Although several repair mechanisms have been described in the human heart, all fall too short to prevent clinical heart disease in most acute or chronic pathological cardiac conditions. Moreover, despite many breakthroughs in cardiovascular medicine, the complications of a myocardial infarction such as chronic heart failure remains a serious worldwide problem. Bone marrow stem cells could provide for a promising strategy to restore myocardial infarctions and prevent postinfarct congestive heart failure, because there is growing body of evidence that bone marrow stem cells, such as mesenchymal stem cells, can generate new cardiomyocytes in animals and humans. In this review, we will discuss important issues on stem cell therapy for cardiac regeneration after myocardial infarction, which might be of paramount importance when considering future human trials.

Nadal-Ginard B, Kajstura J, Leri A, et al: Myocyte death, growth, and regeneration in cardiac hypertrophy and failure. Circ Res 2003;92:139–150.
Anversa P, Kajstura J: Ventricular myocytes are not terminally differentiated in the adult mammalian heart. Circ Res 1998;83:1–14.
Kajstura J, Leri A, Finato N, et al: Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci USA 1998;95:8801–8805.
Anversa P, Nadal-Ginard B: Myocyte renewal and ventricular remodelling. Nature 2002;415:240–243.
Beltrami AP, Urbanek K, Kajstura J, et al: Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001;344:1750–1757.
Leferovich JM, Heber-Katz E: The scarless heart. Sem Cell Devel Biology 2002;13:327–333.
Pasumarthi KBS, Field LJ: Cardiomyocyte cell cycle regulation. Circ Res 2002;90:1044–1054.
Hahn WC, Weinberg RA: Rules for making human tumor cells. N Engl J Med 2002;347:1593–1603.
Bittner RE, Schofer C, Weipoltshammer K, et al: Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat Embryol (Berl) 1999;199:391–396.
Jackson KA, Majka SM, Wang H, et al: Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001;107:1395–1402.
Takayuki S, Kuang JQ, Bittira B, et al: Xenotransplant cardiac chimera: Immune tolerance of adult stem cells. Ann Thorac Surg 2002;74:19–24.
Deb A, Wang S, Skelding KA, et al: Bone marrow-derived cardiomyocytes are present in adult human heart. Circulation 2003;107:1247–1249.
Ghostine S, Carrion C, Guarita Souza LC, et al: Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation 2002;106(suppl I):131–136.
Menasche P, Hagege AA, Vilquin J-T, et al: Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003;41:1078–1083.
Minami E, Reinecke H, Murry CE: Skeletal muscle meets cardiac muscle. Friends or foes? J Am Coll Cardiol 2003;41:1084–1086.
Pagani FD, DerSimonian H, Zawadzka A, et al: Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans: Histological analysis of cell survival and differentiation. J Am Coll Cardiol 2003;41:879–888.
Zubair AC, Silberstein L, Ritz J: Adult hematopoietic stem cell plasticity. Transfusion 2002;42:1096–1101.
Aicher A, Brenner W, Zuhayra M, et al: Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 2003;107:2134–2139.
Pillarisetti K, Gupta SK: Cloning and relative expression analysis of rat stromal cell derived factor-1 (SDF-1): SDF-1 α mRNA is selectively induced in rat model of myocardial infarction. Inflammation 2001;25:293–300.
Heissig B, Hattori K, Dias S, et al: Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002;109:625–637.
Kocher AA, Schutser MD, Bonaros N, et al: Use of stem cells for treatment of cardiovascular disorders. Eur Surg 2002;34:111–113.
Orlic D, Kajstura J, Chimenti S, et al: Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701–705.
Tomita S, Li R-K, Weisel RD, et al: Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999;100 (suppl II):247–256.
Zhang M, Methot D, Poppa V, et al: Cardiomyocyte grafting for cardiac repair: Graft cell death and anti-death strategies. J Mol Cell Cardiol 2001;33:907–921.
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.
Wurtele H, Little KC, Chartrand P: Illegitimate DNA integration in mammalian cells. Gene Ther 2003;10:1791–1799.
Strauer BE, Kornowsky R: Stem cell therapy in perspective. Circulation 2003;107:929–934.
Kollet O, Spiegel A, Peled A, et al: Involvement of SDF-1/CXCR-4 interactions in the migration of immature CD34+ cells into liver of transplanted NOD/SCID mice (abstract). Blood 2001(suppl 98).
Szilvassy SJ, Bass MJ, Van Zant G, et al: Organ-selective homing defines engraftment kinetics of murine hematopoietic stem cells and is compromised by ex-vivo expansion. Blood 1999;93:1557–1566.
Denning-Kendall P, Singha S, Bradley B, et al: Cytokine expansion culture of cord blood CD34+ cells induced marked and sustained changes in adhesion receptor and CXCR4 expressions. Stem Cells 2003;21:61–70.
Borisov AB: Regeneration of skeletal and cardiac muscle in mammals: Do nonprimate models resemble human pathology? Wound Repair Regen 1999;7:26–35.
