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Regeneration Next: Toward Heart Stem Cell Therapeutics

2009; Elsevier BV; Volume: 5; Issue: 4 Linguagem: Inglês

10.1016/j.stem.2009.09.004

1934-5909

Emil M. Hansson, Mark E. Lindsay, Kenneth R. Chien,

Tissue Engineering and Regenerative Medicine

Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and their patients. However, the translational arm of stem cell science is in a relatively primitive state. Although a number of clinical studies have been initiated, the early returns point to several inherent problems. In this regard, the clinical potential of stem cells can only be fully realized by the identification of the key barriers to clinical implementation. Here, we examine experimental paradigms to address the critical steps in the transition from stem cell biology to regenerative medicine, utilizing cardiovascular disease as a case study. Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and their patients. However, the translational arm of stem cell science is in a relatively primitive state. Although a number of clinical studies have been initiated, the early returns point to several inherent problems. In this regard, the clinical potential of stem cells can only be fully realized by the identification of the key barriers to clinical implementation. Here, we examine experimental paradigms to address the critical steps in the transition from stem cell biology to regenerative medicine, utilizing cardiovascular disease as a case study. Few would argue with the sentiments of Charles Spurgeon (1834–1892), the leading preacher of Victorian England, who professed that "every generation needs regeneration." In our modern era of stem cell biology, these words have taken on a new meaning, especially for the millions of patients afflicted with chronic diseases for which there is neither a cure nor further available treatment options. In this regard, the almost monthly major advances in stem cell biology have created an aura of excitement and hope in both the scientific and medical communities, resulting in a sense of urgency to move new developments quickly into the clinical setting. This translational dream has been further boosted by the announcement earlier this year that the United States' Food and Drug Administration (FDA) are considering the approval of the world's first clinical trial using human embryonic stem cell (ESC)-derived cells in an attempt to find a remedy for spinal cord injuries (Couzin, 2009Couzin J. Biotechnology. Celebration and concern over U.S. trial of embryonic stem cells.Science. 2009; 323: 568Crossref PubMed Scopus (25) Google Scholar). With respect to cardiovascular disease, literally hundreds of clinical studies have examined the potential therapeutic effects of heart stem cell therapy. A quick Google search yields over 2.5 million separate listings for heart stem cell therapy, with many overseas centers already offering routine treatment for advanced forms of heart failure often for sums ranging upwards of 50,000 US$ per treatment (reviewed in (Lau et al., 2008Lau D. Ogbogu U. Taylor B. Stafinski T. Menon D. Caulfield T. Stem cell clinics online: The direct-to-consumer portrayal of stem cell medicine.Cell Stem Cell. 2008; 3: 591-594Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar)). At the same time, the bulk of the clinical data to date suggests that these are relatively early days for cell based therapy for heart disease, with a number of negative, marginal, and transient effects recorded in larger scale double-blind placebo controlled trials. Ironically, the major import of these studies is in pointing out specific clinical roadblocks, including the identification of the optimal cell type, ideal in vivo delivery system, novel approaches to promote the conversion to fully functional, mature cardiac muscle, integrated vascularization, and the appropriate alignment and electrical integration with the recipient myocardium (for review, see (Chien, 2008Chien K.R. Regenerative medicine and human models of human disease.Nature. 