for mesenchymal stem cell engraftment on solid organ. Cell Transplantation, 19(12), 1623–1633.PubMedCrossRefGoogle Scholar
  84. 84.
    Shake, J. G., Gruber, P. J., Baumgartner, W. A., et al. (2002). Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. The Annals of Thoracic Surgery, 73(6), 1919–1925. discussion 1926.PubMedCrossRefGoogle Scholar
  85. 85.
    Jiang, W., Ma, A., Wang, T., et al. (2006). Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study. Pflügers Archiv, 453(1), 43–52.PubMedCrossRefGoogle Scholar
  86. 86.
    Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., et al. (2006). Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy, 14(6), 840–850.PubMedCrossRefGoogle Scholar
  87. 87.
    Arminan, A., Gandia, C., Bartual, M., et al. (2009). Cardiac differentiation is driven by NKX2.5 and GATA4 nuclear translocation in tissue-specific mesenchymal stem cells. Stem Cells and Development, 18(6), 907–918.PubMedCrossRefGoogle Scholar
  88. 88.
    Tang, Y. L., Zhao, Q., Qin, X., et al. (2005). Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. The Annals of Thoracic Surgery, 80(1), 229–236. discussion 236-7.PubMedCrossRefGoogle Scholar
  89. 89.
    Gnecchi, M., He, H., Noiseux, N., et al. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. The FASEB Journal, 20(6), 661–669.CrossRefGoogle Scholar
  90. 90.
    Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research, 103(11), 1204–1219.PubMedCrossRefGoogle Scholar
  91. 91.
    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(11), 1414–1421.PubMedCrossRefGoogle Scholar
  92. 92.
    Haynesworth, S. E., Baber, M. A., & Caplan, A. I. (1996). Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. Journal of Cellular Physiology, 166(3), 585–592.PubMedCrossRefGoogle Scholar
  93. 93.
    Iso, Y., Spees, J. L., Serrano, C., et al. (2007). Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment. Biochemical and Biophysical Research Communications, 354(3), 700–706.PubMedCrossRefGoogle Scholar
  94. 94.
    Prockop, D. J. (2007). “Stemness” does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clinical Pharmacology and Therapeutics, 82(3), 241–243.PubMedCrossRefGoogle Scholar
  95. 95.
    Tang, J. M., Wang, J. N., Zhang, L., et al. (2011). VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovascular Research.Google Scholar
  96. 96.
    Nguyen, B. K., Maltais, S., Perrault, L. P., et al. (2010). Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. Journal of Cardiovascular Translational Research, 3(5), 547–558.PubMedCrossRefGoogle Scholar
  97. 97.
    Timmers, L., Lim, S. K., Hoefer, I. E., et al. (2011). Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Research, 6(3), 206–214.PubMedCrossRefGoogle Scholar
  98. 98.
    Zisa, D., Shabbir, A., Suzuki, G., & Lee, T. (2009). Vascular endothelial growth factor (VEGF) as a key therapeutic trophic factor in bone marrow mesenchymal stem cell-mediated cardiac repair. Biochemical and Biophysical Research Communications, 390(3), 834–838.PubMedCrossRefGoogle Scholar
  99. 99.
    Huang, J., Zhang, Z., Guo, J., et al. (2010). Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circulation Research, 106(11), 1753–1762.PubMedCrossRefGoogle Scholar
  100. 100.
    Zhang, D., Fan, G. C., Zhou, X., et al. (2008). Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. Journal of Molecular and Cellular Cardiology, 44(2), 281–292.PubMedCrossRefGoogle Scholar
  101. 101.
    Zhang, M., Mal, N., Kiedrowski, M., et al. (2007). SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. The FASEB Journal, 21(12), 3197–3207.CrossRefGoogle Scholar
  102. 102.
    Tang, J., Wang, J., Guo, L., et al. (2010). Mesenchymal stem cells modified with stromal cell-derived factor 1 alpha improve cardiac remodeling via paracrine activation of hepatocyte growth factor in a rat model of myocardial infarction. Molecules and Cells, 29(1), 9–19.PubMedCrossRefGoogle Scholar
  103. 103.
    Duan, H. F., Wu, C. T., Wu, D. L., et al. (2003). Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Molecular Therapy, 8(3), 467–474.PubMedCrossRefGoogle Scholar
  104. 104.
    Haider, H., Jiang, S., Idris, N. M., & Ashraf, M. (2008). IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circulation Research, 103(11), 1300–1308.PubMedCrossRefGoogle Scholar
  105. 105.
    Liu, X. H., Bai, C. G., Xu, Z. Y., et al. (2008). Therapeutic potential of angiogenin modified mesenchymal stem cells: angiogenin improves mesenchymal stem cells survival under hypoxia and enhances vasculogenesis in myocardial infarction. Microvascular Research, 76(1), 23–30.PubMedCrossRefGoogle Scholar
  106. 106.
