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The role of stem cells in treating coronary artery disease in 2018

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Indian Journal of Thoracic and Cardiovascular Surgery Aims and scope Submit manuscript

Abstract

The last decade has witnessed the publication of a number of stem cell clinical trials, primarily using bone marrow-derived cells as the injected cell. Much has been learned through these “first-generation” clinical trials. The advances in our understanding include the following: (1) cell therapy is safe; (2) cell therapy has been mildly effective; and (3) human bone marrow-derived stem cells do not transdifferentiate into cardiomyocytes or new blood vessels. The primary mechanism of action for cell therapy is now believed to be through paracrine effects that include the release of cytokines, chemokines, and growth factors that inhibit apoptosis and fibrosis, enhance contractility, and activate endogenous regenerative mechanisms through endogenous circulating or site-specific stem cells. The current direction for clinical trials includes the use of stem cells capable of cardiac lineage.

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References

  1. Murphy SL, Xu JQ, Kochanek KD. Deaths: Preliminary data for 2010. National vital statistics reports; vol 60 no 4. Hyattsville, MD: National Center for Health Statistics. 2012.

  2. Miller LW, Missov ED. Epidemiology of heart failure. Cardiol Clin. 2001;19:547–55.

    Article  CAS  PubMed  Google Scholar 

  3. Lenzen MJ, Boersma E, Reimer WJ, et al. Under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the Euro Heart Survey on Heart Failure. Eur Heart J. 2005;26:2706–13.

    Article  CAS  PubMed  Google Scholar 

  4. Asahara T, Bauters C, Zheng LP, et al. Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation. 1995;92:II365–71.

    Article  CAS  PubMed  Google Scholar 

  5. Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res. 2002;91:189–201.

    Article  CAS  PubMed  Google Scholar 

  6. Birbrair A, Frenette PS. Niche heterogeneity in the bone marrow. Ann N Y Acad Sci. 2016;1370:82–96.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Dimmeler S, Zeiher AM. Cell therapy of acute myocardial infarction: open questions. Cardiology. 2009;113:155–60.

    Article  PubMed  Google Scholar 

  8. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.

    Article  CAS  Google Scholar 

  9. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.

    Article  CAS  PubMed  Google Scholar 

  10. Tang YL, Zhao Q, Zhang YC, et al. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept. 2004;117:3–10.

    Article  CAS  PubMed  Google Scholar 

  11. Fukuhara S, Tomita S, Yamashiro S, et al. Direct cell-cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro. J Thorac Cardiovasc Surg. 2003;125:1470–80.

    Article  PubMed  Google Scholar 

  12. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest. 1999;103:697–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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;105:93–8.

    Article  PubMed  Google Scholar 

  14. Sussman MA, Murry CE. Bones of contention: marrow-derived cells in myocardial regeneration. J Mol Cell Cardiol. 2008;44:950–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arai F, Hirao A, Suda T. Regulation of hematopoiesis and its interaction with stem cell niches. Int J Hematol. 2005;82:371–6.

    Article  CAS  PubMed  Google Scholar 

  16. Furness SG, McNagny K. Beyond mere markers: functions for CD34 family of sialomucins in hematopoiesis. Immunol Res. 2006;34:13–32.

    Article  CAS  PubMed  Google Scholar 

  17. Ferreri NR, Escalante BA, Zhao Y, An SJ, McGiff JC. Angiotensin II induces TNF production by the thick ascending limb: functional implications. Am J Physiol. 1998;274:F148–55.

    CAS  PubMed  Google Scholar 

  18. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290:1779–82.

    Article  CAS  PubMed  Google Scholar 

  19. Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6:1229–34.

    Article  CAS  PubMed  Google Scholar 

  20. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–7.

    Article  CAS  PubMed  Google Scholar 

  21. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95:343–53.

    Article  CAS  PubMed  Google Scholar 

  22. Hur J, Yoon CH, Kim HS, et al. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol. 2004;24:288–93.

    Article  CAS  PubMed  Google Scholar 

  23. Giannotti G, Doerries C, Mocharla PS, et al. Impaired endothelial repair capacity of early endothelial progenitor cells in prehypertension: relation to endothelial dysfunction. Hypertension. 2010;55:1389–97.

    Article  CAS  Google Scholar 

  24. Sieveking DP, Buckle A, Celermajer DS, Ng MK. Strikingly different angiogenic properties of endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay. J Am Coll Cardiol. 2008;51:660–8.

    Article  CAS  PubMed  Google Scholar 

  25. Gruh I, Beilner J, Blomer U, et al. No evidence of transdifferentiation of human endothelial progenitor cells into cardiomyocytes after coculture with neonatal rat cardiomyocytes. Circulation. 2006;113:1326–34.

    Article  CAS  PubMed  Google Scholar 

  26. Sinha S, Poh KK, Sodano D, et al. Safety and efficacy of peripheral blood progenitor cell mobilization and collection in patients with advanced coronary heart disease. J Clin Apher. 2006;21:116–20.

    Article  PubMed  Google Scholar 

  27. Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114:763–76.

    Article  CAS  PubMed  Google Scholar 

  28. Dawn B, Stein AB, Urbanek K, et al. Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci U S A. 2005;102:3766–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Messina E, De Angelis L, Frati G, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res. 2004;95:911–21.

