Repairing damaged myocardium: Evaluating cells used for cardiac regeneration

  • Adam J. T. Schuldt
  • Michael R. Rosen
  • Glenn R. Gaudette
  • Ira S. Cohen
Article

Opinion statement

Cellular cardiomyoplasty has raised hopes of regenerating mechanical function in the heart. Several cell sources have been investigated for their ability to repair the damaged heart, providing reason for optimism. Multiple mechanisms have been proposed for the beneficial effects of the delivered cells; however, true reversal of cardiac damage implies the generation of new contractile myocytes. The assessment of a cell’s ability to regenerate contractile cells requires a defined set of criteria that, if met, define success. Here we review data from the four primary players in cellular cardiomyoplasty (skeletal myoblasts, bone marrow cells, embryonic stem cells, and resident cardiac stem cells) and assess their potential to differentiate into contractile myocytes as indicated by their ability to meet such specified milestones. Both animal studies and clinical trials suggest that current experimental approaches to cellular cardiomyoplasty yield short-term improvement, although it may be independent of cell type used. However, the mechanisms underlying this salutary effect, as well as its persistence in the longer term, have remained elusive.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Taylor DA, Atkins BZ, Hungspreugs P, et al.: Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998, 4:929–933.PubMedCrossRefGoogle Scholar
  2. 2.
    Orlic D, Kajstura J, Chimenti S, et al.: Bone marrow cells regenerate infarcted myocardium. Nature 2001, 410:701–705.PubMedCrossRefGoogle Scholar
  3. 3.
    Noble D: Initiation of the Heartbeat. Oxford: Clarendon Press; 1979.Google Scholar
  4. 4.
    Reinecke H, Poppa V, Murry CE: Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 2002, 34:241–249.PubMedCrossRefGoogle Scholar
  5. 5.
    Reinecke H, MacDonald GH, Hauschka SD, Murry CE: Electromechanical coupling between skeletal and cardiac muscle: implications for infarct repair. J Cell Biol 2000, 149:731–740.PubMedCrossRefGoogle Scholar
  6. 6.
    Formigli L, Francini F, Tani A, et al.: Morphofunctional integration between skeletal myoblasts and adult cardiomyocytes in coculture is favored by direct cell-cell contacts and relaxin treatment. Am J Physiol Cell Physiol 2005, 288:C795–C804.PubMedCrossRefGoogle Scholar
  7. 7.
    Mills WR, Mal N, Kiedrowski MJ, et al.: Stem cell therapy enhances electrical viability in myocardial infarction. J Mol Cell Cardiol 2007, 42:304–314.PubMedCrossRefGoogle Scholar
  8. 8.
    Leobon B, Garcin I, Menasche P, et al.: Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc Natl Acad Sci U S A 2003, 100:7808–7811.PubMedCrossRefGoogle Scholar
  9. 9.
    Hagege AA, Carrion C, Menasche P, et al.: Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Lancet 2003, 361:491–492.PubMedCrossRefGoogle Scholar
  10. 10.
    Ghostine S, Carrion C, Souza LCG, et al.: Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation 2002, 106:I-131–I-136.Google Scholar
  11. 11.
    Abraham MR, Henrikson CA, Tung L, et al.: Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation. Circ Res 2005, 97:159–167.PubMedCrossRefGoogle Scholar
  12. 12.
    Ott HC, Berjukow S, Marksteiner R, et al.: On the fate of skeletal myoblasts in a cardiac environment: down-regulation of voltage-gated ion channels. J Physiol 2004, 558:793–805.PubMedCrossRefGoogle Scholar
  13. 13.
    van den Bos EJ, Thompson RB, Wagner A, et al.: Functional assessment of myoblast transplantation for cardiac repair with magnetic resonance imaging. Eur J Heart Fail 2005, 7:435–443.PubMedCrossRefGoogle Scholar
  14. 14.
    Cleland JGF, Coletta AP, Abdellah AT, et al.: Clinical trials update from the American Heart Association 2006: OAT, SALT 1 and 2, MAGIC, ABCD, PABA-CHF, IMPROVECHF, and percutaneous mitral annuloplasty. Eur J Heart Fail 2007, 9:92–97.PubMedCrossRefGoogle Scholar
  15. 15.
