Stem cells for clinical use in cardiovascular medicine

Summary

Cell transplantation is currently gaining a growing interest as a potential new means of improving the prognosis of patients with cardiac failure. The basic assumption is that left ventricular dysfunction is largely due to the loss of a critical number of cardiomyocytes and that it can be partly reversed by implantation of new contractile cells into the postinfarction scars. Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials and now that the feasibility of the procedure is well established, efficacy data are expected from the ongoing randomized studies. Bone marrow stem cells are also generating a great deal of interest, particularly in patients with acute myocardial infarction, and are currently undergoing extensive clinical testing although recent data have raised a cautionary note about the transdifferentiation potential of these cells. While experimental studies and early-phase clinical trials tend to support the concept that cell therapy may enhance cardiac repair, several key issues still need to be addressed including (1) the optimal type of donor cells in relation to the clinical profile of the patients, (2) the mechanism by which cell engraftment improves cardiac function, (3) the optimization of cell survival, (4) the development of less invasive cell delivery techniques and (5) the potential benefits of cell transplantation in nonischemic heart failure. Current evidence suggests, however, that adult stem cells (myogenic or marrow-derived) fail to electromechanically integrate within the recipient heart, thereby mandating the search for second generation cell types able to achieve this goal which is the prerequisite for an effective enhancement of contractile function. Preliminary data suggest that cells that feature a true cardiomyogenic phenotype such as cardiac stem cells and cardiac-precommitted embryonic stem cells may fall in this category and carry the potential for ensuring a true regeneration of dead myocardium.

Keywords

Stem cells - myocardial infarction - heart failure - skeletal myoblasts - bone marrow - embryonic stem cells

