Postinfarction cellular regeneration therapy of the heart muscle

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Cellular regeneration therapy is a promising new way to treat diseases of the cardiovascular system. This review examines various experimental and clinical approaches to cell regeneration therapy, such as: local cytokine therapy, stimulation of the release of resident bone marrow stem cells and stem cell transplantation itself. The paper presents a detailed analysis of various types of donor cells used for cellular cardiomyoplasty in experimental and clinical studies. Particular attention is paid to the discussion of methods of cell delivery to the area of the damaged myocardium and methods of graft imaging.

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About the authors

A. V. Kurtova

Laboratory of Clinical Immunology and Molecular Diagnostics, St. Petersburg State Medical University Academician I.P. Pavlov; St. Petersburg State University

Author for correspondence.

Department of Cytology and Histology, Faculty of Biology and Soil

Russian Federation, Saint Petersburg; Saint Petersburg

E. E. Zueva

Laboratory of Clinical Immunology and Molecular Diagnostics, St. Petersburg State Medical University Academician I.P. Pavlov

Russian Federation, Saint Petersburg

A. S. Nemkov

St. Petersburg State Medical University named after Academician I.P. Pavlov


Department of Faculty Surgery

Russian Federation, Saint Petersburg


  1. Marthur A., Martin J.F. Stem cells and repair the heart. Lancet 2004; 364: 183-92.
  2. Dimarakis I., Habib N.A., Gordon M.Y.A. Adult bone marrow-derived stem cells and the injured heart: just the beginning? Eur. J Cardiothorac. Surg. 2005; 28: 665-76.
  3. Lee M.S., Makkar R.R. Stem-cell transplantation in myocardial infarction: a status report. Ann. Intern. Med. 2004; 140[9): 729-37.
  4. Heng B.C., Husnain K.H., Kwang-Wei Sim E. et al. Strategies for directing the differentiation of stem cells into the cardiomyogenic lineage in vitro. Cardiovasc. Res. 2004; 62: 34-42.
  5. Batista R.J., Verde J., Nery P., et al. Partial left ventriculoctomy to treat end-stage heart disease. Ann. Thorac. Surg. 1997; 64[3): 634-38.
  6. Davani S., Deschaseaux F., Chalmers D. et al. Can stem cells mend a broken heart? Cardiovasc. Res. 2005; 65: 305-16.
  7. Welch S., Plank D„ Witt S. et al. Cardiac specific IGF—1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. Circ. Res. 2002; 90: 641-48.
  8. Parsa C.J., Matsumoto A., Kim J. et al. A novel protective effect of erythropoietin in the infarcted heart. J. Clin. Invest. 2003; 112: 999-1007.
  9. Moon C., Krawczyk M„ Ahn D. et al. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary ligation in rats. Proc. Natl. Acad. Soi. USA 2003; 100:11612-7.
  10. Orlic D., Kajstura J., Chimenty S. et al. Mobilized bone marrow cells repair the infracted heart, improving function and survival. Proc. Natl. Acad. Soi. USA 2001:98: 10344-9.
  11. Leone A.M., Rutello S., Bonanno G. et al. Endogenous G-CSF and CD34+ cell mobilization after acute myocardium infarction. Int. J. Cardiol. In Press 2005.
  12. Ceradini D.J., Gurther G.C. Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends Cardiovasc. Med. 2005; 15: 57-63.
  13. Yamani M.H., Ratliff N.B., Cook D.J. et al. Peritransplant ischemic injury is associated with up regulation of SDF-1. J. Am. Coll. Cardiol. 2005; 46[6): 1029-35.
  14. Schober A., Knarren S., Lietz M. et al. Crucial role of stromal cell-derived factor-16 in neointima formation after vascular injury in apolipoprotein-E- deficient mice. Circulation 2003; 108: 2491-7.
  15. Massa M„ Rosti V., Ferrario M. et al. Increased circulating hematopoietic and endothelial progenitorcellsinthe early phaseofacute myocardial infarction. Blood 2005; 105(1): 199-206.
  16. Abbott J., Huang Y., Liu D. et al. Stromal cell-derived factor-16 plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 2004; 110: 3300-5.
  17. Zohlnhofer D., Ott I., Mehilli J. et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 2006; 295[9): 1003-10.
