The potential usefulness of human embryonic stem cells for therapy derives from their ability to form any cell in the body. This potential has been used to justify intensive research despite some ethical concerns. In parallel, scientists have searched for adult stem cells that can be used as an alternative to embryonic cells, and, for the heart at least, these efforts have led to promising results. However, most adult cardiomyocytes are unable to divide and form new cardiomyocytes and would therefore be unable to replace those lost as a result of disease. Basic questions — for example, whether cardiomyocyte replacement or alternatives, such as providing the damaged heart with new blood vessels or growth factors to activate resident stem cells, are the best approach — remain to be fully addressed. Despite this, preclinical studies on cardiomyocyte transplantation in animals and the first clinical trials with adult stem cells have recently been published with mixed results.
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Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Draper, J. S. et al. Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nature Biotechnol. 22, 53–54 (2004).
Wu, S., Chien, K. & Mummery, C. Origin and biology of nultipotent cardiovascular progenitor cells. Reverse translational medicine towards models of human heart disease. Cell 132, 537–543 (2008). This review describes the origin and fate of cardiac progenitor cells in embryonic and adult hearts, as well as those derived from ES cells.
Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007).
Pouly, J. et al. Cardiac stem cells in the real world. J. Thorac. Cardiovasc. Surg. 135, 673–678 (2007).
Wu, S. M. et al. Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell 127, 1137–1150 (2006). This paper describes the molecular identity of Kit+NKX2-5+ progenitor cells in the heart and traces their fate during development in mice.
Moretti, A. et al. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127, 1151–1165 (2006). This paper describes genetic fate-mapping studies and shows that expression of Isl1, Nkx2-5 and Kdr defines multipotent cardiovascular progenitor cells, which can give rise to endothelial cells, cardiomyocytes and smooth muscle cells.
Brazelton, T. R., Rossi, F. M., Keshet, G. I. & Blau, H. M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1775–1779 (2000).
Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).
Guan, K. & Hasenfuss, G. Do stem cells in the heart truly differentiate into cardiomyocytes? J. Mol. Cell Cardiol. 43, 377–387 (2007).
Assmus, B. et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N. Engl. J. Med. 355, 1222–1232 (2006).
Schachinger, V. et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N. Engl. J. Med. 355, 1210–1221 (2006).
Lunde, K. et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N. Engl. J. Med. 355, 1199–1209 (2006).
Janssens, S. et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367, 113–121 (2006).
Cintron, G., Johnson, G., Francis, G., Cobb, F. & Cohn, J. N. Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation 87, VI17–VI23 (1993).
Adler, E. D. & Maddox, T. M. Cell therapy for cardiac disease: where do we go from here? Nature Clin. Pract. Cardiovasc. Med. 4, 2–3 (2007).
Lunde, K. et al. Exercise capacity and quality of life after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: results from the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) randomized controlled trial. Am. Heart J. 154, 710–718 (2007).
Schachinger, V., Tonn, T., Dimmeler, S. & Zeiher, A. M. Bone-marrow-derived progenitor cell therapy in need of proof of concept: design of the REPAIR-AMI trial. Nature Clin. Pract. Cardiovasc. Med. 3 (Suppl. 1), S23–S28 (2006).
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). References 19 and 20 were the first studies to show that haematopoietic stem cells do not transdifferentiate into cardiomyocytes when transplanted into a mouse heart.
Nygren, J. M. et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nature Med. 10, 494–501 (2004).
van Laake, L. W. et al. Human embryonic stem cell-derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction. Stem Cell Res. 1, 9–24 (2007). This paper showed an improvement in cardiac function at 4 weeks after transplantation of human ES-cell-derived cardiomyocytes into mice that had undergone a myocardial infarction; however, this effect was not sustained at 12 weeks compared with mice receiving human ES-cell-derived non-cardiomyocytes.
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).
Yoshioka, T. et al. Repair of infarcted myocardium mediated by transplanted bone marrow-derived CD34+ stem cells in a nonhuman primate model. Stem Cells 23, 355–364 (2005).
Limbourg, F. P. et al. Haematopoietic stem cells improve cardiac function after infarction without permanent cardiac engraftment. Eur. J. Heart Fail. 7, 722–729 (2005).
Feygin, J., Mansoor, A., Eckman, P., Swingen, C. & Zhang, J. Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation. Am. J. Physiol. Heart Circ. Physiol. 293, H1772–H1780 (2007).
Amsalem, Y. et al. Iron-oxide labeling and outcome of transplanted mesenchymal stem cells in the infarcted myocardium. Circulation 116, I38–I45 (2007).
Breitbach, M. et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110, 1362–1369 (2007).
