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Mesenchymal Stem Cell Therapy for Cardiac Repair

  • Regenerative Medicine and Stem-cell Therapy (S Wu and P Hsieh, Section Editors)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Opinion statement

Owing to the prevalence of heart disease and the lack of effective long-term solutions for managing cardiac injury, research has turned to cell therapy as a potential mechanism for myocardial repair. Mesenchymal stem cells (MSC) in particular have become popular because their differentiative ability and their angiogenic and immunomodulatory properties make them attractive candidates for transplantation. However, there is still debate regarding the optimal strategy for the delivery of these cells. Recent clinical studies have isolated MSCs from a variety of tissue origins and have also tested the benefits of pretreatment with cardiogenic growth factors. Meanwhile, a newer school of thought instead supports the utilization of cardiomyocytes generated from MSC-derived induced pluripotent stem cells. This review will examine the promise of MSC therapy, discuss the results of past work, and propose steps that must be taken in the future.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Executive summary: heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127(1):143–52.

    Article  PubMed  Google Scholar 

  2. Braunwald E, Pfeffer MA. Ventricular enlargement and remodeling following acute myocardial infarction: mechanisms and management. Am J Cardiol. 1991;68(14):1D–6.

    Article  CAS  PubMed  Google Scholar 

  3. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81(4):1161–72.

    Article  CAS  PubMed  Google Scholar 

  4. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000;101(25):2981–8.

    Article  CAS  PubMed  Google Scholar 

  5. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol. 2000;35(3):569–82.

    Article  CAS  PubMed  Google Scholar 

  6. Lee TH, Hamilton MA, Stevenson LW, Moriguchi JD, Fonarow GC, Child JS, et al. Impact of left ventricular cavity size on survival in advanced heart failure. Am J Cardiol. 1993;72(9):672–6.

    Article  CAS  PubMed  Google Scholar 

  7. Loughran JH, Chugh AR, Ismail I, Bolli R. Stem cell therapy: promising treatment in heart failure? Curr Heart Fail Rep. 2013;10(1):73–80.

    Article  PubMed  Google Scholar 

  8. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114(6):763–76.

    Article  CAS  PubMed  Google Scholar 

  9. Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16(3):381–90. Research that led to the discovery of MSC and eventually their therapeutic properties.

    CAS  PubMed  Google Scholar 

  10. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3(4):393–403.

    CAS  PubMed  Google Scholar 

  11. Friedenstein AJ, Chailakhyan RK, Gerasimov UV. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet. 1987;20(3):263–72.

    CAS  PubMed  Google Scholar 

  12. Owen M, Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp. 1988;136:42–60.

    CAS  PubMed  Google Scholar 

  13. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641–50.

    Article  CAS  PubMed  Google Scholar 

  14. Murray IR, West CC, Hardy WR, James AW, Park TS, Nguyen A, et al. Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci. 2013;Epub ahead of print.

  15. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.

    Article  CAS  PubMed  Google Scholar 

  16. Caplan AI. Mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Eng. 2005;11(7–8):1198–211.

    Article  CAS  PubMed  Google Scholar 

  17. Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009;217(2):318–24.

    Article  CAS  PubMed  Google Scholar 

  18. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002;105(1):93–8.

    Article  PubMed  Google Scholar 

  19. Nakanishi C, Yamagishi M, Yamahara K, Hagino I, Mori H, Sawa Y, et al. Activation of cardiac progenitor cells through paracrine effects of mesenchymal stem cells. Biochem Biophys Res Commun. 2008;374(1):11–6.

    Article  CAS  PubMed  Google Scholar 

  20. Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010;107(7):913–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell. 2012;10(3):244–58.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Park CW, Kim K, Bae S, Son HK, Myung P, Hong HJ, et al. Cytokine secretion profiling of human mesenchymal stem cells by antibody array. Int J Stem Cells. 2009;2(1):59–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Hoffmann J, Glassford AJ, Doyle TC, Robbins RC, Schrepfer S, Pelletier MP. Angiogenic effects despite limited cell survival of bone marrow-derived mesenchymal stem cells under ischemia. Thorac Cardiovasc Surg. 2010;58(3):136–42.

