Stem Cell Reviews and Reports

, Volume 9, Issue 3, pp 254–265

Mesenchymal Stem Cells for Cardiac Therapy: Practical Challenges and Potential Mechanisms

  • Timothy J. Cashman
  • Valerie Gouon-Evans
  • Kevin D. Costa
Article

Abstract

Cell based treatments for myocardial infarction have demonstrated efficacy in the laboratory and in phase I clinical trials, but the understanding of such therapies remains incomplete. Mesenchymal stem cells (MSCs) are classically defined as maintaining the ability to generate mesenchyme-derived cell types, namely adipocytes, chondrocytes and osteocytes. Recent evidence suggests these cells may in fact harbor much greater potency than originally realized, as several groups have found that MSCs can form cardiac lineage cells in vitro. Additionally, experimental coculture of MSCs with cardiomyocytes appears to improve contractile function of the latter. Bolstered by such findings, several clinical trials have begun to test MSC transplantation for improving post-infarct cardiac function in human patients. The results of these trials have been mixed, underscoring the need to develop a deeper understanding of the underlying stem cell biology. To help synthesize the breadth of studies on the topic, this paper discusses current challenges in the field of MSC cellular therapies for cardiac repair, including methods of cell delivery and the identification of molecular markers that accurately specify the therapeutically relevant mesenchymal cell types. The various possible mechanisms of MSC mediated cardiac improvement, including somatic reprogramming, transdifferentiation, paracrine signaling, and direct electrophysiological coupling are also reviewed. Finally, we consider the traditional cell culture microenvironment, and the promise of cardiac tissue engineering to provide biomimetic in vitro model systems to more faithfully investigate MSC biology, helping to safely and effectively translate exciting discoveries in the laboratory to meaningful therapies in the clinic.

Keywords

Marrow stromal cell Cardiac repair Cellular therapy Molecular markers Reprogramming Differentiation Paracrine signaling Tissue engineering 