• References

• 1 Dowell J, Rubart M, Pasumarthi K B. et al. Myocyte and myogenic stem cell transplantation in the heart. Cardiovasc Res 2003; 58: 336-50.
• 2 Reinecke H, Minami E, Poppa V. et al. Evidence for fusion between cardiac and skeletal muscle cells. Circulation 2004; 94: 1-5.
• 3 Rubart M, Soonpaa MH, Nakajima H. et al. Spontaneous and evoked intracellular calcium transients in donor-derived myocytes following intracardiac myoblast transplantation. J Clin Invest 2004; 114: 775-83.
• 4 Murtuza B, Suzuki K, Bou-Gharios G. et al. Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium. Proc Natl Acd Sci USA 2004; 101: 4216-21.
• 5 Menasché P, Hagege AA, Vilquin J T. et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003; 41: 1078-83.
• 6 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.
• 7 Siminiak T, Kalawski R, Fiszer D. et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J 2004; 148: 531-7.
• 8 Dib N, McCarthy P, Dinsmore J. et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: Interim analysis from the United States experience. Circulation 2002; 106 (Suppl. 02) II-463 (Abstract).
• 9 Smits PC, Geuns RJM, Poldermans D. et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure. J Am Coll Cardiol 2003; 42: 2063-9.
• 10 Siminiak T, Fiszer D, Jerykcwska O. et al. Percutaneous transvenous transplantation of autologous myoblasts in the treatment of postinfarction myocardial contractility impairment – the POZNAN trial. Eur Heart J 2005; 26: 1188-95.
• 11 Hagege AA, Carrion C, Menasche P. et al. Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Lancet 2003; 361: 91-2.
• 12 Brasselet C, Carrion C, Morichetti M C. et al. Skeletal myoblast transplantation through a catheter-based coronary sinus approach: an effective means of improving function of infarcted myocardium. Eur Heart J 2005; 26: 1551-6.
• 13 Orlic D, Kajstura J, Chimenti S. et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701-5.
• 14 Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: The scientific foundations of cardiac repair. J Clin Invest 2005; 115: 572-83.
• 15 Tse HF, Kwong YL, Chan J K. et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003; 36: 47-9.
• 16 Perin EC, Dohmann HFR, Borojevik R. et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003; 107: 2294-302.
• 17 Murry CE, Soonpa MH, Reinecke H. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428: 664-8.
• 18 Alvarez-Dolado M, Pardal R, Garcia-Verdugo J. et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocyes. Nature 2003; 425: 968-73.
• 19 Kinnaird T, Stabile E, Burnett M S. et al. Marrowderived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro andin vivo arteriogenesis through paracrine mechanisms. Circ Res 2004; 94: 670-85.
• 20 Maurel M, Azarnoush K, Sabbah L. et al. Patterns of cell death and proliferation after skeletal myoblast transplantation in infarcted rat myocardium. Transplantation. (in press).
• 21 Pedrotty D, Koh J, Davis B. et al. Engineering skeletal myoblasts : roles of 3-D culture and electrical stimulation. Am J Physiol Heart Circ Physiol 2005; 288: H1620-6.
• 22 Chazaud B, Sonnet C, Lafuste P. et al. Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth. J Cell Biol 2003; 163: 1133-43.
• 23 Hofmann M, Wollert KC, Meyer G P. et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 2005; 111: 2198-202.
• 24 Tambara K, Sakakibara Y, Sakaguchi G. et al. Transplanted skeletal myoblasts can fully replace the infarcted myocardium when they survive in the host in large numbers. Circulation 2003; 108 (Suppl. 01) II 259-63.
• 25 Azarnoush K, Maurel A, Sebbah L. et al. Enhancement of the functional benefits of skeletal myoblast transplantation by co-administration of hypoxia-inducible factor 1α. J Thorac Cardiovasc Surg 2005; 130: 173-9.
• 26 Suzuki K, Murtuza B, Smolenski R T. et al. Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts. Circulation 2001; 104 (Suppl. 01) I-207-12.
• 27 Christman KL, Verdanian AJ, Fang Q. et al. Injectable fibrin scaffold improves cell transplant survival reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J Am Coll Cardiol 2004; 44: 654-60.
• 28 Himes N, Min JY, Lee R. et al. In vivo MRI of embryonic stem cells in a mouse model of myocardial infarction. Magn Reson Med 2004; 52: 1214-9.
• 29 Stamm C, Westphal B, Kleine H D. et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003; 36: 45-6.
• 30 Yoon YS, 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: 326-38.
• 31 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815-22.
• 32 Winitsky SO, Gopal TV, Hassanzadeh S. et al. Adult murine skeletal muscle contains cells that can differentiate into beating cardiomyocytes in vitro. PLoS Biol 2005; 3: e87.
• 33 Reinecke H, Poppa V, Murry CE. Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 2002; 34: 241-9.
• 34 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: 7808-11.
• 35 Rastan AJ, Walther T, Kostelka M. et al. Morphological, electrophysiological and coupling characteristics of bone marrow-derived mononuclear cells-an in vitro-model. Eur J Cardiothorac Surg 2005; 27: 104-10.
• 36 Rubart M, Pasumarthi KB, Nakajima H. et al. Physiological coupling of donor and host cardiomyocytes after cellular transplantation. Circ Res 2003; 92: 1217-24.
• 37 Laugwitz KL, Moretti A, Lam J. et al. Post-natal isl+1 cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 2005; 433: 647-53.
• 38 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 USA 2005; 102: 3766-71.
• 39 Hodgson DM, Behfar A, Zingman L V. et al. Stable benefit of embryonic stem cell therapy in myocardial infarction. Am J Physiol Heart Circ Physiol 2004; 287: H471-9.
• 40 Kehat I, Khimovitch L, Caspi O. et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 2004; 22: 1282-9.
• 41 Min JY, Yang Y, Sullivan M F. et al. Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells. J Thorac Cardiovasc Surg 2003; 125: 361-9.
• 42 Pouly J, Hagege AA, Vilquin J T. et al. Does the functional efficacy of skeletal myoblast transplantation extend to nonischemic cardiomyopathy?. Circulation 2004; 110: 1626-31.