    Gao, F., He, T., Wang, H., et al. (2007). A promising strategy for the treatment of ischemic heart disease: mesenchymal stem cell-mediated vascular endothelial growth factor gene transfer in rats. Canadian Journal of Cardiology, 23(11), 891–898.PubMedCrossRefGoogle Scholar
  107. 107.
    Cho, J., Zhai, P., Maejima, Y., & Sadoshima, J. (2011). Myocardial injection with GSK-3beta-overexpressing bone marrow-derived mesenchymal stem cells attenuates cardiac dysfunction after myocardial infarction. Circulation Research, 108(4), 478–489.PubMedCrossRefGoogle Scholar
  108. 108.
    Grauss, R. W., van Tuyn, J., Steendijk, P., et al. (2008). Forced myocardin expression enhances the therapeutic effect of human mesenchymal stem cells after transplantation in ischemic mouse hearts. Stem Cells, 26(4), 1083–1093.PubMedCrossRefGoogle Scholar
  109. 109.
    Alfaro, M. P., Vincent, A., Saraswati, S., et al. (2010). sFRP2 suppression of bone morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-renewal promoting engraftment and myocardial repair. Journal of Biological Chemistry, 285(46), 35645–35653.PubMedCrossRefGoogle Scholar
  110. 110.
    Kobayashi, K., Luo, M., Zhang, Y., et al. (2009). Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nature Cell Biology, 11(1), 46–55.PubMedCrossRefGoogle Scholar
  111. 111.
    Alfaro, M. P., Pagni, M., Vincent, A., et al. (2008). The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proceedings of the National Academy of Sciences of the United States of America, 105(47), 18366–18371.PubMedCrossRefGoogle Scholar
  112. 112.
    Mangi, A. A., Noiseux, N., Kong, D., et al. (2003). Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nature Medicine, 9(9), 1195–1201.PubMedCrossRefGoogle Scholar
  113. 113.
    Jiang, S., Haider, H., Idris, N. M., Salim, A., & Ashraf, M. (2006). Supportive interaction between cell survival signaling and angiocompetent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair. Circulation Research, 99(7), 776–784.PubMedCrossRefGoogle Scholar
  114. 114.
    Shujia, J., Haider, H. K., Idris, N. M., Lu, G., & Ashraf, M. (2008). Stable therapeutic effects of mesenchymal stem cell-based multiple gene delivery for cardiac repair. Cardiovascular Research, 77(3), 525–533.PubMedCrossRefGoogle Scholar
  115. 115.
    Tang, Y. L., Tang, Y., Zhang, Y. C., Qian, K., Shen, L., & Phillips, M. I. (2005). Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. Journal of the American College of Cardiology, 46(7), 1339–1350.PubMedCrossRefGoogle Scholar
  116. 116.
    Tsubokawa, T., Yagi, K., Nakanishi, C., et al. (2010). Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. American Journal of Physiology - Heart and Circulatory Physiology, 298(5), H1320–H1329.PubMedCrossRefGoogle Scholar
  117. 117.
    Zeng, B., Lin, G., Ren, X., Zhang, Y., & Chen, H. (2010). Over-expression of HO-1 on mesenchymal stem cells promotes angiogenesis and improves myocardial function in infarcted myocardium. Journal of Biomedical Science, 17, 80.PubMedCrossRefGoogle Scholar
  118. 118.
    Jiang, Y. B., Zhang, X. L., Tang, Y. L., et al. (2011). Effects of heme oxygenase-1 gene modulated mesenchymal stem cells on vasculogenesis in ischemic swine hearts. Chinese Medical Journal, 124(3), 401–407.PubMedGoogle Scholar
  119. 119.
    Shu, T., Zeng, B., Ren, X., & Li, Y. (2010). HO-1 modified mesenchymal stem cells modulate MMPs/TIMPs system and adverse remodeling in infarcted myocardium. Tissue & Cell, 42(4), 217–222.CrossRefGoogle Scholar
  120. 120.
    Lim, S. Y., Kim, Y. S., Ahn, Y., et al. (2006). The effects of mesenchymal stem cells transduced with Akt in a porcine myocardial infarction model. Cardiovascular Research, 70(3), 530–542.PubMedCrossRefGoogle Scholar
  121. 121.
    Yu, Y. S., Shen, Z. Y., Ye, W. X., et al. (2010). AKT-modified autologous intracoronary mesenchymal stem cells prevent remodeling and repair in swine infarcted myocardium. Chinese Medical Journal, 123(13), 1702–1708.PubMedGoogle Scholar
  122. 122.