    McConnell PI, del Rio CL, Jacoby DB, et al.: Correlation of autologous skeletal myoblast survival with changes in left ventricular remodeling in dilated ischemic heart failure. J Thorac Cardiovasc Surg 2005, 130:1001.e1001–1001.e1012.CrossRefGoogle Scholar
  16. 16.
    Dib N: CAUSMIC (first US randomized controlled trial utilizing 3-dimensional guided, catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy: feasibility, safety and improvement in cardiac performance). Clin Cardiol 2007, 30:414.Google Scholar
  17. 17.
    Hagege AA, Marolleau J-P, Vilquin J-T, et al.: Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients. Circulation 2006, 114(Suppl 1):I-108–I-113.CrossRefGoogle Scholar
  18. 18.
    Smits PC, van Geuns R-JM, Poldermans D, et al.: Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 2003, 42:2063–2069.PubMedCrossRefGoogle Scholar
  19. 19.
    Lyon A, Harding S: The potential of cardiac stem cell therapy for heart failure. Curr Opin Pharmacol 2007, 7:164–170.PubMedCrossRefGoogle Scholar
  20. 20.
    Fernandes S, Amirault J-C, Lande G, et al.: Autologous myoblast transplantation after myocardial infarction increases the inducibility of ventricular arrhythmias. Cardiovasc Res 2006, 69:348–358.PubMedCrossRefGoogle Scholar
  21. 21.
    Murry CE, Wiseman RW, Schwartz SM, Hauschka SD: Skeletal myoblast transplantation for repair of myocardial necrosis. J Clin Invest 1996, 98:2512–2523.PubMedCrossRefGoogle Scholar
  22. 22.
    Murry CE, Soonpaa MH, Reinecke H, et al.: Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004, 428:664–668.PubMedCrossRefGoogle Scholar
  23. 23.
    Balsam LB, Wagers AJ, Christensen JL, et al.: Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004, 428:668–673.PubMedCrossRefGoogle Scholar
  24. 24.
    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, et al.: Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003, 425:968–973.PubMedCrossRefGoogle Scholar
  25. 25.
    Nygren JM, Jovinge S, Breitbach M, et al.: Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 2004, 10:494–501.PubMedCrossRefGoogle Scholar
  26. 26.
    Lagostena L, Avitabile D, De Falco E, et al.: Electrophysiological properties of mouse bone marrow c-kit+ cells co-cultured onto neonatal cardiac myocytes. Cardiovasc Res 2005, 66:482–492.PubMedCrossRefGoogle Scholar
  27. 27.
    Laflamme MA, Murry CE: Regenerating the heart. Nat Biotechnol 2005, 23:845–856.PubMedCrossRefGoogle Scholar
  28. 28.
    Xu M, Wani M, Dai Y-S, et al.: Differentiation of bone marrow stromal cells into the cardiac phenotype requires intercellular communication with myocytes. Circulation 2004, 110:2658–2665.PubMedCrossRefGoogle Scholar
  29. 29.
    Li X, Yu X, Lin Q, et al.: Bone marrow mesenchymal stem cells differentiate into functional cardiac phenotypes by cardiac microenvironment. J Mol Cell Cardiol 2007, 42:295–303.PubMedCrossRefGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    Potapova IA, Doronin SV, Kelly DJ, et al.: A novel method to commit mesenchymal stem cells to a cardiac lineage results in improved mechanical function and MSC derived striated cardiac myocytes in the adult canine heart [abstract]. Circ Res 2006, 99:1278.Google Scholar
  32. 32.
    Beeres SLMA, Atsma DE, van der Laarse A, et al.: Human adult bone marrow mesenchymal stem cells repair experimental conduction block in rat cardiomyocyte cultures. J Am Coll Cardiol 2005, 46:1943–1952.PubMedCrossRefGoogle Scholar
  33. 33.
    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.PubMedGoogle Scholar
  34. 34.
    Kamihata H, Matsubara H, Nishiue T, et al.: Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001, 104:1046–1052.PubMedCrossRefGoogle Scholar
  35. 35.
    Yoon Y-S, Wecker A, Heyd L, et al.: Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J Clin Invest 2005, 115:326–338.PubMedCrossRefGoogle Scholar
  36. 36.