  18. Penn M.S., Zhang M., Deglurkar I. et al. Role of stem cell homing in myocardial regeneration. Int. J. Cardiol. 2004; 95 Suppl 1: 23-5.
  19. Lapidot T., Dar A., Kollet 0. How do stem cells find their way to home? Blood 2005; 106(6): 1901-10.
  20. Siepe M., Heilmann C., von Samson P. et al. Stem cell research and cell transplantation for myocardial infarction. Eur. J. Cardiothorac. Surg. 2005; 28: 318-24.
  21. Shah R.V., Mitchell R.N. The role of stem cells in the response to myocardial and vascular wall injury. Cadriovasc. Pathol. 2005; 14: 225-31.
  22. Palumbo R. Extracellular hmgpl, a signal of tissue damage, induces mesangioblast migration and proliferation. J. Cell Biol. 2004; 164: 441-9.
  23. Cao Y., Hong A., Schulten H. et al. Update on therapeutic neovascularization. Cardiovasc. Res. 2005; 65: 639-48.
  24. WangT., Xu Z., Jiang W„ Ma A. Cell-to-cell contact induces mesenchymal stem cells to differentiate into cardiomyocyte and smooth muscle cell. Int. J. Cardiol. In Press 2005.
  25. Abbott J.D., Giordano F.J.Stem cells and cardiovascular disease. J. Nucl. Cardiol. 2003; 10: 403-12.
  26. Quesenberry P., Colvin G., Abedi M. Perspective: Fundamental and clinical concepts on stem cell homing and engraftment: A journey to niches and beyond. Exp. Hematol. 2005; 33: 9-19.
  27. Dvash T., Benvenisty N. Human embryonic stem cells as a model for early human development. Best Pract. Res. Clin. Obstet. Gynaecol. 2004; 18(6): 929-40.
  28. Goldenthal M.J., Marin-Garcia J. Stem cells and cardiac disorders: an appraisal. Cardiovasc. Res. 2003; 58: 369-77.
  29. Min J.Y., Yang Y„ Converse K.L. et al. Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. J. Appl. Physiol. 2002; 92: 288-96.
  30. Zhang Y.M., Hartzell C., Narlow M. et al. Stem cells derived cardiomyocytes demonstrate arrythmic potential. Circulation 2002; 106(10): 1294-99.
  31. Rosen M.R., Brink P.R., Cohen I.S. et al Genes, stem cells and biological pacemakers. Cardiovasc. Res. 2004; 64:12-23.
  32. Torella D., Ellison G.M., Nadal-Ginard B. et al. Cardiac stem and progenitor cell biology for regenerative medicine. Trends Cardiovasc. Med. 2005; 15: 229-36.
  33. Zhang M„ Methot D., Poppa V. et al. Cardiomyocytes grafting for cardiac repair: graft cell death and antideath strategies. J. Mol. Cell. Cardiol. 2001; 33: 907-21.
  34. Foley A., Mercola M. Heart induction: embriology to cardiomyocyte regeneration. Trends Cardiovasc. Med. 2004; 14:121-25.
  35. Koh G.Y., Soonpaa M.H., Klug M.G. et al. Stable fetal cardiomyocytes grafts in the hearts of dystrophic mice and dogs. J. Clin. Invest. 1995; 96: 2034-42.
  36. Scorcin M., Hagege A.,Vilquin J.T. et al. Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function. J. Thorac. Cardiovasc. Surg. 2000; 119(6): 1169-75.
  37. Muller-Ehmsen J., Whittaker P., Kloner R.A. et al. Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. J. Mol. Cell Cardiol. 2002; 34:107-16.
  38. O'Donoghue K„ Fisk N.M. Fetal stem cells. Best Pract. Res. Clin. Obstet. Gynaecol. 2004; 18(6): 853-75.
  39. Asakura A. Stem cellsin adultskeletal muscle.Trends Cardiovasc. Med. 2003; 13: 123-28.
  40. Menasche P., Hagege A., Scorsin M. et al. Myoblast transplantation for heart failure. Lancet 2001; 357: 279-80.
  41. Herreros J., Prosper F., Perez A. et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur. Heart. J. 2003; 24: 2012-20.
  42. Dai W„ Hale S., Kloner R. Stem cell transplantation for the treatment of myocardial infarction. Transpl Immunol 2005: In Press.
  43. Taylor D.A. Cell-based myocardial repair: how should we proceed? Int. J. Cardiol. 2004; 95 Suppl: 8-12.
  44. Menasche P. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003; 41:1078-83.
  45. Kessler P.D., Byrne B.J. Myoblast cell grafting into heart muscle: cellular biology and potential application. Annu. Rev. Physiol. 1999; 61: 219-42.
  46. Suzuki K„ Brand N.J., Smolensk! R.T. et al. Development of novel method for cell transplantation through tne coronary artery. Circulation 2002; 102: 359-64.
