Mesenchymal Stem Cells for Myocardial Infarction

Abstract

HomeCirculationVol. 112, No. 2Mesenchymal Stem Cells for Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMesenchymal Stem Cells for Myocardial InfarctionPromises and Pitfalls Kai C. Wollert, MD and Helmut Drexler, MD Kai C. WollertKai C. Wollert From the Department of Cardiology and Angiology, Hanover Medical School, Hanover, Germany. Search for more papers by this author and Helmut DrexlerHelmut Drexler From the Department of Cardiology and Angiology, Hanover Medical School, Hanover, Germany. Search for more papers by this author Originally published12 Jul 2005https://doi.org/10.1161/CIRCULATIONAHA.105.551895Circulation. 2005;112:151–153Recent studies indicate that cardiac transfer of adult stem cells can have a favorable impact on tissue perfusion and contractile performance of the infarcted heart. Several cell sources are being explored in an effort to regenerate infarcted myocardium, including hematopoietic stem cells, endothelial progenitor cells, cardiac resident stem cells, bone marrow–derived multipotent stem cells, and mesenchymal stem cells (MSCs). Each of these cell types may have its own profile of advantages, limitations, and practicability issues in specific settings. Studies comparing the regenerative capacity of distinct cell populations are scarce. Most clinical investigators have therefore chosen a pragmatic approach by using unselected bone marrow cells that contain different stem cell populations. Basic scientists, by contrast, are focusing more on specific cell populations in a quest to understand the biological foundations of cell therapy and to identify the most promising stem cells for cardiac regeneration.1See p 214MSCs are a rare population of self-renewing, multipotent cells present in adult bone marrow. Although MSCs represent <0.01% of all nucleated bone marrow cells, they can be readily expanded in vitro. In defined culture media, MSCs differentiate into several mesenchymal cell lineages, including cardiomyocytes.2,3 When injected into normal adult myocardium, MSCs differentiate into cardiomyocyte-like cells with sarcomeric organization.4 In an earlier study in pigs with myocardial infarction (MI), MSCs grafted into the infarcted area were shown to express muscle-specific markers and to improve regional wall motion.5 Ease of isolation, high expansion capability, and cardiomyogenic potential have led to the proposition that MSCs may be a good choice for cell-based therapies of MI.6In a report published in this issue of Circulation, Dai et al7 have further explored the therapeutic potential of MSCs. Their study is unique because it provides a correlation between MSC engraftment/differentiation and functional outcomes at different time points during long-term follow-up after MI. As with any good research, this study has come up with some surprising results and new questions. The most salient findings can be summarized as follows: One week after permanent coronary artery ligation in rats (postacute phase of MI), culture-expanded MSCs were labeled with the fluorescent dye DiI and injected into the infarcted area. Four weeks after MSC transplantation, left ventricular systolic function was significantly improved. Although DiI-labeled MSCs were readily detectable in the infarct scar at this time point, they did not consistently express muscle-specific marker proteins or visibly replace the infarct scar with muscle tissue. Six months after cell transfer, left ventricular systolic function was no longer improved compared with the control group, yet ≈40% of the surviving DiI-positive MSCs now expressed muscle-specific markers. Of note, even at this later time point, differentiation of MSCs to cardiomyocytes was incomplete because only immature myofibrillar organization