Tomita S, Mickle DAG, Weisel RD, et al: Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg 2001;122:699–705.
Wang JS, Shum-Tim D, Chedrawy E, et al: The coronay delivery of marrow stromal cells for myocardial regeneration: Pathophysiological and therapeutic implications. J Thorac Cardiovasc Surg 2001;122:699–705.
Poss KD, Wilson LG, Keating MT: Heart regeneration in zebrafish. Science 2002;298:2188–2190.
Leferovich JM, Bedelbaeva K, Samulewics S, et al: Heart regeneration in adult MRL mice. Proc Natl Acad Sci USA 2001;98:9830–9835.
Condorelli G, Borello U, De Angelis L, et al: Cardiomyocytes induce endothelial cells to transdifferentiate into cardiac muscle: Implications for myocardial regeneration. Proc Natl Acad Sci USA 2001;98:10733–10738.
Badorff C, Brandes RP, Popp R, et al: Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 2003;107:1024–1032.
Orlic D, Kajstura J, Chimenti S, et al: Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001;98:10344–10349.
Hassink RJ, de la Riviere AB, Mummery CL, et al: Transplantation of cells for cardiac repair. J Am Coll Cardiol 2003;41:711–717.
Li Ren-Ke, Mickle DAG, Weisel RD, et al: Optimal time for cardiomyocyte transplantation to maximize myocardial function after left ventricular injury. Ann Thorac Surg 2001;72:1957–1963.
Min J-Y, Sullivan MF, Yang Y, et al: Significant improvement of heart function by cotransplantation of human mesenchymal stem cells and fetal cardiomyocytes in postinfarcted pigs. Ann Thorac Surg 2002;74:1568–1575.
Strauer BE, Brehm M, Zeus T, et al: Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913–1918.
Assmus B, Schächinger V, Teupe C, et al: Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE – AMI). Circulation 2002;106:3009–3017.
Orlic D, Hill JM, Arai EA: Stem cells for myocardial regeneration. Circ Res 2002;91:1092–1102.
Anderlini P, Przepiorka D, Champlin R, et al: Biological and clinical effects of granulocyte colony-stimulating factor in normal individuals. Blood 1996;88:2819–2825.
Seiler C, Pohl T, Wustmann K, et al: Promotion of collateral growth by granulocyte-macrophage colony-stimulating factor in patients with coronary artery disease. A randomised, double-blind, placebo-controlled study. Circulation 2001;104:2012–2017.
Buffon A, Biasucci LM, Liuzzo G, et al: Widespread coronary inflammation in unstable angina. N Engl J Med 2002;347:5–12.
Park JL, Luchessi BR: Mechanisms of myocardial reperfusion injury. Ann Thorac Surg 1999;68:1905–1912.
Shi W, Zakhartchenko V, Wolf E: Epigenetic reprogramming in mammalian nuclear transfer. Differentiation 2003;71:91–113.
Pittenger MF, Mackay AM, Beck SC, et al: Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147.
Blau HM, Brazelton TR, Weimann JM: The evolving concept of a stem cell: Entity or function? Cell 2001;105:829–841.
Vassilopoulos G, Wang P-R, Russell DW: Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901–904.
Wang X, Willenbring H, Akkari Y, et al: Cell fusion is the principal source of bone-marrow- derived hepatocytes. Nature 2003;422:897–901.
Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD: Cardiac progenitor cells from adult myocardium: homing, differentiation and fusion after infarction. Proc Natl Acad Sci USA 2003;100:12313–12318.
Wurmser AE, Gage FH: Cell fusion causes confusion. Nature 2002;416:485–487.
Poulsom R, Alison MR, Forbes SJ, et al: Adult stem cell plasticity. J Pathol 2002;197:441–456.
Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P: Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763–776.
Blau HM: A twist of fate. Nature 2003;419:437.
Prockop DJ, Gregory CA, Spees JL: One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci USA 2003;100(suppl 1):11917–11923.
Forrester JS, Price MJ, Makkar RR: Stem cell repair of infarcted myocardium: an overview for clinicians. Circulation 2003;108:1139–1145.
Jiang Y, Jahagirdar BN, Reinhardt RL, et al: Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41–49.
Holden C: Cells find destiny though merger. Science 2003;300:35.
Orkin SH, Zon LI: Hematopoiesis and stem cells: Plasticity versus developmental heterogeneity. Nature Immunol 2002;3:323–328.
Behfar A, Zingman LV, Hodgson DM, et al: Stem cell differentiation requires a paracrine pathway in the heart. FASEB J 2002;16:1558–1566.
Iijima Y, Nagai T, Mizukami M, et al: Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes. FASEB J 2003;17:1361–1363.
Bittira B, Kuang J-Q, Al-Khaldi A, et al: In vitro preprogramming of marrow stromal cells for myocardial regeneration. Ann Thorac Surg 2002;74:1154–1160.
Tomita S, Li R-K, Weisel RD, et al: Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999;100 (19 suppl):247–256.