    Amado LC, Saliaris AP, Schuleri KH, et al.: Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A 2005, 102:11474–11479.PubMedCrossRefGoogle Scholar
  37. 37.
    Assmus B, Schachinger V, Teupe C, et al.: Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002, 106:3009–3017.PubMedCrossRefGoogle Scholar
  38. 38.
    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, 364:141–148.PubMedCrossRefGoogle Scholar
  39. 39.
    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.PubMedCrossRefGoogle Scholar
  40. 40.
    Lunde K, Solheim S, Aakhus S, et al.: Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006, 355:1199–1209.PubMedCrossRefGoogle Scholar
  41. 41.
    Janssens S, Dubois C, Bogaert J, et al.: Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006, 367:113–121.PubMedCrossRefGoogle Scholar
  42. 42.
    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.PubMedCrossRefGoogle Scholar
  43. 43.
    Schachinger V, Erbs S, Elsasser A, et al.: Improved clinical outcome after intracoronary administration of bonemarrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006, 27:2775–2783.PubMedCrossRefGoogle Scholar
  44. 44.
    Seeger FH, Tonn T, Krzossok N, et al.: Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J 2007, 28:766–772.PubMedCrossRefGoogle Scholar
  45. 45.
    Britten MB, Abolmaali ND, Assmus B, et al.: Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003, 108:2212–2218.PubMedCrossRefGoogle Scholar
  46. 46.
    Mollmann H, Nef HM, Kostin S, et al.: Bone marrowderived cells contribute to infarct remodelling. Cardiovasc Res 2006, 71:661–671.PubMedCrossRefGoogle Scholar
  47. 47.
    Murry CE, Reinecke H, Pabon LM: Regeneration gaps: observations on stem cells and cardiac repair. J Am Coll Cardiol 2006, 47:1777–1785.PubMedCrossRefGoogle Scholar
  48. 48.
    Gnecchi M, He H, Liang OD, et al.: Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 2005, 11:367–368.PubMedCrossRefGoogle Scholar
  49. 49.
    Schachinger V, Assmus B, Britten MB, et al.: Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI trial. J Am Coll Cardiol 2004, 44:1690–1699.PubMedCrossRefGoogle Scholar
  50. 50.
    Rosenzweig A: Cardiac cell therapy—mixed results from mixed cells. N Engl J Med 2006, 355:1274–1277.PubMedCrossRefGoogle Scholar
  51. 51.
    Vulliet PR, Greeley M, Halloran SM, et al.: Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet 2004, 363:783–784.PubMedCrossRefGoogle Scholar
  52. 52.
    Kehat I, Kenyagin-Karsenti D, Snir M, et al.: Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 2001, 108:407–414.PubMedCrossRefGoogle Scholar
  53. 53.
    He J-Q, Ma Y, Lee Y, et al.: Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ Res 2003, 93:32–39.PubMedCrossRefGoogle Scholar
  54. 54.
    Mummery C, Ward-van Oostwaard D, Doevendans P, et al.: Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 2003, 107:2733–2740.PubMedCrossRefGoogle Scholar
  55. 55.
    Sartiani L, Bettiol E, Stillitano F, et al.: Developmental changes in cardiomyocytes differentiated from human embryonic stem cells: a molecular and electrophysiological approach. Stem Cells 2007, 25:1136–1144.PubMedCrossRefGoogle Scholar
  56. 56.
    Satin J, Kehat I, Caspi O, et al.: Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. J Physiol 2004, 559:479–496.PubMedCrossRefGoogle Scholar
  57. 57.
    Kolossov E, Bostani T, Roell W, et al.: Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med 2006, 203:2315–2327.PubMedCrossRefGoogle Scholar
  58. 58.
    Kofidis T, Lebl DR, Swijnenburg R-J, et al.: Allopurinol/uricase and ibuprofen enhance engraftment of cardiomyocyte-enriched human embryonic stem cells and improve cardiac function following myocardial injury. Eur J Cardiothorac Surg 2006, 29:50–55.PubMedCrossRefGoogle Scholar
  59. 59.
    Behfar A, Perez-Terzic C, Faustino RS, et al.: Cardiopoietic programming of embryonic stem cells for tumor-free heart repair. J Exp Med 2007, 204:405–420.PubMedCrossRefGoogle Scholar
  60. 60.
