Current and Future Status of Stem Cell Therapy in Heart Failure

Valvular, Myocardial, Pericardial, and Cardiopulmonary Diseases

Opinion statement

As heart transplantation and mechanical assist technology are inadequate solutions for the growing clinical epidemic of heart failure, myocardial regeneration has moved to the forefront. Multiple laboratories using a variety of cell types have demonstrated myocardial repair in different animal models. Translating these results into clinical practice through clinical trial research has thus far proved challenging. Amassing clinical evidence suggests that cell therapy is safe and offers a modest clinical benefit, but the long-term effect of such therapy as well as the overall impact on the natural progression of heart failure and, ultimately, survival are unknown. Furthermore, cost-benefit analysis of such therapy, which will likely become increasingly important as health care reform takes shape, has not been examined to any degree. Although scientific competition has driven this field with remarkable speed, it is also responsible for its fragmentation, with multiple avenues of pursuit happening in parallel. Consensus opinion is absent with respect to mechanism of action, effectiveness of cell type or delivery method, timing and dosing of cell therapy, adjunctive medication or therapies, and optimum cell type or combination of cell types. Nevertheless, in the arena of clinical medicine, ease of cell availability and cell delivery has proved paramount to cell type selection. The flourish of clinical trials investigating bone marrow–derived stem cells (BMSCs) delivered via direct intracoronary injection testifies to this opinion. The modest improvements in cardiac function demonstrated in trials to date will likely not have a significant clinical impact. We expect, however, that scientific competition will make continued contributions over the next decade that will propel the field forward, resulting in more pronounced clinical benefits in future trials. The authors further believe that the realization of true cardiac regeneration will require the use of autologous cells more capable of retention and differentiation to cardiac cell lineages. We believe that endogenous cardiac progenitor cells have superior regenerative potential to current cell types in this regard. The difficulty in accessing, isolating, and expanding these cells has resulted in less preclinical and clinical interest. Ongoing investigation will better define the capabilities of these cardiac progenitor cells.