was detected. These intriguing observations indicate that MSCs lack the potential to acquire a mature cardiomyocytic phenotype in the infarcted myocardium and suggest that mechanisms apart from cell incorporation and differentiation contribute to the early functional effects of MSC transplantation.7 Although Dai et al have not further explored such alternative mechanisms, paracrine effects seem to be a plausible explanation because it has been shown that MSCs secrete a great number of growth factors and cytokines, including vascular endothelial growth factor, basic fibroblast growth factor, placental growth factor, transforming growth factor-β, tumor necrosis factor-α, hepatocyte growth factor, and insulin-like growth factor-1.8–11Given the importance of paracrine signaling in MSC/hematopoietic stem cell interactions in the bone marrow niche,8,12 the capacity of MSCs to promote paracrine effects may not be surprising. The significance of paracrine factors in mediating MSC effects in ischemic tissues has been examined in the murine hindlimb ischemia model. On the basis of the observations that intramuscular injections of MSCs improve collateral formation and distal limb perfusion with no apparent incorporation into growing collaterals, and that the effects of MSC transplantation on hindlimb perfusion can be mimicked by intramuscular injection of MSC-conditioned media, it has been proposed that MSCs enhance collateral formation via paracrine effects.10,11 In line with this conclusion, many of the factors secreted from MSCs are well-known proangiogenic cytokines.Do MSCs improve LV systolic function after MI by promoting proangiogenic effects and improving tissue perfusion, for example, in areas with hibernating myocardium? When transplanted during the postacute7 or chronic phase after MI,13 MSCs promote an increase in capillary density in the infarcted area, perhaps to a certain extent by incorporating into growing vessels.7,13 Although MSCs may promote capillarization of the scar area, they do not enhance arteriolar density and regional blood flow.7 Therefore, the functional relevance of MSC-mediated proangiogenic effects after MI remains uncertain. It is conceivable, however, that cytokines secreted from MSCs mediate pleiotropic effects on a variety of nonvascular cell types in the heart, including cardiomyocytes, fibroblasts, and resident cardiac stem cells. In this regard, paracrine factors released from MSCs were recently shown to promote antiapoptotic effects in cardiomyocytes subjected to hypoxia.14 Future studies need to define the spectrum of paracrine factors secreted from MSCs and their progeny, the temporal pattern of their release, and the downstream targets of these factors in the infarcted heart.The short-lived nature of the functional benefits in the present study would limit the attractiveness of MSC transfer as a therapeutic concept.7 It is possible that MSCs only transiently enhance cardiac contractility without promoting structural repair; alternatively, MSCs may expedite regenerative processes that also occur endogenously after MI, albeit at a slower pace. Although Dai et al have detected MSCs in the infarct area for up to 6 months, the percentage of transplanted cells that survived in the infarct scar is not known (but the number is probably small). Long-term survival and functional effects of MSCs may be substantially improved if cells were transplanted into a reperfused infarct area, which would also better reflect the clinical scenario in patients with MI. Also, Dai et al have transplanted MSCs during an intermediate postacute phase in their model, which actually does not mimic the situation in patients with acute MI or with chronic ischemic cardiomyopathy. If MSCs are to be applied late after MI with limited tissue perfusion, then