    Kehat I, Khimovich L, Caspi O, et al.: Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotech 2004, 22:1282–1289.CrossRefGoogle Scholar
  61. 61.
    Xue T, Cho HC, Akar FG, et al.: Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation 2005, 111:11–20.PubMedCrossRefGoogle Scholar
  62. 62.
    Klug MG, Soonpaa MH, Koh GY, Field LJ: Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J Clin Invest 1996, 98:216–224.PubMedGoogle Scholar
  63. 63.
    Müller M, Fleischmann BK, Selbert S, et al.: Selection of ventricular-like cardiomyocytes from ES cells in vitro. FASEB J 2000, 14:2540–2548.PubMedCrossRefGoogle Scholar
  64. 64.
    Beltrami AP, Barlucchi L, Torella D, et al.: Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003, 114:763–776.PubMedCrossRefGoogle Scholar
  65. 65.
    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.PubMedCrossRefGoogle Scholar
  66. 66.
    Oh H, Bradfute SB, Gallardo TD, et al.: Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A 2003, 100:12313–12318.PubMedCrossRefGoogle Scholar
  67. 67.
    Martin CM, Meeson AP, Robertson SM, et al.: Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 2004, 265:262–275.PubMedCrossRefGoogle Scholar
  68. 68.
    Laugwitz K-L, Moretti A, Lam J, et al.: Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 2005, 433:647–653.PubMedCrossRefGoogle Scholar
  69. 69.
    Pfister O, Mouquet F, Jain M, et al.: CD31− but not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 2005, 97:52–61.PubMedCrossRefGoogle Scholar
  70. 70.
    Wang X, Hu Q, Nakamura Y, et al.: The role of the Sca-1+/CD31− cardiac progenitor cell population in postinfarction left ventricular remodeling. Stem Cells 2006, 24:1779–1788.PubMedCrossRefGoogle Scholar
  71. 71.
    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.PubMedCrossRefGoogle Scholar
  72. 72.
    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.PubMedCrossRefGoogle Scholar
  73. 73.
    Widimsky P, Penicka M, Lang O, et al.: Intracoronary transplantation of bone marrow stem cells: background, techniques, and limitations. Eur Heart J Suppl 2006, 8(Suppl H):H16–H22.CrossRefGoogle Scholar
  74. 74.
    Penicka M, Lang O, Widimsky P, et al.: One-day kinetics of myocardial engraftment after intracoronary injection of bone marrow mononuclear cells in patients with acute and chronic myocardial infarction. Heart 2007, 93:837–841.PubMedCrossRefGoogle Scholar
  75. 75.
    Beltrami CA, Finato N, Rocco M, et al.: Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation 1994, 89:151–163.PubMedGoogle Scholar
  76. 76.
    Bartunek J, Dimmeler S, Drexler H, et al.: The consensus of the task force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for repair of the heart. Eur Heart J 2006, 27:1338–1340.PubMedCrossRefGoogle Scholar
  77. 77.
    Chien KR: Stem cells: lost in translation. Nature 2004, 428:607–608.PubMedCrossRefGoogle Scholar
  78. 78.
    Pillekamp F, Reppel M, Rubenchyk O, et al.: Force measurements of human embryonic stem cell-derived cardiomyocytes in an in vitro transplantation model. Stem Cells 2007, 25:174–180.PubMedCrossRefGoogle Scholar
  79. 79.
    Tomescot A, Leschik J, Bellamy V, et al.: Differentiation in vivo of cardiac committed human embryonic stem cells in post-myocardial infarcted rats. Stem Cells 2007, 25:2200–2205.PubMedCrossRefGoogle Scholar
  80. 80.
    Laflamme MA, Gold J, Xu C, et al.: Formation of human myocardium in the rat heart from human embryonic stem cells. Am J Pathol 2005, 167:663–671.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Adam J. T. Schuldt
  • Michael R. Rosen
  • Glenn R. Gaudette
  • Ira S. Cohen
    • 1
  1. 1.Department of Physiology and Biophysics, Health Science CenterStony Brook UniversityStony BrookUSA

Personalised recommendations