References and Recommended Reading

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

  1. 1.
    Rosamond W, Flegal K, Furie K, et al.: Heart disease and stroke statistics—2008 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008, 117:e25–e146.CrossRefPubMedGoogle Scholar
  2. 2.
    Bergmann O, Bhardwaj RD, Bernard S, et al.: Evidence for cardiomyocyte renewal in humans. Science 2009, 324:98–102.CrossRefPubMedGoogle Scholar
  3. 3.
    Bearzi C, Rota M, Hosoda T, et al.: Human cardiac stem cells. Proc Natl Acad Sci U S A 2007, 104:14068–14073.CrossRefPubMedGoogle Scholar
  4. 4.
    Beltrami AP, Barlucchi L, Torella D, et al.: Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003, 114:763–776.CrossRefPubMedGoogle Scholar
  5. 5.
    Nelson TJ, Ge ZD, Van Orman J, et al.: Improved cardiac function in infarcted mice after treatment with pluripotent embryonic stem cells. Anat Rec A Discov Mol Cell Evol Biol 2006, 288:1216–1224.PubMedGoogle Scholar
  6. 6.
    Molcayni M, Bentz K, Maegele M, et al.: Embryonic stem cell transplantation after experimental traumatic brain injury dramatically improves neurological outcome, but may cause tumors. J Neurotrauma 2007, 4:216–225.Google Scholar
  7. 7.
    Yoshida Y, Yamanaka S: Recent stem cell advances: induced pluripotent stem cells for disease modeling and stem cell–based regeneration. Circulation 2010, 122:80–87.CrossRefPubMedGoogle Scholar
  8. 8.
    Rumyantsev P: Some comparative aspects of myocardial regeneration. In Muscle Regeneration. By Mauro A. New York: Raven Press; 1979:335–355.Google Scholar
  9. 9.
    Koh GY, Klug MG, Soonpaa MH, Field LJ: Differentiation and long-term survival of C2C12 myoblast grafts in heart. J Clin Invest 1993, 92:1548–1554.CrossRefPubMedGoogle Scholar
  10. 10.
    Murry CE, Wiseman RW, Schwartz SM, Hauschka SD: Skeletal myoblast transplantation for repair of myocardial necrosis. J Clin Invest 1996, 98:2512–2523.CrossRefPubMedGoogle Scholar
  11. 11.
    Taylor DA, Atkins BZ, Hungspreugs P, et al.: Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998, 4:929–933.CrossRefPubMedGoogle Scholar
  12. 12.
    Ghostine S, Carrion C, Souza LC, et al.: Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation 2002, 106(Suppl 1):I131–136.PubMedGoogle Scholar
  13. 13.
    Mills WR, Mal N, Kiedrowski P, et al.: Stem cell therapy enhances electrical viability in myocardial infarction. J Mol Cell Cardiol 2007, 42:304–314.CrossRefPubMedGoogle Scholar
  14. 14.
    •• Menasché P, Alfieri O, Janssens S, et al.: The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial: first randomized ized placebo-controlled study of myoblast transplantation. Circulation 2008, 117:1189 –1200. CrossRefPubMedGoogle Scholar
  15. 15.
    Hamdi H, Furuta A, Bellamy V, et al.: Cell delivery: intramyocardial injections or epicardial deposition? A head-to-head comparison. Ann Thorac Surg 2009, 87:1196–1203.CrossRefPubMedGoogle Scholar
  16. 16.
    Lee RH, Kim B, Choi I, et al.: Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 2004, 14:311–324.CrossRefPubMedGoogle Scholar
  17. 17.
    Li B, Zeng Q, Wang H, et al.: Adipose tissue stromal cells transplantation in rats of acute myocardial infarction. Coron Artery Dis 2007, 18:221–227.CrossRefPubMedGoogle Scholar
  18. 18.
    Randomized clinical trial of adipose-derived stem cells in the treatment of pts with st-elevation myocardial infarction. Available at Accessed August 2010.
  19. 19.
    A randomized clinical trial of adipose-derived stem cells in treatment of non revascularizable ischemic myocardium. Available at Accessed August 2010.
  20. 20.
    Choi JH, Hur J, Yoon CH, et al.: Augmentation of therapeutic angiogenesis using genetically modified human endothelial progenitor cells with altered glycogen synthase kinase-3beta activity. J Biol Chem 2004, 279:49430–49438.CrossRefPubMedGoogle Scholar
  21. 21.
    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, 24:288–293.CrossRefPubMedGoogle Scholar
  22. 22.
    Koyanagi M, Brandes RP, Haendeler J, et al.: Cell-to-cell connection of endothelial progenitor cells with cardiac myocytes by nanotubes: a novel mechanism for cell fate changes? Circ Res 2005, 96:1039–1041.CrossRefPubMedGoogle Scholar