survival of MSCs becomes crucial. Intriguingly, retroviral transduction of MSCs with the survival-promoting kinase Akt greatly increases the resistance of transplanted MSCs to apoptosis and enhances their beneficial effects on systolic function in a rat model of acute MI.15 Of note, paracrine antiapoptotic effects on resident cardiomyocytes account for the marked protection of ischemic myocardium by Akt-modified MSCs.14 Thus, it will be interesting to see whether overexpression of Akt15 or specific paracrine factors16 enhances the therapeutic benefits of MSCs in the setting of chronic MI.Let us speculate for a moment about the potential clinical implications of these findings. Recent studies have highlighted the potential of other bone marrow cell populations to promote paracrine effects in the infarcted myocardium.17–19 Considering the prominent role of stem cell–mediated paracrine effects, should we not try to identify and use specific factors for cardiac regeneration, thereby avoiding the practical and regulatory issues related to stem cell therapy? Compared with single-cytokine approaches, stem cells deliver a cocktail of paracrine factors that may promote additive or synergistic effects in ischemic tissues.20,21 Moreover, stem cells appear to express a unique set of cell surface receptors that may enable these cells to efficiently home and engraft in the infarcted myocardium.22 Another feature that may make MSCs particularly appealing for clinical use is their ability to be transplanted in an allogeneic setting, which may be related to their secretion of immunosuppressive factors.23,24 Allogeneic MSCs could be isolated and expanded from selected donors, tested for their functional capabilities in advance, and be available as a standardized cell preparation. If additional studies confirm that MSCs mediate only transient functional benefits and that genetic strategies are required to provide substantial efficacy of MSCs, then rapid translation into the clinic will not be feasible. Currently, retroviral transduction of stem cells is hampered by the possibility of serious side effects, including insertional mutagenesis. Nevertheless, newer approaches such as insertion-site targeting may circumvent these risks25 and may eventually allow us to exploit the full potential of MSCs not only in rats but also in patients with MI.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Prof Dr Helmut Drexler, Abt Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Str 1, 30625 Hannover, Germany. E-mail [email protected] References 1 Wollert KC, Drexler H. Clinical applications of stem cells for the heart. Circ Res. 2005; 96: 151–163.LinkGoogle Scholar2 Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999; 284: 143–147.CrossrefMedlineGoogle Scholar3 Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest. 1999; 103: 697–705.CrossrefMedlineGoogle Scholar4 Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002; 105: 93–98.CrossrefMedlineGoogle Scholar5 Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, Pittenger MF, Martin BJ. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg. 2002; 73: 1919–1926.CrossrefMedlineGoogle Scholar6 Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res. 2004; 95: 9–20.LinkGoogle Scholar7 Dai W, Hale SL, Martin BJ, Kuang J-Q, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation. 2005; 112: 214–223.LinkGoogle Scholar8 Weimar IS, Miranda N, Muller EJ, Hekman A, Kerst JM, de Gast GC, Gerritsen WR. Hepatocyte growth factor/scatter factor (HGF/SF) is produced by human bone marrow stromal cells and promotes proliferation, adhesion and survival of human hematopoietic progenitor cells (CD34+). Exp Hematol. 