Makino S, Fukada K, Miyoshi S, et al: Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 1999;103:697–705.
Mummery C, Ward van Oostwaard, Doevendans P, et al: Differentiation of human embryonic stem cells to cardiomyocytes. Role of coculture with visceral endoderm-like cells. Circulation 2002;107:2733–2740.
Frangiogiannis NG, Smith CW, Entman ML, et al: The inflammatory response in myocardial infarction. Cardiovasc Res 2002;53:31–47.
Ren G, Michael LH, Entman ML, et al: Morphological characteristics of the microvasculature in healing myocardial infarcts. J Histochem Cytochem 2002;50:71–79.
Kocher AA, Schuster MD, Szabolcs MJ, et al: Neovascularisation of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodelling and improves cardiac function. Nat Med 2001;7:430–436.
Isner JM: Myocardial Gene Therapy. Nature 2002;415:234–239.
Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000;6:389–395.
Asahara T, Masuda H, Takahashi T, et al: Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularisation. Circ Res 1999;85:221–228.
Gordon DW, Nolta JA, Jin Y-S, et al: Migration of mesenchymal stem cells to heart allografts during chronic rejection. Transplantation 2003;75:679–685.
Liechty KW, Mackenzie TC, Shaaban AF, et al: Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 2000;11:1282–1286.
Sun Y, Kiani MF, Postleth AE, et al: Infarct scar as living tissue. Basic Res Cardiol 2002;97:343–347.
Dowell JD, Rubart M, Pasumarthi KBS, et al: Myocyte and myogenic stem cell transplantation in the heart. Cardiovasc Res 2003;58:336–350.
Garot J, Unterseeh T, Teiger E, et al: Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll Cardiol 2003;41:1841–1846.
Kraitchman DL, Heldman AW, Atalar E, et al: In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 2003;107:2290–2293.
Hinds KA, Hill JM, Shapiro EM, et al: Highly efficient endosomal labelling of progenitors and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood, published online April 3, 2003.
Wickline SA, Lanza GM: Nanotechnology for molecular imaging and targeted therapy. Circulation 2003;107:1092–1095.
Prockop DJ: Further proof of the plasticity of adult stem cells and their role in tissue repair. J Cell Biol 2003;160:807–809.
Caplice NM, Gersh BJ: Stem cells to repair the heart. Circ Res 2003;92:6–8.
Stamm C, Westphal B, Kleine H-D, et al: Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003;361:45–46.
Rehman J, Li J, Orschell CM, et al: Peripheral blood ‘endothelial progenitor cells’ are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003;107:1174–1169.
Emerson CP, Dohmann HFR, Borojevic R, et al: Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischaemic heart failure. Circulation 2003;107:2294–2302.
Sakai T, Li R-K, Weisel RD, et al: Cardiothoracic transplantation: Fetal cell transplantation: A comparison of three cell types. J Thorac Cardiovasc Surg 1999;118:715–725.
Rubart M, Pasumarthi KBS, Nakajima H, et al: Physiological coupling of donor and host cardiomyocytes after cellular transplantation. Circ Res 2003;92:1217–1224.
Hamano K, Li TS, Kobayashi T, et al: Therapeutic angiogenesis induced by local autologous bone marrow cell implantation. Ann Thorac Surg 2002;73:1210–1215.
Gao J, Dennis JE, Muzic RF, et al: The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001;169:12–20.
Kopen G, Prockop D, Phinney D: Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate intro astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 1999;96:10711–10716.
Devine SM, Cobbs C, Jennings M, et al: Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into non-human primates. Blood, published online, 2002.
Ferrari N, Gold J, Lee J, et al: Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors. Gene Therapy 2003;10:647–656.
Horwitz EM, Prockop DJ, Fitzpatrick LA, et al: Transplantability and therapeutic effects of bone marrow-derived mesenchymal stem cells in children with osteogenesis imperfecta. Nat Med 1999;5:309–313.
Orkin SH, Morrison SJ: Stem-cell competition. Nature 2002;418:25–27.
Dawson L, Bateman-House AS, Mueller Agnew D, Bok H, Brock DW, Chakravarti A, Greene M, King PA, O’Brien SJ, Sachs DH, Schill KE, Siegel A, Solter D, Suter SM, Verfaillie CM, Walters LB, Gearhart JD, Faden RR: Safety issues in cell-based intervention trials. Fertil Steril 2003;80:1077–1085.
Hirschi KK, Goodell MA: Hematopoietic, vascular and cardiac fates of bone marrow derived stem cells. Gene Therapy 2002;9:648–652.
Brickman JM, Burdon TG: Pluripotency and tumorigenicity. Nat Genet 2002;32:557–558.
Zhang YM, Hartzell C, Narlow M, et al: Stem cell derived cardiomyocytes demonstrate arrhythmic potential. Circulation 2002;106:1294–1299.
Miake J, Marban E, Nuss HB: Gene therapy: Biological pacemaker created by gene transfer. Nature 2002;419:132–133.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.