Abstract
Heart failure is the leading cause of death worldwide, and current therapies only delay progression of the disease. Laboratory experiments and recent clinical trials suggest that cell-based therapies can improve cardiac function, and the implications of this for cardiac regeneration are causing great excitement. Bone-marrow-derived progenitor cells and other progenitor cells can differentiate into vascular cell types, restoring blood flow. More recently, resident cardiac stem cells have been shown to differentiate into multiple cell types present in the heart, including cardiac muscle cells, indicating that the heart is not terminally differentiated. These new findings have stimulated optimism that the progression of heart failure can be prevented or even reversed with cell-based therapy.
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References
Lopez, A. D. et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367, 1747–1757 (2006).
Diwan, A. & Dorn, G. W. Decompensation of cardiac hypertrophy: cellular mechanisms and novel therapeutic targets. Physiology (Bethesda) 22, 56–64 (2007).
Diwan, A. et al. Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J. Clin. Invest. 117, 2825–2833 (2007).
Wagers, A. J. & Conboy, I. M. Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis. Cell 122, 659–667 (2005).
Shi, X. & Garry, D. J. Muscle stem cells in development, regeneration, and disease. Genes Dev. 20, 1692–1708 (2006).
Borchardt, T. & Braun, T. Cardiovascular regeneration in non-mammalian model systems: what are the differences between newts and man? Thromb. Haemost. 98, 311–318 (2007).
Poss, K. D. Getting to the heart of regeneration in zebrafish. Semin. Cell Dev. Biol. 18, 36–45 (2007).
Lepilina, A. et al. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127, 607–619 (2006).
Ahuja, P., Sdek, P. & MacLellan, W. R. Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol. Rev. 87, 521–544 (2007).
Rubart, M. & Field, L. J. Cardiac regeneration: repopulating the heart. Annu. Rev. Physiol. 68, 29–49 (2006).
Laflamme, M. A. & Murry, C. E. Regenerating the heart. Nature Biotechnol. 23, 845–856 (2005). This comprehensive review discusses the cardiac regeneration potential of different stem cells and the possible experimental artefacts.
Beltrami, A. P. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776 (2003).
Laugwitz, K. L. et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005).
Martin, C. M. et al. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev. Biol. 265, 262–275 (2004).
Oh, H. et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl Acad. Sci. USA 100, 12313–12318 (2003).
Hsieh, P. C. et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nature Med. 13, 970–974 (2007).
Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002).
Heber-Katz, E. et al. The scarless heart and the MRL mouse. Phil. Trans. R. Soc. B 359, 785–793 (2004).
Haris Naseem, R. et al. Reparative myocardial mechanisms in adult C57BL/6 and MRL mice following injury. Physiol. Genomics 30, 44–52 (2007).
Wollert, K. C. & Drexler, H. Clinical applications of stem cells for the heart. Circ. Res. 96, 151–163 (2005).
Menasche, P. Skeletal myoblasts as a therapeutic agent. Prog. Cardiovasc. Dis. 50, 7–17 (2007).
Cleland, J. G. et al. Clinical trials update from the American Heart Association 2006: OAT, SALT 1 and 2, MAGIC, ABCD, PABA-CHF, IMPROVE-CHF, and percutaneous mitral annuloplasty. Eur. J. Heart Fail. 9, 92–97 (2007).
Winitsky, S. O. et al. Adult murine skeletal muscle contains cells that can differentiate into beating cardiomyocytes in vitro. PLoS Biol. 3, e87 (2005).
Leri, A., Kajstura, J. & Anversa, P. Cardiac stem cells and mechanisms of myocardial regeneration. Physiol. Rev. 85, 1373–1416 (2005). This is a comprehensive review of CSCs.
Quaini, F. et al. Chimerism of the transplanted heart. N. Engl. J. Med. 346, 5–15 (2002).
Jackson, K. A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001). This classic study reveals the participation of bone-marrow-derived stem cells in cardiac regeneration.
Murry, C. E. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428, 664–668 (2004).
Balsam, L. B. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 668–673 (2004).
Stuckey, D. J. et al. Iron particles for noninvasive monitoring of bone marrow stromal cell engraftment into, and isolation of viable engrafted donor cells from, the heart. Stem Cells 24, 1968–1975 (2006).
Young, P. P., Vaughan, D. E. & Hatzopoulos, A. K. Biologic properties of endothelial progenitor cells and their potential for cell therapy. Prog. Cardiovasc. Dis. 49, 421–429 (2007).
Narmoneva, D. A. et al. Endothelial cells promote cardiac myocyte survival and spatial reorganization: implications for cardiac regeneration. Circulation 110, 962–968 (2004).
Abdel-Latif, A. et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch. Intern. Med. 167, 989–997 (2007).
Erbs, S. et al. Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. Circulation 116, 366–374 (2007).
Caplan, A. I. & Dennis, J. E. Mesenchymal stem cells as trophic mediators. J. Cell. Biochem. 98, 1076–1084 (2006).
Miyahara, Y. et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nature Med. 12, 459–465 (2006).
Amado, L. C. et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc. Natl Acad. Sci. USA 102, 11474–11479 (2005).
Gnecchi, M. et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20, 661–669 (2006).
Breitbach, M. et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110, 1362–1369 (2007).
Pallante, B. A. et al. Bone marrow Oct3/4+ cells differentiate into cardiac myocytes via age-dependent paracrine mechanisms. Circ. Res. 100, e1–e11 (2007).