1998; 26: 885–894.MedlineGoogle Scholar9 Cheng SL, Zhang SF, Mohan S, Lecanda F, Fausto A, Hunt AH, Canalis E, Avioli LV. Regulation of insulin-like growth factors I and II and their binding proteins in human bone marrow stromal cells by dexamethasone. J Cell Biochem. 1998; 71: 449–458.CrossrefMedlineGoogle Scholar10 Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004; 109: 1543–1549.LinkGoogle Scholar11 Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004; 94: 678–685.LinkGoogle Scholar12 Haynesworth SE, Baber MA, Caplan AI. Cytokine expression by human marrow–derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol. 1996; 166: 585–592.CrossrefMedlineGoogle Scholar13 Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D, Coulter SC, Lin J, Ober J, Vaughn WK, Branco RV, Oliveira EM, He R, Geng YJ, Willerson JT, Perin EC. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation. 2005; 111: 150–156.LinkGoogle Scholar14 Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005; 11: 367–368.CrossrefMedlineGoogle Scholar15 Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 2003; 9: 1195–1201.CrossrefMedlineGoogle Scholar16 Matsumoto R, Omura T, Yoshiyama M, Hayashi T, Inamoto S, Koh KR, Ohta K, Izumi Y, Nakamura Y, Akioka K, Kitaura Y, Takeuchi K, Yoshikawa J. Vascular endothelial growth factor-expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction. Arterioscler Thromb Vasc Biol. 2005; 25: 1168–1173.LinkGoogle Scholar17 Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation. 2001; 104: 1046–1052.CrossrefMedlineGoogle Scholar18 Rehman J, Li J, Orschell CM, March KL. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation. 2003; 107: 1164–1169.LinkGoogle Scholar19 Yoon YS, Wecker A, Heyd L, Park JS, Tkebuchava T, Kusano K, Hanley A, Scadova H, Qin G, Cha DH, Johnson KL, Aikawa R, Asahara T, Losordo DW. Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J Clin Invest. 2005; 115: 326–338.CrossrefMedlineGoogle Scholar20 Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001; 7: 575–583.CrossrefMedlineGoogle Scholar21 Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, Leboulch P, Cao Y. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med. 2003; 9: 604–613.CrossrefMedlineGoogle Scholar22 Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H. Monitoring of bone marrow cell homing to the infarcted human myocardium. Circulation. 2005; 111: 2198–2202.LinkGoogle Scholar23 Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002; 99: 3838–3843.CrossrefMedlineGoogle Scholar24 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005; 105: 1815–1822.CrossrefMedlineGoogle Scholar25 Baum C, von Kalle C, Staal FJ, Li Z, Fehse B, Schmidt M, Weerkamp F, Karlsson S, Wagemaker G, Williams DA. Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther. 2004; 9: 5–13.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zhang R, Yu J, Zhang N, Li W, Wang J, Cai G, Chen Y, Yang Y and Liu Z (2021) Bone marrow mesenchymal stem cells transfer in patients with ST-segment elevation myocardial infarction: single-blind, multicenter, randomized controlled trial, Stem Cell Research & Therapy, 10.1186/s13287-020-02096-6, 12:1, Online publication date: 1-Dec-2021. Beer L, Simader E, Mildner M, Gyöngyösi M and Ankersmit H (2018) Peripheral Blood Mononuclear Cell Secretome for Tissue Repair Cell Engineering and Regeneration, 10.1007/978-3-319-37076-7_61-2, (1-22), . Beer L, Simader E, Mildner M, Gyöngyösi M and Ankersmit H (2020) Peripheral Blood Mononuclear Cell Secretome for Tissue Repair Cell Engineering and Regeneration, 10.1007/978-3-319-08831-0_61, (667-688), . Sarvepalli J, Santhakumar R and Verma R (2019) Evolving Concepts for Use of Stem Cells and Tissue Engineering for Cardiac Regeneration Coronary and Cardiothoracic Critical Care, 10.4018/978-1-5225-8185-7.ch024, (509-543) Beer L, Mildner M, Gyöngyösi M, Ankersmit H and Simader E (2018) Peripheral Blood Mononuclear