  47. Abraham M.R., Henrikson C.A., Tung L. et al. Antiarrythmic engineering of skeletal myoblasts for cardiac transplantation. Giro. Res. 2005; 97(2): 159-67.
  48. Goodell M.A., Brose K., Paradis G. et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 1996; 183: 1797-06.
  49. Asakura A., Seale P., Girgis-Gabardo A. et al. Myogenic specification of side population in skeletal muscle. J. Cell Biol. 2002; 159:123-34.
  50. Geiger H., True J.M., Grimes B. et al. Analysis of the hematopoietic potential of muscle-derived cells in mice. Blood 2002; 100: 721-23.
  51. Urbich C., Dimmeler S. Endothelial progenitor cells: functional characterization. Trends Cardiovasc. Med. 2004; 14(8): 318-22.
  52. Badorff C., Brandes R.P., Popp R. et al. Transdifferentiation of blood derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 2003; 107:1024-32.
  53. Rupp S., Badorff C., Koyanagi M. et al. Statin therapy in patients with coronary artery disease improves the impaired endothelial progenitor cell differentiation into cardiomyogenic cells. Basic Res. Cardiol. 2004; 99: 61-8.
  54. Hristov M., Erl W., Weber P.C. Endothelial progenitor cells: mobilization, differentiation and homing. Arterioscler. Thromb. Vase. Biol. 2003; 23: 1185-89.
  55. Sola S., Mir M., Rajagopalan S. et al. Statin therapy is associated with improved cardiovascular outcomes and levels of inflammatory markers in patients with heart failure. J. Card. Fail. 2005; 11(8): 607-13.
  56. Kan I., Melamed E., Offen E. Integral therapeutic potential of bone marrow mesenchymal stem cells. Curr. Drug. Targ. 2005; 6: 31-41.
  57. Gojo S., Gojo N.. Takeda Y. et al. In vivo cardiovasculogenesis by direct injection of isolated adult mesenchymal stem cells. Exp. Cell Res. 2003; 288: 51-9.
  58. Pak H.N., Qayyum M„ Kim D.T. etal. Mesenchymal stem cell injection induces cardiac nerve sprouting and increased tenascin expression in a swine model of myocardium infarction. J. Cardiovasc. Electrophysiol. 2003; 14: 841-48.
  59. Daskalakis M., Nguyen T.T., Nguyen C. et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodisplastic syndrome by 5-Aza-2'-deoxycytidine [decitabine) treatment. Blood 2002; 100: 2957-64.
  60. Fazel S., Chen R., Wiesel R.D. et al. Cell transplantation preserves cardiac function after infarction by infarct stabilization: augmentation by stem cell factor. J. Thorac. Cardiovasc. Surg. 2005; 130(5): 1310.
  61. Heissig B., Hattori K., Dias S. et al. Recruitment of stem and progenitor cells from bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002;109:625-37.
  62. Gailit J., Marches M.J., KewP.P. etal.The differentiation and function of myofibroblasts is regulated by mast cell mediators. J. Invest. Dermatol. 2001; 117: 1113-9.
  63. Yano T., Miura T., Ikeda Y. et al. Intracardiac fibroblasts, but not bone marrow derived cells, are the origin of myofibroblasts in myocardial infarct repair. Cardiovasc. Pathol. 2005; 14: 241-6.
  64. Balsam L.B., Wagers A.J., Christensen J.L. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischemic myocardium. Nature 2004; 428: 668-73.
  65. Kajstura J., Leri A., Finato N. et al. Myocyte proliferation in end-stage cardiac failure in humans. Proc. Natl. Acad. Soi. USA 1998; 95: 8801-5.
  66. Beltrami A.P., Barlucchi L, Torella D. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114: 763-7.
  67. Urbanek K., Quaini F., Taska J. et al. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc. Natl. Acad. Soi. USA 2003; 100: 10440-5.
  68. Oh H., Bradfute S.B., Gallardo T.D. et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl. Acad. Soi. USA 2003; 100:12313-8.
  69. Torella D., Rota A., Nurzynska D. et al. Cardiac stem cells and myocyte aging, heart failure and insulin-like growth factor-1 overexpression. Giro. Res. 2004; 94: 514-24.
  70. Murry C.E., Soonpaa M.H., Reinecke H. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428: 664-8.