Rubart, M. & Field, L. J. Cardiac regeneration: repopulating the heart. Annu. Rev. Physiol. 68, 29–49 (2006).
Gnecchi, M. et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nature Med. 11, 367–368 (2005).
Pelacho, B. et al. Multipotent adult progenitor cell transplantation increases vascularity and improves left ventricular function after myocardial infarction. J. Tissue Eng. Regen. Med. 1, 51–59 (2007).
Smart, N. et al. Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445, 177–182 (2007).
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).
Lepilina, A. et al. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127, 607–619 (2006).
Leobon, B. et al. Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc. Natl Acad. Sci. USA 100, 7808–7811 (2003).
Dellavalle, A. et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nature Cell Biol. 9, 255–267 (2007).
Roell, W. et al. Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 450, 819–824 (2007).
Liu, J., Fu, J. D., Siu, C. W. & Li, R. A. Functional sarcoplasmic reticulum for calcium-handling of human embryonic stem cell-derived cardiomyocytes: Insights for driven maturation. Stem Cells 25, 3038–3044 (2007).
Reinecke, H., Zhang, M., Bartosek, T. & Murry, C. E. Survival, integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts. Circulation 100, 193–202 (1999).
Miragoli, M., Salvarani, N. & Rohr, S. Myofibroblasts induce ectopic activity in cardiac tissue. Circ. Res. 101, 755–758 (2007).
Ferreira, L. S. et al. Vascular progenitor cells isolated from human embryonic stem cells give rise to endothelial and smooth muscle like cells and form vascular networks in vivo. Circ. Res. 101, 286–294 (2007).
Huang, H. et al. Differentiation of human embryonic stem cells into smooth muscle cells in adherent monolayer culture. Biochem. Biophys. Res. Commun. 351, 321–327 (2006).
Levenberg, S., Golub, J. S., Amit, M., Itskovitz-Eldor, J. & Langer, R. Endothelial cells derived from human embryonic stem cells. Proc. Natl Acad. Sci. USA 99, 4391–4396 (2002).
Kehat, I. et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J. Clin. Invest. 108, 407–414 (2001). This was the first paper to describe the formation of cardiomyocytes from human ES cells.
Mummery, C. et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107, 2733–2740 (2003).
He, J. Q., Ma, Y., Lee, Y., Thomson, J. A. & Kamp, T. J. Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ. Res. 93, 32–39 (2003).
Xu, C., Police, S., Rao, N. & Carpenter, M. K. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ. Res. 91, 501–508 (2002).
Beqqali, A., Kloots, J., Ward-van Oostwaard, D., Mummery, C. & Passier, R. Genome-wide transcriptional profiling of human embryonic stem cells differentiating to cardiomyocytes. Stem Cells 24, 1956–1967 (2006).
Passier, R. et al. Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures. Stem Cells 23, 772–780 (2005).
Kehat, I. et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nature Biotechnol. 22, 1282–1289 (2004).
Xue, T. 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 111, 11–20 (2005).
Laflamme, M. A. et al. Formation of human myocardium in the rat heart from human embryonic stem cells. Am. J. Pathol. 167, 663–671 (2005).
Dai, W. et al. Survival and maturation of human embryonic stem cell-derived cardiomyocytes in rat hearts. J. Mol. Cell Cardiol. 43, 504–516 (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). This paper showed that rodents that had undergone a myocardial infarction had improved cardiac function at 4 weeks after transplantation of human ES-cell-derived cardiomyocytes.
Leor, J. et al. Human embryonic stem cell transplantation to repair the infarcted myocardium. Heart 93, 1278–1284 (2007).
van Laake, L. W. et al. Monitoring of cell therapy and assessment of cardiac function using magnetic resonance imaging in a mouse model of myocardial infarction. Nature Protocols 2, 2551–2567 (2007).
Rubart, M., Wang, E., Dunn, K. W. & Field, L. J. Two-photon molecular excitation imaging of Ca2+ transients in Langendorff-perfused mouse hearts. Am. J. Physiol. Cell Physiol. 284, C1654–C1668 (2003).
Rubart, M. et al. Physiological coupling of donor and host cardiomyocytes after cellular transplantation. Circ. Res. 92, 1217–1224 (2003).
Erdo, F. et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J. Cereb. Blood Flow Metab. 23, 780–785 (2003).
Zimmermann, W. H. et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nature Med. 12, 452–458 (2006). This paper showed that tissue engineering is an attractive prospect for cardiac repair.
Feinberg, A. W. et al. Muscular thin films for building actuators and powering devices. Science 317, 1366–1370 (2007).
Furuta, A. et al. Pulsatile cardiac tissue grafts using a novel three-dimensional cell sheet manipulation technique functionally integrates with the host heart, in vivo. Circ. Res. 98, 705–712 (2006).