    Wang, X., Zhao, T., Huang, W., et al. (2009). Hsp20-engineered mesenchymal stem cells are resistant to oxidative stress via enhanced activation of Akt and increased secretion of growth factors. Stem Cells, 27(12), 3021–3031.PubMedGoogle Scholar
  123. 123.
    Eun, L. Y., Song, B. W., Cha, M. J., et al. (2010). Overexpression of phosphoinositide-3-kinase class II alpha enhances mesenchymal stem cell survival in infarcted myocardium. Biochemical and Biophysical Research Communications, 402(2), 272–279.PubMedCrossRefGoogle Scholar
  124. 124.
    Li, W., Ma, N., Ong, L. L., et al. (2007). Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells, 25(8), 2118–2127.PubMedCrossRefGoogle Scholar
  125. 125.
    Wang, D., Shen, W., Zhang, F., Chen, M., Chen, H., & Cao, K. (2010). Connexin43 promotes survival of mesenchymal stem cells in ischaemic heart. Cell Biology International, 34(4), 415–423.PubMedCrossRefGoogle Scholar
  126. 126.
    Guo, Y., He, J., Wu, J., et al. (2008). Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis. Archives of Medical Research, 39(2), 179–188.PubMedCrossRefGoogle Scholar
  127. 127.
    Deuse, T., Peter, C., Fedak, P. W., et al. (2009). Hepatocyte growth factor or vascular endothelial growth factor gene transfer maximizes mesenchymal stem cell-based myocardial salvage after acute myocardial infarction. Circulation, 120(11 Suppl), S247–S254.PubMedCrossRefGoogle Scholar
  128. 128.
    Yang, J., Zhou, W., Zheng, W., et al. (2007). Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction. Cardiology, 107(1), 17–29.PubMedCrossRefGoogle Scholar
  129. 129.
    Kim, S. H., Moon, H. H., Kim, H. A., Hwang, K. C., Lee, M., & Choi, D. (2011). Hypoxia-inducible vascular endothelial growth factor-engineered mesenchymal stem cells prevent myocardial ischemic injury. Molecular Therapy, 19(4), 741–750.PubMedCrossRefGoogle Scholar
  130. 130.
    Chen, J. J., & Zhou, S. H. (2011). Mesenchymal stem cells overexpressing MiR-126 enhance ischemic angiogenesis via the AKT/ERK–related pathway. Cardiology Journal. 18(X), 1–X.Google Scholar
  131. 131.
    Song, S. W., Chang, W., Song, B. W., et al. (2009). Integrin-linked kinase is required in hypoxic mesenchymal stem cells for strengthening cell adhesion to ischemic myocardium. Stem Cells, 27(6), 1358–1365.PubMedCrossRefGoogle Scholar
  132. 132.
    Song, H., Chang, W., Lim, S., et al. (2007). Tissue transglutaminase is essential for integrin-mediated survival of bone marrow-derived mesenchymal stem cells. Stem Cells, 25(6), 1431–1438.PubMedCrossRefGoogle Scholar
  133. 133.
    Shibuya, M. (2001). Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Structure and Function, 26(1), 25–35.PubMedCrossRefGoogle Scholar
  134. 134.
    Cross, M. J., & Claesson-Welsh, L. (2001). FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends in Pharmacological Sciences, 22(4), 201–207.PubMedCrossRefGoogle Scholar
  135. 135.
    Galzie, Z., Kinsella, A. R., & Smith, J. A. (1997). Fibroblast growth factors and their receptors. Biochemical Cell Biology, 75(6), 669–685.CrossRefGoogle Scholar
  136. 136.
    Le Roith, D. (1997). Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. New England Journal of Medicine, 336(9), 633–640.PubMedCrossRefGoogle Scholar
  137. 137.
    Bleul, C. C., Fuhlbrigge, R. C., Casasnovas, J. M., Aiuti, A., & Springer, T. A. (1996). A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). The Journal of Experimental Medicine, 184(3), 1101–1109.PubMedCrossRefGoogle Scholar
  138. 138.
    Dennler, S., Goumans, M. J., & ten Dijke, P. (2002). Transforming growth factor beta signal transduction. Journal of Leukocyte Biology, 71(5), 731–740.PubMedGoogle Scholar
  139. 139.
    Massague, J. (1998). TGF-beta signal transduction. Annual Review of Biochemistry, 67, 753–791.PubMedCrossRefGoogle Scholar
  140. 140.
    Van Snick, J. (1990). Interleukin-6: an overview. Annual Review of Immunology, 8, 253–278.PubMedCrossRefGoogle Scholar
  141. 141.