2008; 453: 302-305Crossref PubMed Scopus (48) Google Scholar, Chien et al., 2008Chien K.R. Domian I.J. Parker K.K. Cardiogenesis and the complex biology of regenerative cardiovascular medicine.Science. 2008; 322: 1494-1497Crossref PubMed Scopus (110) Google Scholar). Given the above, the question arises as to exactly where we are on the translational road map from cardiovascular stem cell biology to heart stem cell therapy. At this moment, are we headed in the right direction, taking a tangential course, reaching a fork in the road, or simply "lost in translation" (Chien, 2004Chien K.R. Stem cells: Lost in translation.Nature. 2004; 428: 607-608Crossref PubMed Scopus (162) Google Scholar)? If the latter is the case, how do we get back on track and what are the critical issues that must be addressed to correct our course? In this review, we utilize studies of regenerative cardiovascular therapy as a paradigm to identify critical issues for stem cell therapeutics in other organ systems, with the long range view that a common core set of problems must be solved to unlock the potential of stem cell biology for regenerative therapy. Cardiovascular disease is the leading cause of death in the world today (Lopez et al., 2006Lopez A.D. Mathers C.D. Ezzati M. Jamison D.T. Murray C.J. Global and regional burden of disease and risk factors, 2001: Systematic analysis of population health data.Lancet. 2006; 367: 1747-1757Abstract Full Text Full Text PDF PubMed Scopus (2030) Google Scholar). Specifically, myocardial infarction is the leading cardiovascular cause of mortality, and in cases where it does not lead to sudden death, it frequently injures a large enough proportion of the cardiomyocytes of the heart to diminish its contractile capacity below a critical threshold. This damage leads to heart failure, a condition where almost half of the affected patients die within one year from the onset of symptoms - a grimmer prognosis than in many forms of cancer (Jessup and Brozena, 2003Jessup M. Brozena S. Heart failure.N. Engl. J. Med. 2003; 348: 2007-2018Crossref PubMed Scopus (1012) Google Scholar). Effective treatment of heart failure is the holy grail of regenerative cardiology, and the conceptual framework regarding therapy is quite simple - stem cells would be used in a replacement setting, thereby replenishing tissue lost as a result of disease. There is no question that this approach is a highly meritorious area of investigation, but, at the same time, there are some important barriers that need to be addressed to allow stem cell-mediated repair to become clinical reality. One frequently underestimated challenge in regenerative medicine is the sheer number of cells that needs to be replaced. The most common cause of heart failure is a myocardial infarction caused by an occlusion of the left anterior descending coronary artery, supplying the left ventricle of the heart with freshly oxygenated blood. The outcome is a loss of cardiomyocytes, accompanied by the formation of a fibrous scar, resulting in decreased pumping capacity of the heart. In a typical myocardial infarct it is estimated that one billion cardiomyocytes are lost (Laflamme and Murry, 2005Laflamme M.A. Murry C.E. Regenerating the heart.Nat. Biotechnol. 2005; 23: 845-856Crossref PubMed Scopus (510) Google Scholar). To put this staggering number of cells in perspective, it is approximately equivalent to one hundred standard 10 cm tissue culture dishes of cells. Although an improvement of cardiac function can be achieved without replacing all lost cells, it is evident that stem cell-derived treatment of heart failure will have to be based on a cellular system permitting the isolation of sufficient number of cells to generate hundreds of millions of cardiomyocytes upon transplantation for a single patient. In considering the prevalence of heart failure world wide, and its recent exponential increase, the challenge of the scalability of heart stem cell therapy, as well as that of other tissues, is a considerable, and often overlooked, challenge (Kirouac and