Moelker, A. D. et al. Intracoronary delivery of umbilical cord blood derived unrestricted somatic stem cells is not suitable to improve LV function after myocardial infarction in swine. J. Mol. Cell Cardiol. 42, 735–745 (2007).
Wang, Z. Z. et al. Endothelial cells derived from human embryonic stem cells form durable blood vessels in vivo. Nature Biotechnol. 25, 317–318 (2007).
Sone, M. et al. Pathway for differentiation of human embryonic stem cells to vascular cell components and their potential for vascular regeneration. Arterioscler. Thromb. Vasc. Biol. 27, 2127–2134 (2007).
Cho, S. W. et al. Improvement of postnatal neovascularization by human embryonic stem cell derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. Circulation 116, 2409–2419 (2007).
Caspi, O. et al. Tissue engineering of vascularized cardiac muscle from human embryonic stem cells. Circ. Res. 100, 263–272 (2007).
Lu, S. J. et al. Generation of functional hemangioblasts from human embryonic stem cells. Nature Methods 4, 501–509 (2007).
Tian, X., Woll, P. S., Morris, J. K., Linehan, J. L. & Kaufman, D. S. Hematopoietic engraftment of human embryonic stem cell-derived cells is regulated by recipient innate immunity. Stem Cells 24, 1370–1380 (2006).
Narayan, A. D. et al. Human embryonic stem cell-derived hematopoietic cells are capable of engrafting primary as well as secondary fetal sheep recipients. Blood 107, 2180–2183 (2006).
van Laake, L. W. et al. Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation 114, 2288–2297 (2006).
Goldman, S. Stem and progenitor cell-based therapy of the human central nervous system. Nature Biotechnol. 23, 862–871 (2005).
Shim, J. H. et al. Directed differentiation of human embryonic stem cells towards a pancreatic cell fate. Diabetologia 50, 1228–1238 (2007).
Duan, Y. et al. Differentiation and enrichment of hepatocyte-like cells from human embryonic stem cells in vitro and in vivo. Stem Cells 25, 3058–3068 (2007).
Huber, I. et al. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J. 21, 2551–2563 (2007).
Anderson, D. et al. Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Mol. Ther. 15, 2027–2036 (2007).
Zeng, L. et al. Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling. Circulation 115, 1866–1875 (2007).
Jain, M. et al. Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction. Circulation 103, 1920–1927 (2001).
Ghostine, S. et al. Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation 106, I131–I136 (2002).
Menard, C. et al. Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study. Lancet 366, 1005–1012 (2005).
Kolossov, E. et al. Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J. Exp. Med. 203, 2315–2327 (2006).
Caspi, O. et al. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J. Am. Coll. Cardiol. 50, 1884–1893 (2007).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Yu, J. et al. Induced pluripotent stem cell lnes derived from human somatic cells. Science 318, 1917–1920 (2007).
Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnol. 26, 101–106 (2007).
Hanna, J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920–1923 (2007).
Beltrami, A. P. et al. Evidence that human cardiac myocytes divide after myocardial infarction. N. Engl. J. Med. 344, 1750–1757 (2001).
Beltrami, A. P. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776 (2003).
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).
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).
Murry, C. E., Reinecke, H. & Pabon, L. M. Regeneration gaps: observations on stem cells and cardiac repair. J. Am. Coll. Cardiol. 47, 1777–1785 (2006).
Evans, S. M., Mummery, C. & Doevendans, P. A. Progenitor cells for cardiac repair. Semin. Cell Dev. Biol. 18, 153–160 (2007).
Parmacek, M. S. & Epstein, J. A. Pursuing cardiac progenitors: regeneration redux. Cell 120, 295–298 (2005).
Laugwitz, K. L. et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005).
Messina, E. et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ. Res. 95, 911–921 (2004).
Smith, R. R. et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896–908 (2007).
Bearzi, C. et al. Human cardiac stem cells. Proc. Natl Acad. Sci. USA 104, 14068–14073 (2007).
Quaini, F. et al. Chimerism of the transplanted heart. N. Engl. J. Med. 346, 5–15 (2002).
Urbanek, K. et al. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc. Natl Acad. Sci. USA 100, 10440–10445 (2003).
R.P. and L.W.v.L. were supported by the European Community's Sixth Framework Programme (Heart Repair). ES Cell International provided the human ES3–GFP.
The authors declare no competing financial interests.
Correspondence should be addressed to C.L.M. (email@example.com).
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Passier, R., van Laake, L. & Mummery, C. Stem-cell-based therapy and lessons from the heart. Nature 453, 322–329 (2008). https://doi.org/10.1038/nature07040
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