Cell Secretome for Tissue Repair Cell Engineering and Regeneration, 10.1007/978-3-319-37076-7_61-1, (1-22), . Melhem M, Park J, Knapp L, Reinkensmeyer L, Cvetkovic C, Flewellyn J, Lee M, Jensen T, Bashir R, Kong H and Schook L (2016) 3D Printed Stem-Cell-Laden, Microchanneled Hydrogel Patch for the Enhanced Release of Cell-Secreting Factors and Treatment of Myocardial Infarctions, ACS Biomaterials Science & Engineering, 10.1021/acsbiomaterials.6b00176, 3:9, (1980-1987), Online publication date: 11-Sep-2017. Ouchi T, Morikawa S, Shibata S, Fukuda K, Okuno H, Fujimura T, Kuroda T, Ohyama M, Akamatsu W, Nakagawa T and Okano H (2016) LNGFR+THY-1+ human pluripotent stem cell-derived neural crest-like cells have the potential to develop into mesenchymal stem cells, Differentiation, 10.1016/j.diff.2016.04.003, 92:5, (270-280), Online publication date: 1-Dec-2016. Beer L, Mildner M, Gyöngyösi M and Ankersmit H (2016) Peripheral blood mononuclear cell secretome for tissue repair, Apoptosis, 10.1007/s10495-016-1292-8, 21:12, (1336-1353), Online publication date: 1-Dec-2016. Nazari M, Ni N, Lüdke A, Li S, Guo J, Weisel R and Li R (2016) Mast cells promote proliferation and migration and inhibit differentiation of mesenchymal stem cells through PDGF, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2016.03.007, 94, (32-42), Online publication date: 1-May-2016. Sarvepalli J, Santhakumar R and Verma R (2016) Evolving Concepts for Use of Stem Cells and Tissue Engineering for Cardiac Regeneration Optimizing Assistive Technologies for Aging Populations, 10.4018/978-1-4666-9530-6.ch011, (279-313) Tatullo M, Marrelli M, Shakesheff K and White L (2014) Dental pulp stem cells: function, isolation and applications in regenerative medicine, Journal of Tissue Engineering and Regenerative Medicine, 10.1002/term.1899, 9:11, (1205-1216), Online publication date: 1-Nov-2015. Beltramo E, Lopatina T, Berrone E, Mazzeo A, Iavello A, Camussi G and Porta M (2014) Extracellular vesicles derived from mesenchymal stem cells induce features of diabetic retinopathy in vitro, Acta Diabetologica, 10.1007/s00592-014-0672-1, 51:6, (1055-1064), Online publication date: 1-Dec-2014. Vogel S, Chatterjee M, Metzger K, Borst O, Geisler T, Seizer P, Müller I, Mack A, Schumann S, Bühring H, Lang F, Sorg R, Langer H and Gawaz M (2014) Activated Platelets Interfere with Recruitment of Mesenchymal Stem Cells to Apoptotic Cardiac Cells via High Mobility Group Box 1/Toll-like Receptor 4-mediated Down-regulation of Hepatocyte Growth Factor Receptor MET, Journal of Biological Chemistry, 10.1074/jbc.M113.530287, 289:16, (11068-11082), Online publication date: 1-Apr-2014. Fraga A, de Araújo É, Vergani N, Fonseca S and Pereira L (2014) Use of Human Embryonic Stem Cells in Therapy Stem Cells and Cell Therapy, 10.1007/978-94-007-7196-3_1, (1-19), . Georgiadis V, Knight R, Jayasinghe S and Stephanou A (2014) Cardiac tissue engineering: renewing the arsenal for the battle against heart disease, Integr. Biol., 10.1039/C3IB40097B, 6:2, (111-126) Peng L, Mao Z, Qi X, Chen X, Li N, Tabata Y and Gao J (2013) Transplantation of bone-marrow-derived mesenchymal and epidermal stem cells contribute to wound healing with different regenerative features, Cell and Tissue Research, 10.1007/s00441-013-1609-7, 352:3, (573-583), Online publication date: 1-Jun-2013. Escobedo-Uribe C, Monsiváis-Urenda A, López-Quijano J, Carrillo-Calvillo J, Leiva-Pons J and Peña-Duque M (2012) La terapia celular en la cardiopatía isquémica, Archivos de Cardiología de México, 10.1016/j.acmx.2012.04.004, 82:3, (218-229), Online publication date: 1-Jul-2012. Karam J, Muscari C and Montero-Menei C (2012) Combining adult stem cells and polymeric devices for tissue engineering in infarcted myocardium, Biomaterials, 10.1016/j.biomaterials.2012.04.028, 