Zandstra, 2008Kirouac D.C. Zandstra P.W. The systematic production of cells for cell therapies.Cell Stem Cell. 2008; 3: 369-381Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). The clinical therapeutic paradigm will have to be sufficiently robust, scalable, and effective to be adopted widely. The first experimental attempts to use regeneration to restore cardiac function in an injured myocardium focused on two extra-cardiac sources of cells: progenitors from skeletal muscle and bone marrow. Although both these sources are clearly not authentic heart stem cells, they address the problem of an accessible, scalable cell type, i.e., an autologous stem cell source capable of generating a sufficient number of cells to potentially match the cell loss after myocardial infarction. The first approach was to transplant satellite cells, skeletal muscle-specific stem cells ("myoblasts"), to the injured heart, with the hope that the cardiac microenvironment would promote the transdifferentiation of myoblasts into cardiomyocytes with a resultant increase in contractile capacity. Unfortunately, experiments in rodents showed that even though satellite cells transplanted to infarcted hearts of syngenic hosts survived and matured to fully differentiated skeletal muscle fibers, there was no evidence of conversion to a cardiomyocyte fate (Reinecke et al., 2002Reinecke H. Poppa V. Murry C.E. Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting.J. Mol. Cell. Cardiol. 2002; 34: 241-249Abstract Full Text PDF PubMed Scopus (247) Google Scholar). Furthermore, the engrafted cells did not exhibit electromechanical coupling with the cardiomyocytes of the host myocardium, but functioned in isolation from the native cardiac tissue (Rubart et al., 2004Rubart M. Soonpaa M.H. Nakajima H. Field L.J. Spontaneous and evoked intracellular calcium transients in donor-derived myocytes following intracardiac myoblast transplantation.J. Clin. Invest. 2004; 114: 775-783Crossref PubMed Scopus (115) Google Scholar). However, several groups reported a positive effect on heart function in rodent (Taylor et al., 1998Taylor D.A. Atkins B.Z. Hungspreugs P. Jones T.R. Reedy M.C. Hutcheson K.A. Glower D.D. Kraus W.E. Regenerating functional myocardium: Improved performance after skeletal myoblast transplantation.Nat. Med. 1998; 4: 929-933Crossref PubMed Scopus (793) Google Scholar) and larger animal (Ghostine et al., 2002Ghostine S. Carrion C. Souza L.C. Richard P. Bruneval P. Vilquin J.T. Pouzet B. Schwartz K. Menasche P. Hagege A.A. Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction.Circulation. 2002; 106: I131-I136PubMed Google Scholar) models of myocardial infarction. The mechanistic basis for such a beneficial effect is not fully understood, but may be due to an increased stiffness of the ischemic area of the ventricular wall from the simple increase in cell mass, or the release of paracrine factors from the grafted cells that somehow provide a positive effect for the injured heart. Despite the lack of mechanistic understanding regarding their mode of action, a phase I clinical trial that transplanted satellite cells to the hearts of patients with chronic heart failure was initiated eight years ago (Menasche et al., 2001Menasche P. Hagege A.A. Scorsin M. Pouzet B. Desnos M. Duboc D. Schwartz K. Vilquin J.T. Marolleau J.P. Myoblast transplantation for heart failure.Lancet. 2001; 357: 279-280Abstract Full Text Full Text PDF PubMed Scopus (752) Google Scholar). A subsequent, more in-depth study (randomized, double blind, placebo controlled, with several centers participating) failed to show improvement in several key parameters of cardiac function after a follow-up period of six months (Menasche et al., 2008Menasche P. Alfieri O. Janssens S. McKenna W. Reichenspurner H. Trinquart L. Vilquin J.T. Marolleau J.P. Seymour B. Larghero J. et al.The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial: First randomized placebo-controlled study of myoblast transplantation.Circulation. 