    Article  CAS  PubMed  Google Scholar 

  30. Urbanek K, Quaini F, Tasca G, et al. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci U S A. 2003;100:10440–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Davis DR, Zhang Y, Smith RR, et al. Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. PLoS One. 2009;e7195:4.

    Google Scholar 

  32. Malliaras K, Marbán E. Cardiac cell therapy: where we’ve been, where we are, and where we should be headed. Br Med Bull. 2011;98:161–85.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Smith RR, Barile L, Cho HC, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115:896–908.

    Article  CAS  PubMed  Google Scholar 

  34. Assmus B, Schächinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106:3009–17.

    Article  PubMed  Google Scholar 

  35. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004;364:141–8.

    Article  PubMed  Google Scholar 

  36. Meyer GP, Wollert KC, Lotz J, et al. 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. 2006;113:1287–94.

    Article  PubMed  Google Scholar 

  37. Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006;355:1199–209.

    Article  CAS  PubMed  Google Scholar 

  38. Schachinger V, Erbs S, Elsasser A, et al. 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. Eur Heart J. 2006;27:2775–83.

    Article  PubMed  Google Scholar 

  39. Assmus B, Tonn T, Seeger FH, et al. Red blood cell contamination of the final cell product impairs the efficacy of autologous bone marrow mononuclear cell therapy. J Am Coll Cardiol. 2010;55:1385–94.

    Article  PubMed  Google Scholar 

  40. Wöhrle J, Merkle N, Mailänder V, et al. Results of intracoronary stem cell therapy after acute myocardial infarction. Am J Cardiol. 2010;105:804–12.

    Article  CAS  PubMed  Google Scholar 

  41. Wöhrle J, von Scheidt F, Schauwecker P. et. al. Impact of cell number and microvascular obstruction in patients with bone-marrow derived cell therapy: final results from the randomized, double-blind, placebo controlled intracoronary Stem Cell therapy in patients with Acute Myocardial Infarction (SCAMI) trial. Clin Res Cardiol. 2013;102:765–70.

    Article  CAS  PubMed  Google Scholar 

  42. Tendera M, Wojakowski W, Ruzyłło W, et al. REGENT Investigators. Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicenter Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial. Eur Heart J. 2009;30:1313–21.

    Article  PubMed  Google Scholar 

  43. Hare JM, Traverse JH, Henry TD, 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;54:2277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Quyyumi AA, Vasquez A, Kereiakes DJ, et al. PreSERVE-AMI: a randomized, double-blind, placebo-controlled clinical trial of intracoronary administration of autologous CD34+ cells in patients with left ventricular dysfunction post STEMI. Circ Res. 2017;120:324–31.

    Article  CAS  PubMed  Google Scholar 

  45. Gyöngyösi M, Lang I, Dettke M, et al. Combined delivery approach of bone marrow mononuclear stem cells early and late after myocardial infarction: the MYSTAR prospective, randomized study. Nat Clin Pract Cardiovasc Med. 2009;6:70–81.

    Article  PubMed  Google Scholar 

  46. Sürder D, Schwitter J, Moccetti T, et al. Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI). Am Heart J. 2010;160:58–64.

    Article  PubMed  Google Scholar 

  47. Traverse JH, Henry TD, Pepine CJ, et al. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012;308:2380–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Traverse JH, Henry TD, Ellis SG, et al. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA. 2011;306:2110–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107:2294–302.

    Article  PubMed  Google Scholar 

  50. Perin EC, Dohmann HF, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation. 2004;110:II213–8.

    Article  PubMed  Google Scholar 

  51. Hendrikx M, Hensen K, Clijsters C, et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation. 2006;114:I101–7.

    Article  PubMed  Google Scholar 

  52. Assmus B, Honold J, Schächinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med. 2006;355:1222–32.

    Article  CAS  PubMed  Google Scholar 

  53. Flores-Ramírez R, Uribe-Longoria A, Rangel-Fuentes MM, et al. Intracoronary infusion of CD133+ endothelial progenitor cells improves heart function and quality of life in patients with chronic post-infarct heart insufficiency. Cardiovasc Revasc Med. 2010;11:72–8.

    Article  PubMed  Google Scholar 

  54. Strauer BE, Yousef M, Schannwell CM. The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heart failure: the STAR-heart study. Eur J Heart Fail. 2010;12:721–9.

    Article  PubMed  Google Scholar 

  55. Stamm C, Kleine HD, Choi YH, et al. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. J Thorac Cardiovasc Surg. 2007;133:717–25.

    Article  PubMed  Google Scholar 

  56. Hare JM, Fishman JE, Gerstenblith G, 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;308:2369–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ascheim DD, Gelijns AC, Goldstein D, et al. Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices. Circulation. 2014;129:2287–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012;379:895–904.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Malliaras K, Makkar RR, Smith RR, et al. Intracoronary cardiosphere-derived cells after myocardial infarction: Evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial. J Am Coll Cardiol. 2014;63:110–22.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Greene Medical Arts Pavilion 5th Floor, 3400 Bainbridge Avenue, New York City, NY, 10467, USA

    Robert E. Michler

  2. Department of Cardiothoracic & Vascular Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Greene Medical Arts Pavilion 5th Floor, 3400 Bainbridge Avenue, New York City, NY, 10467, USA

    Robert E. Michler

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Michler, R.E. The role of stem cells in treating coronary artery disease in 2018. Indian J Thorac Cardiovasc Surg 34 (Suppl 3), 340–348 (2018). https://doi.org/10.1007/s12055-018-0739-7

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