  23. 23.
    Murasawa S, Kawamoto A, Horii M, et al.: Niche-dependent translineage commitment of endothelial progenitor cells, not cell fusion in general, into myocardial lineage cells. Arterioscler Thromb Vasc Biol 2005, 25:1388–1394.CrossRefPubMedGoogle Scholar
  24. 24.
    Taljaard M, Ward MR, Kutryk MJ, et al.: Tational and design of enhanced angiogenic cell therapy in acute myocardial infarction (ENACT-AMI): the first randomized placebo-controlled trial of enhanced progenitor cell therapy for acute myocardial infarction. Am Heart J 2010, 159:354–360.CrossRefPubMedGoogle Scholar
  25. 25.
    Arai F, Hirao A, Suda T: Regulation of hematopoiesis and its interaction with stem cell niches. Int J Hematol 2005, 82:371–376.CrossRefPubMedGoogle Scholar
  26. 26.
    Furness SG, McNagny K: Beyond mere markers: functions for CD34 family of sialomucins in hematopoiesis. Immunol Res 2006, 34:13–32.CrossRefPubMedGoogle Scholar
  27. 27.
    Ferrari G, Cusella-De Angelis G, Coletta M, et al.: Muscle regeneration by bone marrow-derived myogenic progenitors. Science 1998, 279:1528–1530.CrossRefPubMedGoogle Scholar
  28. 28.
    Mezey E, Chandross KJ, Harta G, et al.: Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000, 290:1779–1782.CrossRefPubMedGoogle Scholar
  29. 29.
    Lagasse E, Connors H, Al-Dhalimy M, et al.: Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2001, 6:1229–1234.CrossRefGoogle Scholar
  30. 30.
    Jackson KA, Majka SM, Wang H, et al.: Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001, 107:1395–1402.CrossRefPubMedGoogle Scholar
  31. 31.
    Orlic D, Kajstura J, Chimenti S, et al.: Bone marrow cells regenerate infarcted myocardium. Nature 2001, 410:701–705.CrossRefPubMedGoogle Scholar
  32. 32.
    Ma N, Stamm C, Kaminski A, et al.: Human cord blood cells induce angiogenesis following myocardial infarction in NOD/scid-mice. Cardiovasc Res 2005, 66:45–54.CrossRefPubMedGoogle Scholar
  33. 33.
    Kawamoto A, Tkebuchava T, Yamaguchi J, et al.: Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 2003, 107:461–468.CrossRefPubMedGoogle Scholar
  34. 34.
    Kocher AA, Schuster MD, Szabolcs MJ, et al.: Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001, 7:430–436.CrossRefPubMedGoogle Scholar
  35. 35.
    Castro-Malaspina H, Gay RE, Resnick G, et al.: Characterization of human bone marrow fibroblast colony-forming cells (CFU-F) and their progeny. Blood 1980, 56:289–301.PubMedGoogle Scholar
  36. 36.
    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, 125:1470–1480.CrossRefPubMedGoogle Scholar
  37. 37.
    Toma C, Pittenger MF, Cahill KS, et al.: Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2002, 105:93–98.CrossRefPubMedGoogle Scholar
  38. 38.
    ••Singh S, Arora R, Handa K, et al.: Stem cells improve left ventricular function in acute myocardial infarction. Clin Cardiol 2009, 32:176–180.CrossRefPubMedGoogle Scholar
  39. 39.
    ••Zhang S, Sun A, Xu D, et al.: Impact of timing on efficiency and safety of intracoronary autologous bone marrow stem cells transplantation in acute myocardial infarction: a pooled subgroup analysis of randomized controlled trials. Clin Cardiol 2009, 32:458–466. CrossRefPubMedGoogle Scholar
  40. 40.
    Wohrle J, Merkle N, Mailander V, et al.: Results of intracoronary stem cell therapy after acute myocardial infarction. Am J Cardiol 2010, 105:804–812.CrossRefPubMedGoogle Scholar
  41. 41.
    Tendera M, Wojakowski W, Ruzyllo W, et al.: Intracoronary infusion of bone marrow-derived selected CD34 + CXCR4+ cells and nonselected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial. Eur Heart J 2009, 30:1313–1321.CrossRefPubMedGoogle Scholar
  42. 42.
    Arnold R, Villa A, Gutierrex H, et al.: Absence of accelerated atherosclerotic disease progression after intracoronary infusion of bone marrowdervied mononuclear cells in patients with acute myocardial infarctio-angiographic and intravascular ultrasound-results from the terapia cellular aplcada al miocardio pilot study. Am Heart J 2010, 159:1154.e1–1154.e8.Google Scholar