2008; 117: 1189-1200Crossref PubMed Scopus (390) Google Scholar). What might explain this disappointing result, given the encouraging data obtained using animal models? Clearly, the mouse offers many advantages as a model system, including transgenesis, many different genetic backgrounds, and a comparatively low cost. However, several important differences are equally clear when human and mouse cardiovascular systems are compared, including parameters such as heart rate, oxygen consumption, properties of the coronary arteries, and response to input from innervation and circulating regulatory peptides (Dixon and Spinale, 2009Dixon J.A. Spinale F.G. Large animal models of heart failure: A critical link in the translation of basic science to clinical practice.Circ. Heart Fail. 2009; 2: 262-271Crossref PubMed Scopus (59) Google Scholar). Furthermore, most injury models used commonly in mice do not capture all aspects of the pathobiology of human disease, and frequently result in a thin fibrous cap/aneurysm where any cell of interest might have a benenficial effect by simply augmenting the chamber wall mass and secondarily improving function by decreasing wall stress. Consequently, a word of caution is warranted when extrapolating data from mouse models to human patients, and moving to a larger animal model for validating data obtained in mice is necessary. In the cardiovascular field, candidate models include sheep, dog and pig models of cardiac pathology (Dixon and Spinale, 2009Dixon J.A. Spinale F.G. Large animal models of heart failure: A critical link in the translation of basic science to clinical practice.Circ. Heart Fail. 2009; 2: 262-271Crossref PubMed Scopus (59) Google Scholar). The physiology of the cardiovascular system in these model organisms more closely resemble the human. However, as evident from the above, even encouraging data from experiments in larger animal models do not necessarily translate to a successful outcome in clinical trials. An inescapable conclusion is that positive therapeutic effects of cell-based therapy in small and large animal models of myocardial infarction may not be predictive of clinical success. In short, there is a need for better validated animal model systems for cardiac regenerative therapy. An alternative strategy to using skeletal muscle has been to transplant bone marrow cells to the injured heart. Over a decade ago, several research groups reported that populations of autologous stem cells, including bone marrow stem cells, appeared to possess a considerably higher degree of developmental potential than previously appreciated (reviewed in (Morrison, 2001Morrison S.J. Stem cell potential: Can anything make anything?.Curr. Biol. 2001; 11: R7-R9Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar)). Upon transplantation, such bone marrow-derived cells were reported to give rise to differentiated progeny in several solid organs, including the heart. Given the relative accessibility of bone marrow, this finding spurred researchers to study the fate of bone marrow stem cells upon transplantation in rodent models of myocardial infarction, reporting a robust transdifferentiation of injected bone marrow cells to cardiomyocytes (Jackson et al., 2001Jackson K.A. Majka S.M. Wang H. Pocius J. Hartley C.J. Majesky M.W. Entman M.L. Michael L.H. Hirschi K.K. Goodell M.A. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.J. Clin. Invest. 2001; 107: 1395-1402Crossref PubMed Google Scholar, Orlic et al., 2001Orlic D. Kajstura J. Chimenti S. Jakoniuk I. Anderson S.M. Li B. Pickel J. McKay R. Nadal-Ginard B. Bodine D.M. et al.Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 410: 701-705Crossref PubMed Scopus (3556) Google Scholar). Enthusiasm in the field was further boosted by a report examining postmortem tissue from patients that had received a heart transplant. In female donor hearts transplanted to male recipients, Y-chromosome-positive cardiomyocytes were detected, indicating cellular chimerism of the transplanted heart (Quaini et al., 2002Quaini F. Urbanek K. Beltrami A.P. Finato N. Beltrami C.A. Nadal-Ginard B. Kajstura J. Leri A. Anversa P. Chimerism of the transplanted heart.N. Engl. J. Med. 2002; 346: 5-15Crossref PubMed Scopus (859) Google Scholar). Similar findings, albeit with a much lower frequency of cardiac chimerism, were reported by other groups, including one study examining cardiac tissue in patients receiving bone marrow transplants (Deb et al., 2003Deb A. Wang S. Skelding K.A. Miller D. Simper D. Caplice N.M. Bone marrow-derived cardiomyocytes are present in adult human heart: A study of gender-mismatched bone marrow transplantation patients.Circulation. 2003; 107: 1247-1249Crossref PubMed Scopus (256) Google Scholar). However, several groups have since contested the original claims that bone marrow cells can efficiently transdifferentiate to a cardiomyocyte fate (Balsam et al., 2004Balsam L.B. Wagers A.J. Christensen J.L. Kofidis T. Weissman I.L. Robbins R.C. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.Nature. 2004; 428: 668-673Crossref PubMed Scopus (1167) Google Scholar, Murry et al., 2004Murry C.E. Soonpaa M.H. Reinecke H. Nakajima H. Nakajima H.O. Rubart M. Pasumarthi K.B. Virag J.I. Bartelmez S.H. Poppa V. et al.Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts.Nature. 2004; 428: 664-668Crossref PubMed Scopus (1416) Google Scholar). Subsequent studies have documented that what originally was interpreted as transdifferentiation may indeed have been the result of cell fusion events, where transplanted cells fuse with differentiated cardiac cells in the recipient (Alvarez-Dolado et al., 2003Alvarez-Dolado M. Pardal R. Garcia-Verdugo J.M. Fike J.R. Lee H.O. Pfeffer K. Lois C. Morrison S.J. Alvarez-Buylla A. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.Nature. 2003; 425: 968-973Crossref PubMed Scopus (1086) Google Scholar, Nygren et al., 2004Nygren J.M. Jovinge S. Breitbach M. Sawen P. Roll W. Hescheler J. Taneera J. Fleischmann B.K. Jacobsen S.E. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation.Nat. Med. 2004; 10: 494-501Crossref PubMed Scopus (675) Google Scholar, Terada et al., 2002Terada N. Hamazaki T. Oka M. Hoki M. Mastalerz D.M. Nakano Y. Meyer E.M. Morel L. Petersen B.E. Scott E.W. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion.Nature. 2002; 416: 542-545Crossref PubMed Scopus (1453) Google Scholar). It is widely accepted by the stem cell community at large that cell fusion events, such as these, do not generate new differentiated progeny in other organ systems, and by analogy it is unlikely that new cardiomyocytes are being generated by fusion events. Taking this unexpected finding into account, previously published reports may have to be re-evaluated, and there is currently no consensus on whether bone marrow cells have the capacity to transdifferentiate into the cardiac lineage upon transplantation. Nonetheless, clinical trials using bone marrow infusion in cases of acute myocardial ischemia as well as chronic heart failure have been initiated, with the first pilot study reported seven years ago (Strauer et al., 2002Strauer B.E. Brehm M. Zeus T. Kostering M. Hernandez A. Sorg R.V. Kogler G. Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans.Circulation. 2002; 106: 1913-1918Crossref PubMed Scopus (1553) Google Scholar). The outcomes of these trials have been somewhat conflicting, with some trials showing a beneficial effect, whereas others have failed to see statistically significant differences compared to the control group. Again, any positive effect from such treatment has been attributed to a poorly understood paracrine effect, possibly by direct effect on the myocardium or by contributing to increased vascularization of the heart. Studies have identified a number of putative paracrine factors that might be responsible, including VEGF, FGF, IGF, and SDF (Gnecchi et al., 2005Gnecchi M. He H. Liang O.D. Melo L.G. Morello F. Mu H. Noiseux N. Zhang L. Pratt R.E. Ingwall J.S. Dzau V.J. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells.Nat. Med. 2005; 11: 367-368Crossref PubMed Scopus (669) Google Scholar, Kinnaird et al., 2004Kinnaird T. Stabile E. Burnett M.S. Shou M. Lee C.W. Barr S. Fuchs S. Epstein S.E. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms.Circulation. 2004; 109: 1543-1549Crossref PubMed Scopus (627) Google Scholar, Uemura et al., 2006Uemura R. Xu M. Ahmad N. Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling.Circ. Res. 2006; 98: 1414-1421Crossref PubMed Scopus (342) Google Scholar). Taken together, clinical trials using bone marrow and satellite cells (summarized in Table 1) indicate that both these sources of cells may have some modest effects when administered to the failing heart. At the same time, the effects clearly cannot be ascribed to cardiac regeneration. The fact that the injection of many cell types have been reported to transiently improve cardiac function in animal model systems following myocardial infarction, including, adipose tissue stromal cells (Li et al., 2007Li B. Zeng Q. Wang H. Shao S. Mao X. Zhang F. Li S. Guo Z. Adipose tissue stromal cells transplantation in rats of acute myocardial infarction.Coron. Artery Dis. 2007; 18: 221-227Crossref PubMed Scopus (27) Google Scholar), bone marrow (Orlic et al., 2001Orlic D. Kajstura J. Chimenti S. Jakoniuk I. Anderson S.M. Li B. Pickel J. McKay R. Nadal-Ginard B. Bodine D.M. et al.Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 410: 701-705Crossref PubMed Scopus (3556) Google Scholar), circulating putative endothelial progenitors with features of circulating monocytes (Kocher et al., 2001Kocher A.A. Schuster M.D. Szabolcs M.J. Takuma S. Burkhoff D. Wang J. Homma S. Edwards N.M. Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function.Nat. Med. 2001; 7: 430-436Crossref PubMed Scopus (1862) Google Scholar), skeletal myoblasts (Taylor et al., 1998Taylor D.A. Atkins B.Z. Hungspreugs P. Jones T.R. Reedy M.C. Hutcheson K.A. Glower D.D. Kraus W.E. Regenerating functional myocardium: Improved performance after skeletal myoblast transplantation.Nat. Med. 1998; 4: 929-933Crossref PubMed Scopus (793) Google Scholar), and even undifferentiated embryonic stem cells themselves (Min et al., 2002Min J.Y. Yang Y. Converso K.L. Liu L. Huang Q. Morgan J.P. Xiao Y.F. Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats.J. Appl. Physiol. 2002; 92: 288-296Crossref PubMed Scopus (42) Google Scholar), suggests that the simple short term improvement in cardiac function cannot be taken as direct evidence of cardiac regeneration per se. Moreover, a portion of the effect may relate to effects of decreasing wall stress by increasing the tissue mass in a thinning myocardial wall, an anatomic effect that is independent of a real regenerative effect. Accordingly, a parallel search for identifying populations of stem cells with innate cardiomyogenic potential, i.e., authentic endogenous cardiac progenitor cells seems warranted.Table 1Selected Randomized Trials with At Least 50 PatientsTrialNo.Cell TypeAbsolute LVEF% ΔLVEDV ΔLVESV ΔREPAIR-AMI (Schachinger et al., 2006Schachinger V. Erbs S. Elsasser A. Haberbosch W. Hambrecht R. Holschermann H. Yu J. Corti R. Mathey D.G. Hamm C.W. et al.Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction.N. Engl. J. Med. 2006; 355: 1210-1221Crossref PubMed Scopus (1196) Google Scholar)204BMC+2.5 (4 mon)N.S. (4 mon)N.S. (4 mon)ASTAMI (Lunde et al., 2006Lunde K. Solheim S. Aakhus S. Arnesen H. Abdelnoor M. Egeland T. Endresen K. Ilebekk A. Mangschau A. Fjeld J.G. et al.Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.N. Engl. J. Med. 2006; 355: 1199-1209Crossref PubMed Scopus (807) Google Scholar)100BMCN.S. (6 mon)N.S. (6 mon)N.R.Janssens et al. (Janssens et al., 2006Janssens S. Dubois C. Bogaert J. Theunissen K. Deroose C. Desmet W. Kalantzi M. Herbots L. Sinnaeve P. Dens 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: 113-121Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar)67BMCN.S. (4 mon)N.S. (6 mon)N.S. (6 mon)BOOST (Wollert et al., 2004Wollert K.C. Meyer G.P. Lotz J. Ringes-Lichtenberg S. Lippolt P. Breidenbach C. Fichtner S. Korte T. Hornig B. Messinger D. et al.Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial.Lancet. 