    Zarnegar, R., & Michalopoulos, G. K. (1995). The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. The Journal of Cell Biology, 129(5), 1177–1180.PubMedCrossRefGoogle Scholar
  142. 142.
    Tallquist, M., & Kazlauskas, A. (2004). PDGF signaling in cells and mice. Cytokine & Growth Factor Reviews, 15(4), 205–213.CrossRefGoogle Scholar
  143. 143.
    Koblizek, T. I., Weiss, C., Yancopoulos, G. D., Deutsch, U., & Risau, W. (1998). Angiopoietin-1 induces sprouting angiogenesis in vitro. Current Biology, 8(9), 529–532.PubMedCrossRefGoogle Scholar
  144. 144.
    Cheng, Z., Ou, L., Zhou, X., et al. (2008). Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Molecular Therapy, 16(3), 571–579.PubMedCrossRefGoogle Scholar
  145. 145.
    Song, H., Kwon, K., Lim, S., et al. (2005). Transfection of mesenchymal stem cells with the FGF-2 gene improves their survival under hypoxic conditions. Molecules and Cells, 19(3), 402–407.PubMedGoogle Scholar
  146. 146.
    Li, H., Zuo, S., He, Z., et al. (2010). Paracrine factors released by GATA-4 overexpressed mesenchymal stem cells increase angiogenesis and cell survival. American Journal of Physiology—Heart and Circulatory Physiology, 299(6), H1772–H1781.PubMedCrossRefGoogle Scholar
  147. 147.
    Fan, L., Lin, C., Zhuo, S., et al. (2009). Transplantation with survivin-engineered mesenchymal stem cells results in better prognosis in a rat model of myocardial infarction. European Journal of Heart Failure, 11(11), 1023–1030.PubMedCrossRefGoogle Scholar
  148. 148.
    Jo, J., Nagaya, N., Miyahara, Y., et al. (2007). Transplantation of genetically engineered mesenchymal stem cells improves cardiac function in rats with myocardial infarction: benefit of a novel nonviral vector, cationized dextran. Tissue Engineering, 13(2), 313–322.PubMedCrossRefGoogle Scholar
  149. 149.
    Sun, L., Cui, M., Wang, Z., et al. (2007). Mesenchymal stem cells modified with angiopoietin-1 improve remodeling in a rat model of acute myocardial infarction. Biochemical and Biophysical Research Communications, 357(3), 779–784.PubMedCrossRefGoogle Scholar
  150. 150.
    Huang, S. D., Lu, F. L., Xu, X. Y., et al. (2006). Transplantation of angiogenin-overexpressing mesenchymal stem cells synergistically augments cardiac function in a porcine model of chronic ischemia. The Journal of Thoracic and Cardiovascular Surgery, 132(6), 1329–1338.PubMedCrossRefGoogle Scholar
  151. 151.
    Wang, M., Tan, J., Wang, Y., Meldrum, K. K., Dinarello, C. A., & Meldrum, D. R. (2009). IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction. Proceedings of the National Academy of Sciences of the United States of America, 106(41), 17499–17504.PubMedCrossRefGoogle Scholar
  152. 152.
    Li, Y., Hiroi, Y., Ngoy, S., et al. (2011). Notch1 in bone marrow-derived cells mediates cardiac repair after myocardial infarction. Circulation, 123(8), 866–876.PubMedCrossRefGoogle Scholar
  153. 153.
    Lian, W. S., Cheng, W. T., Cheng, C. C., et al. (2011). In vivo therapy of myocardial infarction with mesenchymal stem cells modified with prostaglandin I synthase gene improves cardiac performance in mice. Life Sciences, 88(9–10), 455–464.PubMedCrossRefGoogle Scholar
  154. 154.
    Bao, C., Guo, J., Lin, G., Hu, M., & Hu, Z. (2008). TNFR gene-modified mesenchymal stem cells attenuate inflammation and cardiac dysfunction following MI. Scandinavian Cardiovascular Journal, 42(1), 56–62.PubMedCrossRefGoogle Scholar
  155. 155.
    Bao, C., Guo, J., Zheng, M., Chen, Y., Lin, G., & Hu, M. (2010). Enhancement of the survival of engrafted mesenchymal stem cells in the ischemic heart by TNFR gene transfection. Biochemical Cell Biology, 88(4), 629–634.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • E. Samper
    • 1
  • A. Diez-Juan
    • 2
  • J. A. Montero
    • 1
  • P. Sepúlveda
    • 1
    Email author
  1. 1.Mixt Unit for cardiovascular repair IIS La Fe-CIPFFundación Hospital La FeValenciaSpain
  2. 2.Mixt Unit for cardiovascular repair IIS La Fe-CIPFCentro Investigación Príncipe FelipeValenciaSpain

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