33:23, (5683-5695), Online publication date: 1-Aug-2012. Yerebakan C, Kaminski A, Westphal B, Donndorf P, Glass A, Liebold A, Stamm C and Steinhoff G (2011) Impact of preoperative left ventricular function and time from infarction on the long-term benefits after intramyocardial CD133+ bone marrow stem cell transplant, The Journal of Thoracic and Cardiovascular Surgery, 10.1016/j.jtcvs.2011.05.002, 142:6, (1530-1539.e3), Online publication date: 1-Dec-2011. Wollert K (2011) Bone Marrow Cell Therapy After Myocardial Infarction: What have we Learned from the Clinical Trials and Where Are We Going? Regenerating the Heart, 10.1007/978-1-61779-021-8_8, (111-129), . Graham J, Foltz W, Vaags A, Ward M, Yang Y, Connelly K, Vijayaraghavan R, Detsky J, Hough M, Stewart D, Wright G and Dick A (2010) Long-term tracking of bone marrow progenitor cells following intracoronary injection post-myocardial infarction in swine using MRI, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.01260.2008, 299:1, (H125-H133), Online publication date: 1-Jul-2010. Wang B, Borazjani A, Tahai M, de Jongh Curry A, Simionescu D, Guan J, To F, Elder S and Liao J (2010) Fabrication of cardiac patch with decellularized porcine myocardial scaffold and bone marrow mononuclear cells, Journal of Biomedical Materials Research Part A, 10.1002/jbm.a.32781, 9999A, (NA-NA), . Wollert K and Drexler H (2010) Cell therapy for the treatment of coronary heart disease: a critical appraisal, Nature Reviews Cardiology, 10.1038/nrcardio.2010.1, 7:4, (204-215), Online publication date: 1-Apr-2010. Schneider C, Jaquet K, Geidel S, Rau T, Malisius R, Boczor S, Zienkiewicz T, Kuck K and Krause K (2009) Transplantation of Bone Marrow-Derived Stem Cells Improves Myocardial Diastolic Function: Strain Rate Imaging in a Model of Hibernating Myocardium, Journal of the American Society of Echocardiography, 10.1016/j.echo.2009.06.011, 22:10, (1180-1189), Online publication date: 1-Oct-2009. Léobon B, Roncalli J, Joffre C, Mazo M, Boisson M, Barreau C, Calise D, Arnaud E, André M, Pucéat M, Pénicaud L, Prosper F, Planat-Bénard V and Casteilla L (2009) Adipose-derived cardiomyogenic cells: in vitro expansion and functional improvement in a mouse model of myocardial infarction, Cardiovascular Research, 10.1093/cvr/cvp167, 83:4, (757-767), Online publication date: 1-Sep-2009., Online publication date: 1-Sep-2009. van der Bogt K, Schrepfer S, Yu J, Sheikh A, Hoyt G, Govaert J, Velotta J, Contag C, Robbins R and Wu J (2009) Comparison of Transplantation of Adipose Tissue- and Bone Marrow-Derived Mesenchymal Stem Cells in the Infarcted Heart, Transplantation, 10.1097/TP.0b013e31819609d9, 87:5, (642-652), Online publication date: 15-Mar-2009. Chen J, Du X and Zhang K (2009) Effects of stromal-derived factor 1 preconditioning on apoptosis of rat bone mesenchymal stem cells, Journal of Huazhong University of Science and Technology [Medical Sciences], 10.1007/s11596-009-0406-8, 29:4, (423-426), Online publication date: 1-Aug-2009. Pal R, Hanwate M, Jan M and Totey S (2009) Phenotypic and functional comparison of optimum culture conditions for upscaling of bone marrow-derived mesenchymal stem cells, Journal of Tissue Engineering and Regenerative Medicine, 10.1002/term.143, 3:3, (163-174), Online publication date: 1-Mar-2009. Röll W, Sasse P, Breitbach M, Wenzel D, Klein A, Bostani T, Fleischmann B and Welz A (2009) Zellersatztherapie am Herzen: Fiktion oder reale MöglichkeitCell replacement therapy in the heart: fiction or a real possibility, Zeitschrift für Herz-,Thorax- und Gefäßchirurgie, 10.1007/s00398-009-0719-8, 23:3, (170-176), Online publication date: 1-Jun-2009. Yerebakan C, Kaminski A, Westphal B, Liebold A and Steinhoff G (2009) Autologous bone marrow stem cell therapy for the ischemic myocardium during coronary