References

  1. 1.
    Pittenger, M. F., Mackay, A. M., Beck, S. C., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147.CrossRefPubMedGoogle Scholar
  2. 2.
    Song, L., & Tuan, R. S. (2004). Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow. The FASEB Journal, 18, 980–982.Google Scholar
  3. 3.
    Jiang, Y., Jahagirdar, B. N., Reinhardt, R. L., et al. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 418, 41–49.CrossRefPubMedGoogle Scholar
  4. 4.
    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, 2277–2286.CrossRefPubMedGoogle Scholar
  5. 5.
    Li, Y., Yao, Y., Sheng, Z., Yang, Y., & Ma, G. (2011). Dual-modal tracking of transplanted mesenchymal stem cells after myocardial infarction. International Journal of Nanomedicine, 6, 815–823.CrossRefPubMedGoogle Scholar
  6. 6.
    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, 792–796.CrossRefPubMedGoogle Scholar
  7. 7.
    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, 14022–14027.CrossRefPubMedGoogle Scholar
  8. 8.
    Amado, L. C., Saliaris, A. P., Schuleri, K. H., et al. (2005). Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America, 102, 11474–11479.CrossRefPubMedGoogle Scholar
  9. 9.
    Miyahara, Y., Nagaya, N., Kataoka, M., et al. (2006). Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nature Medicine, 12, 459–465.CrossRefPubMedGoogle Scholar
  10. 10.
    Koninckx, R., Hensen, K., Daniëls, A., et al. (2009). Human bone marrow stem cells co-cultured with neonatal rat cardiomyocytes display limited cardiomyogenic plasticity. Cytotherapy, 11, 778–792.CrossRefPubMedGoogle Scholar
  11. 11.
    Ranganath, S. H., Levy, O., Inamdar, M. S., & Karp, J. M. (2012). Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell, 10, 244–258.CrossRefPubMedGoogle Scholar
  12. 12.
    Friis, T., Haack-Sørensen, M., Mathiasen, A. B., et al. (2011). Mesenchymal stromal cell derived endothelial progenitor treatment in patients with refractory angina. Scandinavian Cardiovascular Journal, 45, 161–168.CrossRefPubMedGoogle Scholar
  13. 13.
    Penn, M. S., Ellis, S., Gandhi, S., et al. (2012). Adventitial delivery of an allogeneic bone marrow-derived adherent stem cell in acute myocardial infarction: phase I clinical study. Circulation Research, 110, 304–311.CrossRefPubMedGoogle Scholar
  14. 14.
    Lunde, K., Solheim, S., Aakhus, S., et al. (2006). Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. The New England Journal of Medicine, 355, 1199–1209.CrossRefPubMedGoogle Scholar
  15. 15.
    Wollert, K. C., Meyer, G. P., Lotz, J., et al. (2004). Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet, 364, 141–148.CrossRefPubMedGoogle Scholar
  16. 16.
    Schaefer, A., Zwadlo, C., Fuchs, M., et al. (2010). Long-term effects of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: 5-year results from the randomized-controlled BOOST trial–an echocardiographic study. European Journal of Echocardiography, 11, 165–171.CrossRefPubMedGoogle Scholar
  17. 17.
    Meyer, G. P., Wollert, K. C., Lotz, J., et al. (2009). Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. European Heart Journal, 30, 2978–2984.CrossRefPubMedGoogle Scholar
  18. 18.
    Meyer, G. P., Wollert, K. C., Lotz, J., et al. (2006). Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation, 113, 1287–1294.CrossRefPubMedGoogle Scholar
  19. 19.
    Dai, W., Hale, S. L., Martin, B. J., et al. (2005). Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation, 112, 214–223.CrossRefPubMedGoogle Scholar
  20. 20.
    Wen, Y., Meng, L., Xie, J., & Ouyang, J. (2011). Direct autologous bone marrow-derived stem cell transplantation for ischemic heart disease: a meta-analysis. Expert Opinion on Biological Therapy, 11, 559–567.CrossRefPubMedGoogle Scholar
  21. 21.
    Dominici, M., Le Blanc, K., Mueller, I., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8, 315–317.CrossRefPubMedGoogle Scholar
  22. 22.
    Acquistapace, A., Bru, T., Lesault, P.-F., et al. (2011). Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells, 29, 812–824.CrossRefPubMedGoogle Scholar
  23. 23.
    Gaebel, R., Furlani, D., Sorg, H., et al. (2011). Cell origin of human mesenchymal stem cells determines a different healing performance in cardiac regeneration. PloS One, 6, e15652.CrossRefPubMedGoogle Scholar
  24. 24.
