Differential myocardial infarct repair with muscle stem cells compared to myoblasts.

Myoblast transplantation for cardiac repair has generated beneficial results in both animals and humans; however, poor viability and poor engraftment of myoblasts after implantation in vivo limit their regeneration capacity. We and others have identified and isolated a subpopulation of skeletal muscle-derived stem cells (MDSCs) that regenerate skeletal muscle more effectively than myoblasts. Here we report that in comparison with a myoblast population, MDSCs implanted into infarcted hearts displayed greater and more persistent engraftment, induced more neoangiogenesis through graft expression of vascular endothelial growth factor, prevented cardiac remodeling, and elicited significant improvements in cardiac function. MDSCs also exhibited a greater ability to resist oxidative stress-induced apoptosis compared to myoblasts, which may partially explain the improved engraftment of MDSCs. These findings indicate that MDSCs constitute an alternative to other myogenic cells for use in cardiac repair applications.

[1]  D. Torella,et al.  Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration , 2003, Cell.

[2]  R. Brandes,et al.  Antioxidative stress-associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress. , 2004, Blood.

[3]  M. Grounds,et al.  Rapid death of injected myoblasts in myoblast transfer therapy , 1996, Muscle & nerve.

[4]  J. Huard,et al.  Muscle-derived stem cells , 2002, Gene Therapy.

[5]  A. Hagège,et al.  Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. , 2003, Journal of the American College of Cardiology.

[6]  R. C. Chiu,et al.  Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation. , 1995, The Annals of thoracic surgery.

[7]  K Walsh,et al.  Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. , 2001, Journal of molecular and cellular cardiology.

[8]  C. Murry,et al.  Evidence for Fusion Between Cardiac and Skeletal Muscle Cells , 2004, Circulation research.

[9]  D. Sawyer,et al.  Cell Therapy Attenuates Deleterious Ventricular Remodeling and Improves Cardiac Performance After Myocardial Infarction , 2001, Circulation.

[10]  T. Partridge,et al.  Dynamics of Myoblast Transplantation Reveal a Discrete Minority of Precursors with Stem Cell–like Properties as the Myogenic Source , 1999, The Journal of cell biology.

[11]  Y. Kaneda,et al.  Cell Transplantation for the Treatment of Acute Myocardial Infarction Using Vascular Endothelial Growth Factor–Expressing Skeletal Myoblasts , 2001, Circulation.

[12]  M. Rubart,et al.  Myocyte and myogenic stem cell transplantation in the heart. , 2003, Cardiovascular research.

[13]  M. Komeda,et al.  Transplanted Skeletal Myoblasts Can Fully Replace the Infarcted Myocardium When They Survive in the Host in Large Numbers , 2003, Circulation.

[14]  W. Kraus,et al.  Intracardiac transplantation of skeletal myoblasts yields two populations of striated cells in situ. , 1999, The Annals of thoracic surgery.

[15]  J. Bouchard,et al.  Dystrophin expression in myofibers of Duchenne muscular dystrophy patients following intramuscular injections of normal myogenic cells. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  David A. Williams,et al.  Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts , 2004, Nature.

[17]  T Hashimoto,et al.  Ischemic Preconditioning Upregulates Vascular Endothelial Growth Factor mRNA Expression and Neovascularization via Nuclear Translocation of Protein Kinase C &egr; in the Rat Ischemic Myocardium , 2001, Circulation research.

[18]  Johnny Huard,et al.  Clonal Isolation of Muscle-Derived Cells Capable of Enhancing Muscle Regeneration and Bone Healing , 2000, The Journal of cell biology.

[19]  M. Grounds,et al.  Irradiation of dystrophic host tissue prior to myoblast transfer therapy enhances initial (but not long-term) survival of donor myoblasts , 2003, Journal of Cell Science.

[20]  B. Zheng,et al.  Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential , 2003, Nature Cell Biology.

[21]  G. Hannon,et al.  Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD , 1995, Science.

[22]  N. Khaper,et al.  Inflammatory cytokines and postmyocardial infarction remodeling. , 2004, Circulation research.