artery bypass grafting, Minimally Invasive Therapy & Allied Technologies, 10.1080/13645700801969774, 17:2, (143-148), Online publication date: 1-Jan-2008. Lyon A, Harding S and Peters N (2008) Cardiac Stem Cell Therapy and Arrhythmogenicity: Prometheus and the arrows of Apollo and Artemis, Journal of Cardiovascular Translational Research, 10.1007/s12265-008-9045-x, 1:3, (207-216), Online publication date: 1-Sep-2008. Shi R and Li Q (2008) Improving outcome of transplanted mesenchymal stem cells for ischemic heart disease, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2008.09.004, 376:2, (247-250), Online publication date: 1-Nov-2008. Chang S, Lee E, Kang H, Zhang S, Kim J, Li L, Youn S, Lee C, Kim K, Won J, Sohn J, Park K, Cho H, Yang S, Oh W, Yang Y, Ho W, Park Y and Kim H (2008) Impact of Myocardial Infarct Proteins and Oscillating Pressure on the Differentiation of Mesenchymal Stem Cells: Effect of Acute Myocardial Infarction on Stem Cell Differentiation, Stem Cells, 10.1634/stemcells.2007-0708, 26:7, (1901-1912), Online publication date: 1-Jul-2008. Schneider C, Krause K, Jaquet K, Geidel S, Malisius R, Boczor S, Rau T, Zienkiewicz T, Hennig D and Kuck K (2008) Intramyocardial Transplantation of Bone Marrow-Derived Stem Cells: Ultrasonic Strain Rate Imaging in a Model of Hibernating Myocardium, Journal of Cardiac Failure, 10.1016/j.cardfail.2008.08.005, 14:10, (861-872), Online publication date: 1-Dec-2008. Olschewski H (2008) LungenemboliePulmonary embolism, Der Pneumologe, 10.1007/s10405-007-0188-2, 5:1, (45-54), Online publication date: 1-Jan-2008. Yerebakan C, Kaminski A, Liebold A and Steinhoff G (2017) Safety of Intramyocardial Stem Cell Therapy for the Ischemic Myocardium: Results of the Rostock Trial after 5-Year Follow-Up, Cell Transplantation, 10.3727/096368907783338280, 16:9, (935-940), Online publication date: 1-Oct-2007. Deregibus M, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, Bruno S, Bussolati B and Camussi G (2007) Endothelial progenitor cell–derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA, Blood, 10.1182/blood-2007-03-078709, 110:7, (2440-2448), Online publication date: 1-Oct-2007. (2007) Gene Therapies and Stem Cell Therapies Cardiovascular Therapeutics, 10.1016/B978-1-4160-3358-5.50009-7, (40-66), . Wang X and Li Q (2007) The roles of mesenchymal stem cells (MSCs) therapy in ischemic heart diseases, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2007.05.112, 359:2, (189-193), Online publication date: 1-Jul-2007. Jiang W, Ma A, Wang T, Han K, Liu Y, Zhang Y, Dong A, Du Y, Huang X, Wang J, Lei X and Zheng X (2006) Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study, Pflügers Archiv - European Journal of Physiology, 10.1007/s00424-006-0117-y, 453:1, (43-52), Online publication date: 1-Oct-2006. Steinhoff G, Choi Y and Stamm C (2006) Intramyocardial bone marrow stem cell treatment for myocardial regeneration, European Heart Journal Supplements, 10.1093/eurheartj/sul065, 8:suppl_H, (H32-H39), Online publication date: 1-Dec-2006. DONG H, ZHANG Z and ZHOU Z (2006) Effects of endothelin-1 on differentiation of cardiac myocyte induced from rabbit bone marrow stromal cells, Chinese Medical Journal, 10.1097/00029330-200605020-00007, 119:10, (832-839), Online publication date: 1-May-2006. Meiliana A and Wijaya A (2011) Microparticles Novel Mechanisms of Intracellular Communication: Implication in Health and Disease, The Indonesian Biomedical Journal, 10.18585/inabj.v3i1.131, 3:1, (18) July 12, 2005Vol 112, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.105.551895PMID: 16009806 Originally publishedJuly 12, 2005 Keywordsgraftingmyocardial infarctionstem cells, mesenchymalsystoleEditorialsPDF download Advertisement SubjectsCell Biology/Structural BiologyChronic Ischemic Heart DiseaseMyocardial Infarction