  43. 43.
    Flores-Ramirez 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, 11:72–78.CrossRefPubMedGoogle Scholar
  44. 44.
    •Strauer B-E, 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, 12:721–729. CrossRefPubMedGoogle Scholar
  45. 45.
    ••Hare JH, 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, 54:2277–2286.CrossRefPubMedGoogle Scholar
  46. 46.
    ••Plewka M, Krzeminska-Pakula M, Lipiec P, et al.: Effect of intracoronary injection of mononuclear bone marrow stem cells on left ventricular function in patients with acute myocardial infarction. Am J Cardiol 2009, 104:1336–1342. CrossRefPubMedGoogle Scholar
  47. 47.
    Krause K, Jaquet K, Schneider C, et al.: Percutaneous intramyocardial stem cell injection in patients with acute myocardial infarction: first-in-man study. Heart 2009, 95:1145–1152.CrossRefPubMedGoogle Scholar
  48. 48.
    Fischer-Rosakat U, Assmus B, Seeger FH, et al.: A pilot trial to assess potential effects of selective intracoronary bone marrow derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail 2009, 2:417–423.CrossRefGoogle Scholar
  49. 49.
    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, 113:1287–1294.CrossRefPubMedGoogle Scholar
  50. 50.
    Schachinger V, Erbs S, Elsasser A, et al.: Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006, 355:1210–1221.CrossRefPubMedGoogle Scholar
  51. 51.
    Assmus B, Rolf A, Erbs S, et al.: Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ Heart Fail 2010, 3:89–96.CrossRefPubMedGoogle Scholar
  52. 52.
    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, 55:1385–1394.CrossRefPubMedGoogle Scholar
  53. 53.
    Beitnes JO, Hopp E, Lunde K, et al.: Long term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomized, controlled study. Heart 2009, 95:1983–1989.CrossRefPubMedGoogle Scholar
  54. 54.
    Lunde K, Solheim S, Aakhus S, et al.: Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006, 12:1199–1209.CrossRefGoogle Scholar
  55. 55.
    Surder D, Schwitter J, Moccett 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.CrossRefPubMedGoogle Scholar
  56. 56.
    Abdel-Latif A, Bolli R, Tleyjeh IM, et al.: Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med 2007, 167:989–997.CrossRefPubMedGoogle Scholar
  57. 57.
    Traverse JH, Henry TD, Vaughn DE, et al.: Rationale and design for TIME: a phase II, randomized, double-blin, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction. Am Heart J 2009, 158:356–363.CrossRefPubMedGoogle Scholar
  58. 58.
    The Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis Pilot Study (The POSEIDON-Pilot Study). Available at Accessed August 2010.
  59. 59.
    The Transendocardial Autologous Cells (hMSC or hBMC) in Ischemic Heart Failure Trial (TAC-HFT). Available at Accessed August 2010.
  60. 60.
    Beltrami AP, Barlucchi L, Torella D, et al.: Adult cardiac stem cells ar multipotent and support myocardial regeneration. Cell 2003, 114:763–776.CrossRefPubMedGoogle Scholar
  61. 61.
    Bearzi C, Rota M, Hosoda T, et al.: Human cardiac stem cells. Proc Natl Acad Sci U S A 2007, 104:14068–14073.CrossRefPubMedGoogle Scholar
  62. 62.
    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, 95:911–921.CrossRefPubMedGoogle Scholar
  63. 63.
    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, 102:3766–3771.CrossRefPubMedGoogle Scholar
  64. 64.
    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.CrossRefPubMedGoogle Scholar
  65. 65.
    Bearzi C, Leri A, Lo Monaco F, et al.: Identification of a coronary vascular progenitor cell in the human heart. Proc Natl Acad Sci U S A 2009, 106:15885–15890.CrossRefPubMedGoogle Scholar
  66. 66.
    D’Alessandro DA, Kajstura J, Hosoda T, et al.: Progenitor cells from the explanted heart generate immunocompatible myocardium within the transplanted donor heart. Circ Res 2009, 5:1128–1140.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Cardiovascular and Thoracic SurgeryMontefiore Medical Center/Albert Einstein College of MedicineNew YorkUSA

Personalised recommendations