    Bayes-Genis, A., Soler-Botija, C., Farré, J., et al. (2010). Human progenitor cells derived from cardiac adipose tissue ameliorate myocardial infarction in rodents. Journal of Molecular and Cellular Cardiology, 49, 771–780.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhao, Z., Chen, Z., Zhao, X., et al. (2011). Sphingosine-1-phosphate promotes the differentiation of human umbilical cord mesenchymal stem cells into cardiomyocytes under the designated culturing conditions. Journal of Biomedical Science, 18, 37.CrossRefPubMedGoogle Scholar
  26. 26.
    Zvaifler, N. J., Marinova-Mutafchieva, L., Adams, G., et al. (2000). Mesenchymal precursor cells in the blood of normal individuals. Arthritis Research, 2, 477–488.CrossRefPubMedGoogle Scholar
  27. 27.
    Kurth, T. B., Dell’accio, F., Crouch, V., Augello, A., Sharpe, P. T., & De Bari, C. (2011). Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis and Rheumatism, 63, 1289–1300.CrossRefPubMedGoogle Scholar
  28. 28.
    Tsuji, H., Miyoshi, S., Ikegami, Y., et al. (2010). Xenografted human amniotic membrane-derived mesenchymal stem cells are immunologically tolerated and transdifferentiated into cardiomyocytes. Circulation Research, 106, 1613–1623.CrossRefPubMedGoogle Scholar
  29. 29.
    Sabatini, F., Petecchia, L., Tavian, M., Jodon de Villeroché, V., Rossi, G. A., & Brouty-Boyé, D. (2005). Human bronchial fibroblasts exhibit a mesenchymal stem cell phenotype and multilineage differentiating potentialities. Laboratory Investigation, 85, 962–971.CrossRefPubMedGoogle Scholar
  30. 30.
    Kawada, H., Fujita, J., Kinjo, K., et al. (2004). Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood, 104, 3581–3587.CrossRefPubMedGoogle Scholar
  31. 31.
    Peister, A., Mellad, J. A., Larson, B. L., Hall, B. M., Gibson, L. F., & Prockop, D. J. (2004). Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood, 103, 1662–1668.CrossRefPubMedGoogle Scholar
  32. 32.
    Bonios, M., Terrovitis, J., Chang, C. Y., et al. (2011). Myocardial substrate and route of administration determine acute cardiac retention and lung bio-distribution of cardiosphere-derived cells. Journal of Nuclear Cardiology, 18, 443–450.CrossRefPubMedGoogle Scholar
  33. 33.
    Dib, N., Khawaja, H., Varner, S., McCarthy, M., & Campbell, A. (2011). Cell therapy for cardiovascular disease: a comparison of methods of delivery. Journal of Cardiovascular Translational Research, 4, 177–181.CrossRefPubMedGoogle Scholar
  34. 34.
    Wei, F., Wang, T., Liu, J., Du, Y., & Ma, A. (2011). The subpopulation of mesenchymal stem cells that differentiate toward cardiomyocytes is cardiac progenitor cells. Experimental Cell Research, 317, 2661–2670.CrossRefPubMedGoogle Scholar
  35. 35.
    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, 913–922.CrossRefPubMedGoogle Scholar
  36. 36.
    Numasawa, Y., Kimura, T., Miyoshi, S., et al. (2011). Treatment of human mesenchymal stem cells with angiotensin receptor blocker improved efficiency of cardiomyogenic transdifferentiation and improved cardiac function via angiogenesis. Stem Cells, 29, 1405–1414.PubMedGoogle Scholar
  37. 37.
    Siegel. G., Krause, P., Wöhrle, S., et al. (2012). Bone marrow-derived human mesenchymal stem cells express cardiomyogenic proteins but do not exhibit functional cardiomyogenic differentiation potential. Stem Cells and Development, -not available-, ahead of print.Google Scholar
  38. 38.
    Sassoli, C., Pini, A., Mazzanti, B., et al. (2011). Mesenchymal stromal cells affect cardiomyocyte growth through juxtacrine Notch-1/Jagged-1 signaling and paracrine mechanisms: clues for cardiac regeneration. Journal of Molecular and Cellular Cardiology, 51, 399–408.CrossRefPubMedGoogle Scholar
  39. 39.
    Boni, A., Urbanek, K., Nascimbene, A., et al. (2008). Notch1 regulates the fate of cardiac progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 105, 15529–15534.CrossRefPubMedGoogle Scholar
  40. 40.
    Abarbanell, A. M., Wang, Y., Herrmann, J. L., et al. (2010). Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury. American Journal of Physiology: Heart and Circulatory Physiology, 298, H1529–36.CrossRefPubMedGoogle Scholar
  41. 41.
    Varoga, D., Paulsen, F., Mentlein, R., et al. (2006). TLR-2-mediated induction of vascular endothelial growth factor (VEGF) in cartilage in septic joint disease. Journal of Pathology, 210, 315–324.CrossRefPubMedGoogle Scholar
  42. 42.
    Williams, A. R., & Hare, J. M. (2011). Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circulation Research, 109, 923–940.CrossRefPubMedGoogle Scholar