  71. Schachinger V., Assmus B., Britten M.B. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction. Final one-year resultsof the TOPCARE-AMI trial. J. Am. Coll. Cardiol. 2004; 44[8): 1690-9.
  72. Stamm C., Westphal B., Kleine H.D. et al. Autologous bone marrow transplantation for myocardial regeneration. Lancet 2003; 361: 45-6.
  73. Keating A. Bone marrow cells for cardiac repair. Biol. Blood Marrow Transplant. 2005; 11: 2-6.
  74. Wollert K.C, Meyer G.P., Lotz J. et al. Intracoronary autologous bonemarrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004; 364:141-8.
  75. Ghodsizad A., Klein H.M., Borowski A., et al. Intraoperative isolation and processing of BM-derived stem cells. Cytotherapy 2004; 6(5): 523-6.
  76. Perin E.C., Silva G.V., Sarmento-Leite R. et al. Assessing myocardial viability and infarct transmurality with left ventricular electromechanical mapping in patients with stable coronary artery disease: validation by delayed-enchancement magnetic resonance imaging. Circulation 2002; 107: 957-61.
  77. Christman K.L., Vardanian A.J., Fang Q. et al. Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ishemic myocardium. J. Am. Coll. Cardiol. 2004; 44(3): 654-60.
  78. Strauer B.E., Brehm M„ Zeus T. et al. Repair of infracted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106:1913-18.
  79. Perin E.C., Geng Y.J., Willerson J.T. Adult stem cell therapy in perspective. Circucation 2003; 107: 935-8.
  80. Nagaya N., Fujii T., Iwase T. et al. Intravenous administration of mesenchymal stem cells improves cardiacfunction in rats with acute myocardium infarction through angiogenesis and myogenesis. Am. J. Physiol. Heart. Giro. Physiol. 2004; 287: 2670-6.
  81. Zimmermann W.H., Didie M„ Wasmeier G.H. et al. Cardiac grafting of engineered heart tissue in syngenic rats. Circulation 2002; 106:1151-7.
  82. Marzullo P. Nuclear imaging after cell implantation. Int. J. Cardiol. 2004; 95Suppl1:53-4.
  83. Weber A., Pedrosa I., Kawamoto A. et al. Magnetic resonance mapping of trasplanted endothelial progenitor cells for therapeutic neovascularization in ischemic heart disease. Eur. J. Cardiothorac. Surg. 2004; 26:137-43.
  84. Махнев Д.А. Использование культуры кардиомиоцитов в экспериментальной кардиохирургии. Шевченко Ю.Л., Матвеев С.А. Клеточные технологии в сердечно-сосудистой хирургии. М.: Медицина; 2005; 31-75.
  85. Шахов В.П., Рябов В.В., Попов С.В. и др. Позитивные и негативные последствия проведения клеточной терапии острого инфаркта миокарда. Материалы конференции «Клинические и фундаментальные проблемы клеточных биотехнологий»; 2005, Новосибирск: 50-1.
  86. Шумаков В.И., Казаков Э.Н., Гуреев С.В. и др. Трансплантация аутологичных клеток костного мозга как биологический мост к трансплантации сердца. Вестник транспл. и искусствен, органов 2005; 3:10.
  87. Марков В.А., Суслова Т.Е., Рябов В.В. и др. Результаты трансплантации аутологичных мононуклеарных клеток костного мозга при первичном трансмуральном инфаркте миокарда. Материалы конференции "Клинические и фундаментальные проблемы клеточных биотехнологий"; 2005, Новосибирск: 39.
  88. Белый С.А., Зуева Е.Е., Куртова А.В., Немков А.С. Трансплантация аутологичных мононуклеарных клеток костного мозга кардиологическим больным. Медицинская иммунология 2004; 6(3-5): 432.
  89. Немков А.С., Седов В.М., Афанасьев Б.В. Клиническое применение аутологичных мононуклеаров костного мозга у больных ишемической болезнью сердца. Материалы конференции «Биотехнология и онкология», 2005, СПб.: 65-6.
  90. Сускова В.С., Онищенко Н.А., Шальнев Б.И. и др. Трансплантация аутологичных стволовых клеток костного мозга у кардиологических больных: иммунофенотипическая и цитокиновая характеристика аутотрансплантатов. Вестник транспл. и искусствен, органов 2005; 3: 42-3.

Supplementary files

Supplementary Files
1. Fig. 1. Cells transplanted in myocardial infarction and their therapeutic potential

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2. Fig. 2. Methods of delivery of stem cells to the myocardium

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