    Article  CAS  PubMed  Google Scholar 

  24. Watt SM, Gullo F, van der Garde M, Markeson D, Camicia R, Khoo CP, et al. The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. Br Med Bull. 2013;108:25–53.

    Article  PubMed  Google Scholar 

  25. Kim SW, Zhang HZ, Kim CE, Kim JM, Kim MH. Amniotic mesenchymal stem cells with robust chemotactic properties are effective in the treatment of a myocardial infarction model. Int J Cardiol. 2013;168(2):1062–9.

    Article  PubMed  Google Scholar 

  26. Weil BR, Manukyan MC, Herrmann JL, Abarbanell AM, Poynter JA, Wang Y, et al. The immunomodulatory properties of mesenchymal stem cells: implications for surgical disease. J Surg Res. 2011;167(1):78–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Chapel A, Bertho JM, Bensidhoum M, Fouillard L, Young RG, Frick J, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med. 2003;5(12):1028–38.

    Article  PubMed  Google Scholar 

  28. Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES, Scandurro AB. Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells. 2008;26(1):99–107.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Chavakis E, Urbich C, Dimmeler S. Homing and engraftment of progenitor cells: a prerequisite for cell therapy. J Mol Cell Cardiol. 2008;45(4):514–22.

    Article  CAS  PubMed  Google Scholar 

  30. Shi Y, Hu G, Su J, Li W, Chen Q, Shou P, et al. Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 2010;20(5):510–8.

    Article  CAS  PubMed  Google Scholar 

  31. Meirelles LS, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009;20(5–6):419–27.

    Article  CAS  Google Scholar 

  32. Gebler A, Zabel O, Seliger B. The immunomodulatory capacity of mesenchymal stem cells. Trends Mol Med. 2012;18(2):128–34.

    Article  CAS  PubMed  Google Scholar 

  33. Rasmusson I. Immune modulation by mesenchymal stem cells. Exp Cell Res. 2006;312(12):2169–79.

    Article  CAS  PubMed  Google Scholar 

  34. Squadrito F, Altavilla D, Squadrito G, Saitta A, Campo GM, Arlotta M, et al. Cyclosporin-A reduces leukocyte accumulation and protects against myocardial ischaemia reperfusion injury in rats. Eur J Pharmacol. 1999;364(2–3):159–68.

    Article  CAS  PubMed  Google Scholar 

  35. Raffaghello L, Bianchi G, Pistoia V. Immunosuppressive treatments in acute myocardial infarction and stroke. Curr Pharm Biotechnol. 2012;13(1):59–67.

    Article  CAS  PubMed  Google Scholar 

  36. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009;54(24):2277–86. One of the first major clinical trials to prove the safety and efficacy of MSC therapy in cardiac repair.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Telukuntla KS, Suncion VY, Schulman IH, Hare JM. The advancing field of cell-based therapy: insights and lessons from clinical trials. J Am Heart Assoc. 2013;2(5):e000338.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, et al. Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012;308(22):2369–79.

    Article  CAS  PubMed  Google Scholar 

  39. Bartunek J, Behfar A, Dolatabadi D, Vanderheyden M, Ostojic M, Dens J, et al. Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol. 2013;61(23):2329–38.

    Article  PubMed  Google Scholar 

  40. Houtgraaf JH, den Dekker WK, van Dalen BM, Springeling T, de Jong R, van Geuns RJ, et al. First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2012;59(5):539–40.

    Article  PubMed  Google Scholar 

  41. Qayyum AA, Haack-Sorensen M, Mathiasen AB, Jorgensen E, Ekblond A, Kastrup J. Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial): study design. Regen Med. 2012;7(3):421–8.