  43. 43.
    Xu, H., Yang, Y.-J., Qian, H.-Y., Tang, Y.-D., Wang, H., & Zhang, Q. (2011). Rosuvastatin treatment activates JAK-STAT Pathway and increases efficacy of allogeneic mesenchymal stem cell transplantation in infarcted hearts. Circulation Journal, 75, 1476–1485.CrossRefPubMedGoogle Scholar
  44. 44.
    Loffredo, F. S., Steinhauser, M. L., Gannon, J., & Lee, R. T. (2011). Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair. Cell Stem Cell, 8, 389–398.CrossRefPubMedGoogle Scholar
  45. 45.
    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, 834–838.CrossRefPubMedGoogle Scholar
  46. 46.
    Valiunas, V., Doronin, S., Valiuniene, L., et al. (2004). Human mesenchymal stem cells make cardiac connexins and form functional gap junctions. The Journal of Physiology, 555, 617–626.CrossRefPubMedGoogle Scholar
  47. 47.
    Mills, W. R., Mal, N., Kiedrowski, M. J., et al. (2007). Stem cell therapy enhances electrical viability in myocardial infarction. Journal of Molecular and Cellular Cardiology, 42, 304–314.CrossRefPubMedGoogle Scholar
  48. 48.
    Serrao, G.S., Turnbull, I.C., Ancukiewicz, D., et al. (2012). Myocyte-Depleted Engineered Cardiac Tissue Support Therapeutic Potential of Mesenchymal Stem Cells. Tissue Engineering Part A, doi:10.1089/ten.TEA.2011.0278.
  49. 49.
    Chang, M. G., Tung, L., Sekar, R. B., et al. (2006). Proarrhythmic potential of mesenchymal stem cell transplantation revealed in an in vitro coculture model. Circulation, 113, 1832–1841.CrossRefPubMedGoogle Scholar
  50. 50.
    Costa, A. R., Panda, N. C., Yong, S., et al. (2012). Optical mapping of cryoinjured rat myocardium grafted with mesenchymal stem cells. American Journal of Physiology: Heart and Circulatory Physiology, 302, H270–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Ramkisoensing, A. A., Pijnappels, D. A., Askar, S. F. A., et al. (2011). Human embryonic and fetal mesenchymal stem cells differentiate toward three different cardiac lineages in contrast to their adult counterparts. PloS One, 6, e24164.CrossRefPubMedGoogle Scholar
  52. 52.
    Hwang, N. S., Kim, M. S., Sampattavanich, S., Baek, J. H., Zhang, Z., & Elisseeff, J. (2006). Effects of three-dimensional culture and growth factors on the chondrogenic differentiation of murine embryonic stem cells. Stem Cells, 24, 284–291.CrossRefPubMedGoogle Scholar
  53. 53.
    Engler, A. J., Sen, S., Sweeney, H. L., & Discher, D. E. (2006). Matrix elasticity directs stem cell lineage specification. Cell, 126, 677–689.CrossRefPubMedGoogle Scholar
  54. 54.
    Engler, A. J., Carag-Krieger, C., Johnson, C. P., et al. (2008). Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating. Journal of Cell Science, 121, 3794–3802.CrossRefPubMedGoogle Scholar
  55. 55.
    Jacot, J. G., McCulloch, A. D., & Omens, J. H. (2008). Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophysical Journal, 95, 3479–3487.CrossRefPubMedGoogle Scholar
  56. 56.
    Domian, I. J., Chiravuri, M., van der Meer, P., et al. (2009). Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science, 326, 426–429.CrossRefPubMedGoogle Scholar
  57. 57.
    Tulloch, N. L., Muskheli, V., Razumova, M. V., et al. (2011). Growth of engineered human myocardium with mechanical loading and vascular coculture. Circulation Research, 109, 47–59.CrossRefPubMedGoogle Scholar
  58. 58.
    Schaaf, S., Shibamiya, A., Mewe, M., et al. (2011). Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology. PloS One, 6, e26397.CrossRefPubMedGoogle Scholar
  59. 59.
    Chen, C.-H., Wei, H.-J., Lin, W.-W., et al. (2008). Porous tissue grafts sandwiched with multilayered mesenchymal stromal cell sheets induce tissue regeneration for cardiac repair. Cardiovascular Research, 80, 88–95.CrossRefPubMedGoogle Scholar
  60. 60.
    Simpson, D. L., Boyd, N. L., Kaushal, S., Stice, S. L., & Dudley, S. C. (2012). Use of human embryonic stem cell derived-mesenchymal cells for cardiac repair. Biotechnology and Bioengineering, 109, 274–283.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Timothy J. Cashman
    • 1
  • Valerie Gouon-Evans
    • 2
  • Kevin D. Costa
    • 1
  1. 1.Cardiovascular Cell and Tissue Engineering Laboratory, Cardiovascular Research CenterMount Sinai School of MedicineNew YorkUSA
  2. 2.Black Family Stem Cell Institute, Department of Developmental and Regenerative BiologyMount Sinai School of MedicineNew YorkUSA

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