Garry, D. J. & Olson, E. N. A common progenitor at the heart of development. Cell 127, 1101–1104 (2006).
Nussbaum, J. et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J. 21, 1345–1357 (2007).
Huber, I. et al. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J. 21, 2551–2563 (2007).
Laflamme, M. A. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nature Biotechnol. 25, 1015–1024 (2007).
Tomescot, A. et al. Differentiation in vivo of cardiac committed human embryonic stem cells in postmyocardial infarcted rats. Stem Cells 25, 2200–2205 (2007).
Behfar, A. et al. Cardiopoietic programming of embryonic stem cells for tumor-free heart repair. J. Exp. Med. 204, 405–420 (2007).
Tzahor, E. Wnt/β-catenin signaling and cardiogenesis: timing does matter. Dev. Cell 13, 10–13 (2007).
Liao, R., Pfister, O., Jain, M. & Mouquet, F. The bone marrow–cardiac axis of myocardial regeneration. Prog. Cardiovasc. Dis. 50, 18–30 (2007).
Oh, H. et al. Cardiac muscle plasticity in adult and embryo by heart-derived progenitor cells. Ann. N. Y. Acad. Sci. 1015, 182–189 (2004).
Mouquet, F. et al. Restoration of cardiac progenitor cells after myocardial infarction by self-proliferation and selective homing of bone marrow-derived stem cells. Circ. Res. 97, 1090–1092 (2005).
Moretti, A. et al. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127, 1151–1165 (2006).
Winter, E. M. et al. Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardium-derived cells into the infarcted mouse heart. Circulation 116, 917–927 (2007).
Smart, N. et al. Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445, 177–182 (2007).
Bearzi, C. et al. Human cardiac stem cells. Proc. Natl Acad. Sci. USA 104, 14068–14073 (2007).
Smith, R. R. et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896–908 (2007).
Dimmeler, S., Zeiher, A. M. & Schneider, M. D. Unchain my heart: the scientific foundations of cardiac repair. J. Clin. Invest. 115, 572–583 (2005). This extensive review describes the cardiac regeneration potential of different stem cells and discusses the initial clinical studies.
Askari, A. T. et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362, 697–703 (2003).
Fox, J. M., Chamberlain, G., Ashton, B. A. & Middleton, J. Recent advances into the understanding of mesenchymal stem cell trafficking. Br. J. Haematol. 137, 491–502 (2007).
Fazel, S. et al. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J. Clin. Invest. 116, 1865–1877 (2006).
Puceat, M. & Ballis, A. Embryonic stem cells: from bench to bedside. Clin. Pharmacol. Ther. 82, 337–339 (2007).
Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).
Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell doi:10.1016/j.cell.2007.1011.1019 (2007).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Davis, M. E. et al. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc. Natl Acad. Sci. USA 103, 8155–8160 (2006).
Chang, M. G. et al. Proarrhythmic potential of mesenchymal stem cell transplantation revealed in an in vitro coculture model. Circulation 113, 1832–1841 (2006).
Kuhn, B. et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nature Med. 13, 962–969 (2007).
Meluzin, J. et al. Three-, 6-, and 12-month results of autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction. Int. J. Cardiol. doi:10.1016/j.ijcard.2007.04.098 (in the press).
Meluzin, J. et al. Autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction: the effect of the dose of transplanted cells on myocardial function. Am. Heart J. 152, 975.e9–975.e15 (2006).
Schachinger, V. 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. 27, 2775–2783 (2006).
Tatsumi, T. et al. Intracoronary transplantation of non-expanded peripheral blood-derived mononuclear cells promotes improvement of cardiac function in patients with acute myocardial infarction. Circ. J. 71, 1199–1207 (2007).
Choi, J. H. et al. Lack of additional benefit of intracoronary transplantation of autologous peripheral blood stem cell in patients with acute myocardial infarction. Circ. J. 71, 486–494 (2007).
Ahmadi, H. et al. Safety analysis and improved cardiac function following local autologous transplantation of CD133+ enriched bone marrow cells after myocardial infarction. Curr. Neurovasc. Res. 4, 153–160 (2007).
Stamm, C. 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. 133, 717–725 (2007).
Losordo, D. W. et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation 115, 3165–3172 (2007).
Gavira, J. J. et al. Autologous skeletal myoblast transplantation in patients with nonacute myocardial infarction: 1-year follow-up. J. Thorac. Cardiovasc. Surg. 131, 799–804 (2006).
Ince, H. et al. Transcatheter transplantation of autologous skeletal myoblasts in postinfarction patients with severe left ventricular dysfunction. J. Endovasc. Ther. 11, 695–704 (2004).
Chen, S. et al. Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery. J. Invasive Cardiol. 18, 552–556 (2006).
Acknowledgements
V.F.M.S. was supported by a PhD fellowship of the Research Foundation — Flanders (FWO) and by a Belgian American Educational Foundation research fellowship. R.T.L. was supported by grants from the National Institutes of Health. The authors thank J. A. Epstein, P. Menasche and K. B. Margulies for helpful comments.
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Correspondence should be addressed to R.T.L. (rlee@partners.org).
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Segers, V., Lee, R. Stem-cell therapy for cardiac disease. Nature 451, 937–942 (2008). https://doi.org/10.1038/nature06800
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DOI: https://doi.org/10.1038/nature06800
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