    Article  CAS  PubMed  Google Scholar 

  42. Houtgraaf JH, de Jong R, Kazemi K, de Groot D, van der Spoel TI, Arslan F, et al. Intracoronary infusion of allogeneic mesenchymal precursor cells directly after experimental acute myocardial infarction reduces infarct size, abrogates adverse remodeling, and improves cardiac function. Circ Res. 2013;113(2):153–66.

    Article  CAS  PubMed  Google Scholar 

  43. Ge X, Wang IN, Toma I, Sebastiano V, Liu J, Butte MJ, et al. Human amniotic mesenchymal stem cell-derived induced pluripotent stem cells may generate a universal source of cardiac cells. Stem Cells Dev. 2012;21(15):2798–808.Showed that iPSC derived from MSC could be used to generate immunoprivileged cardiac cells for transplantation.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    Article  CAS  PubMed  Google Scholar 

  45. Yamada S, Nelson T, Kane G, Martinez-Fernandez A, Crespo-Diaz RJ, Ikeda Y, et al. Induced pluripotent stem cell intervention rescues wall motion disparity achieving biological cardiac resynchronization post-infarction. J Physiol. 2013;Epub ahead of print.

  46. Oskouei BN, Lamirault G, Joseph C, Treuer AV, Landa S, Da Silva J, et al. Increased potency of cardiac stem cells compared with bone marrow mesenchymal stem cells in cardiac repair. Stem Cells Transl Med. 2012;1(2):116–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, et al. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation. 2013;127(2):213–23.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Rubio D, Garcia-Castro J, Martín MC, de la Fuente R, Cigudosa JC, Lloyd AC, et al. Spontaneous human adult stem cell transformation. Cancer Res. 2005;65(8):3035–9.

    CAS  PubMed  Google Scholar 

  49. Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009;69(13):5331–9.

    Article  CAS  PubMed  Google Scholar 

  50. Miura M, Miura Y, Padilla-Nash HM, Molinolo AA, Fu B, Patel V, et al. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. Stem Cells. 2006;24(4):1095–103.

    Article  PubMed  Google Scholar 

  51. Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S, et al. Sarcoma derived from cultured mesenchymal stem cells. Stem Cells. 2007;25(2):371–9.

    Article  CAS  PubMed  Google Scholar 

  52. Barkholt L, Flory E, Jekerle V, Lucas-Samuel S, Ahnert P, Bisset L, et al. Risk of tumorigenicity in mesenchymal stromal cell-based therapies: bridging scientific observations and regulatory viewpoints. Cytotherapy. 2013;15(7):753–9.

    Article  PubMed  Google Scholar 

  53. Wong RS. Mesenchymal stem cells: angels or demons? J Biomed Biotechnol. 2011;2011:459510.

    PubMed Central  PubMed  Google Scholar 

  54. Bernardo ME, Fibbe WE. Safety and efficacy of mesenchymal stromal cell therapy in autoimmune disorders. Ann N Y Acad Sci. 2012;1266:107–17.

    Article  PubMed  Google Scholar 

  55. Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood. 2007;110(4):1362–9.

    Article  CAS  PubMed  Google Scholar 

  56. Kunter U, Rong S, Boor P, Eitner F, Müller-Newen G, Djuric Z, et al. Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes. J Am Soc Nephrol. 2007;18(6):1754–64.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

The authors would like to acknowledge partial funding for this work through the Cardiovascular Cell Therapy Research Network (CCTRN) under cooperative agreement #5UM1HL087318-08.

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Conflict of Interest

Rahul Thakker and Dr. Phillip Yang each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA

    Rahul Thakker BS & Phillip Yang MD

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  1. Rahul Thakker BS
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  2. Phillip Yang MD
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Correspondence to Rahul Thakker BS.

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This article is part of the Topical Collection on Regenerative Medicine and Stem-cell Therapy

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Thakker, R., Yang, P. Mesenchymal Stem Cell Therapy for Cardiac Repair. Curr Treat Options Cardio Med 16, 323 (2014). https://doi.org/10.1007/s11936-014-0323-4

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