[23]  F. Pagani,et al.  Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. , 2003, Journal of the American College of Cardiology.

[24]  P. Menasché Myoblast transfer in heart failure. , 2004, The Surgical clinics of North America.

[25]  D. Burkhoff,et al.  Anesthetic inhibition in ischemic and nonischemic murine heart: comparison with conscious echocardiographic approach. , 2001, American journal of physiology. Heart and circulatory physiology.

[26]  D. Skuk,et al.  Efficacy of Myoblast Transplantation in Nonhuman Primates Following Simple Intramuscular Cell Injections: Toward Defining Strategies Applicable to Humans , 2002, Experimental Neurology.

[27]  N. Dhalla,et al.  Evidence for the role of oxidative stress in acute ischemic heart disease: a brief review. , 1999, The Canadian journal of cardiology.

[28]  Michael D. Schneider,et al.  Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. Audinat,et al.  Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S M Schwartz,et al.  Skeletal myoblast transplantation for repair of myocardial necrosis. , 1996, The Journal of clinical investigation.

[31]  I. Komuro,et al.  Beating is necessary for transdifferentiation of skeletal muscle‐derived cells into cardiomyocytes , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  M. Yacoub,et al.  Heat Shock Treatment Enhances Graft Cell Survival in Skeletal Myoblast Transplantation to the Heart , 2000, Circulation.

[33]  J. Ingwall,et al.  Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts , 2003, Nature Medicine.

[34]  J. Bouchard,et al.  Human myoblast transplantation: Preliminary results of 4 cases , 1992, Muscle & nerve.

[35]  C. Murry,et al.  Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. , 2000 .

[36]  K. Kamiński,et al.  Oxidative stress and neutrophil activation--the two keystones of ischemia/reperfusion injury. , 2002, International journal of cardiology.

[37]  F. Prósper,et al.  Cellular cardiomyoplasty: clinical application. , 2004, The Annals of thoracic surgery.

[38]  M. J. Thompson,et al.  Fiber type-specific differential expression of angiogenic factors in response to chronic hindlimb ischemia. , 2000, American journal of physiology. Heart and circulatory physiology.

[39]  G. Acsadi,et al.  Gene transfer into skeletal muscles by isogenic myoblasts. , 1994, Human gene therapy.

[40]  Johnny Huard,et al.  Development of Approaches to Improve Cell Survival in Myoblast Transfer Therapy , 1998, The Journal of cell biology.

[41]  I. Weissman,et al.  Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium , 2004, Nature.

[42]  Doris A Taylor,et al.  Regenerating functional myocardium: Improved performance after skeletal myoblast transplantation , 1998, Nature Medicine.

[43]  M. Rubart,et al.  Spontaneous and evoked intracellular calcium transients in donor-derived myocytes following intracardiac myoblast transplantation. , 2004, The Journal of clinical investigation.

[44]  S H Lee,et al.  Early expression of angiogenesis factors in acute myocardial ischemia and infarction. , 2000, The New England journal of medicine.

[45]  Johnny Huard,et al.  Identification of a novel population of muscle stem cells in mice , 2002, The Journal of cell biology.

[46]  Vascular endothelial growth factor modulates skeletal myoblast function. , 2003 .

[47]  P. Menasché Cellular transplantation: hurdles remaining before widespread clinical use , 2004, Current opinion in cardiology.

[48]  Johnny Huard,et al.  The use of ex vivo gene transfer based on muscle-derived stem cells for cardiovascular medicine. , 2002, Trends in cardiovascular medicine.

[49]  R. Kauppinen,et al.  Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration. , 2002, The American journal of pathology.

[50]  M. Grounds,et al.  Superior Survival and Proliferation after Transplantation of Myoblasts Obtained from Adult Mice Compared with Neonatal Mice , 2004, Transplantation.

[51]  M. Rudnicki,et al.  Pax7 Is Required for the Specification of Myogenic Satellite Cells , 2000, Cell.

[52]  Johnny Huard,et al.  The role of CD34 expression and cellular fusion in the regeneration capacity of myogenic progenitor cells , 2002, Journal of Cell Science.