2004; 364: 141-148Abstract Full Text Full Text PDF PubMed Scopus (1492) Google Scholar)60BMC+6.0 (6 mon); N.S. (18 mon)N.S. (6 mon); N.S. (18 mon)N.S. (6 mon); N.S. (18 mon)Meluzin et al. (Meluzin et al., 2008Meluzin J. Janousek S. Mayer J. Groch L. Hornacek I. Hlinomaz O. Kala P. Panovsky R. Prasek J. Kaminek M. 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. 2008; 128: 185-192Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar)60BMC+6.0 (3 mon); +7.0 (12 mon)N.S. (3, 6, 12 mon)N.S. (3, 6, 12 mon)TOPCARE-AMI (Schachinger et al., 2004Schachinger V. Assmus B. Britten M.B. Honold J. Lehmann R. Teupe C. Abolmaali N.D. Vogl T.J. Hofmann W.K. Martin H. 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: 1690-1699Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar)59BMC+8.3 (4 mon); +9.3 (12 mon)N.S. (4 mon)−10 cc (4 mon)MAGIC (Menasche et al., 2008Menasche P. Alfieri O. Janssens S. McKenna W. Reichenspurner H. Trinquart L. Vilquin J.T. Marolleau J.P. Seymour B. Larghero J. et al.The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial: First randomized placebo-controlled study of myoblast transplantation.Circulation. 2008; 117: 1189-1200Crossref PubMed Scopus (390) Google Scholar)97SMBN.S. (6 mon)N.S. (6 mon)−8.3 cc/m2 (6 mon)Chen et al. (Chen et al., 2004Chen S.L. Fang W.W. Ye F. Liu Y.H. Qian J. Shan S.J. Zhang J.J. Chunhua R.Z. Liao L.M. Lin S. Sun J.P. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction.Am. J. Cardiol. 2004; 94: 92-95Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar)69BMSC+14.0 (3 mon); +13.0 (6 mon)−38 cc (3 mon)−18 cc (3 mon)MAGIC CELL-3-DES (Kang et al., 2006Kang H.J. Lee H.Y. Na S.H. Chang S.A. Park K.W. Kim H.K. Kim S.Y. Chang H.J. Lee W. Kang W.J. et al.Differential effect of intracoronary infusion of mobilized peripheral blood stem cells by granulocyte colony-stimulating factor on left ventricular function and remodeling in patients with acute myocardial infarction versus old myocardial infarction: the MAGIC Cell-3-DES randomized, controlled trial.Circulation. 2006; 114: I145-I151PubMed Google Scholar)82PBSC+5.1 (6 mon for AMI)N.S. (6 mon)N.S. (6 mon)van Ramhoorst et al. (van Ramshorst et al., 2009van Ramshorst J. Bax J.J. Beeres S.L. Dibbets-Schneider P. Roes S.D. Stokkel M.P. de Roos A. Fibbe W.E. Zwaginga J.J. Boersma E. et al.Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial.JAMA. 2009; 301: 1997-2004Crossref PubMed Scopus (141) Google Scholar)50BMC+3 (3 mon)N.S. (3 mon)N.S. (3 mon)The following abbreviations are used: BMC, bone marrow stem cell; SMB, skeletal myoblast; BSMC, bone marrow mesenchymal stem cell; PBSC, peripheral blood stem cell; LVEF% Δ, left ventricular ejection fraction, percent difference; LVEDV Δ, left ventricular end diastolic volume, difference; LVESV Δ, left ventricular end systolic volume, difference; mon, months follow up after treatment; AMI, acute myocardial infarct; N.S., not significant; and N.R., not recorded. Open table in a new tab The following abbreviations are used: BMC, bone marrow stem cell; SMB, skeletal myoblast; BSMC, bone marrow mesenchymal stem cell; PBSC, peripheral blood stem cell; LVEF% Δ, left ventricular ejection fraction, percent difference; LVEDV Δ, left ventricular end diastolic volume, difference; LVESV Δ, left ventricular end systolic volume, difference; mon, months follow up after treatment; AMI, acute myocardial infarct; N.S., not significant; and N.R., not recorded. Promoting the mobilization of a putative endogenous pool of cardiac progenitors in the adult human heart would represent an alternative to replacing lost cardiomyocytes by transplantation. In this manner, the concept would be to activate the endogenous heart regenerative machinery, a process akin to boosting erythrocyte levels with erythropoietin. In this paradigm, the potential problems associated with the surgical procedure, in vitro culturing of cells for grafting, immunological incompatibility, and so forth, are avoided. Cardiac regeneration has been documented in at least two vertebrate species, newt and zebrafish, where cardiac inju