Unchain my heart: the scientific foundations of cardiac repair.

In humans, the biological limitations to cardiac regenerative growth create both a clinical imperative--to offset cell death in acute ischemic injury and chronic heart failure--and a clinical opportunity; that is, for using cells, genes, and proteins to rescue cardiac muscle cell number or in other ways promote more efficacious cardiac repair. Recent experimental studies and early-phase clinical trials lend credence to the visionary goal of enhancing cardiac repair as an achievable therapeutic target.

[1]  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) , 2002 .

[2]  Fred H. Gage,et al.  Can stem cells cross lineage boundaries? , 2001, Nature Medicine.

[3]  S. Rafii,et al.  Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment , 2002, Nature Medicine.

[4]  J. Isner,et al.  Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury , 2003, Circulation.

[5]  M. Pesce,et al.  SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. , 2004, Blood.

[6]  Stefanie Dimmeler,et al.  Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I: angiogenic cytokines. , 2004, Circulation.

[7]  E. Chavakis,et al.  Role of (cid:1) 2-integrins for homing and neovascularization capacity of endothelial progenitor cells , 2004 .

[8]  S. Homma,et al.  Neovascularization of ischemic myocardium by human bone-marrow–derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function , 2001, Nature Medicine.

[9]  A. Zeiher,et al.  Infarct Remodeling After Intracoronary Progenitor Cell Treatment in Patients With Acute Myocardial Infarction (TOPCARE-AMI): Mechanistic Insights From Serial Contrast-Enhanced Magnetic Resonance Imaging , 2003, Circulation.

[10]  M. Bianchi,et al.  Chromatin and cell death. , 2004, Biochimica et biophysica acta.

[11]  Catherine M. Verfaillie,et al.  Pluripotency of mesenchymal stem cells derived from adult marrow , 2007, Nature.

[12]  Michael D. Schneider,et al.  Statins Enhance Migratory Capacity by Upregulation of the Telomere Repeat-Binding Factor TRF2 in Endothelial Progenitor Cells , 2004, Circulation.

[13]  Takayuki Saito,et al.  Transcoronary implantation of bone marrow stromal cells ameliorates cardiac function after myocardial infarction. , 2003, The Journal of thoracic and cardiovascular surgery.

[14]  J. García-Sancho,et al.  Experimental and Clinical Regenerative Capability of Human Bone Marrow Cells After Myocardial Infarction , 2004, Circulation research.

[15]  D. Srivastava,et al.  Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair , 2004, Nature.

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

[17]  Patrick W Serruys,et al.  Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. , 2003, Journal of the American College of Cardiology.

[18]  M. Keating,et al.  Heart Regeneration in Zebrafish , 2002, Science.

[19]  E. Blackburn.  Bioethics and the political distortion of biomedical science. , 2004, The New England journal of medicine.

[20]  M. Soonpaa,et al.  Targeted Expression of Cyclin D2 Results in Cardiomyocyte DNA Synthesis and Infarct Regression in Transgenic Mice , 2004, Circulation research.

[21]  B. Engelhardt,et al.  Multistep Nature of Microvascular Recruitment of Ex Vivo–expanded Embryonic Endothelial Progenitor Cells during Tumor Angiogenesis , 2003, The Journal of experimental medicine.

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

[23]  L. Harrington.  Does the reservoir for self-renewal stem from the ends? , 2004, Oncogene.

[24]  S. Dimmeler,et al.  Endothelial Progenitor Cells: Characterization and Role in Vascular Biology , 2004, Circulation research.

[25]  M. Mercola,et al.  Heart induction: embryology to cardiomyocyte regeneration. , 2004, Trends in cardiovascular medicine.

[26]  Koichi Hattori,et al.  Young Adult Bone Marrow–Derived Endothelial Precursor Cells Restore Aging-Impaired Cardiac Angiogenic Function , 2002, Circulation research.

[27]  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.

[28]  A. Quyyumi,et al.  Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. , 2003, The New England journal of medicine.

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

[30]  P. Wernet,et al.  Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans , 2002, Circulation.

[31]  Michael D. Schneider,et al.  Telomere attrition and Chk2 activation in human heart failure , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. Johnson,et al.  Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species , 1997, Nature Medicine.

[33]  H. Okano,et al.  Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. , 2004, Blood.

[34]  H. Okano,et al.  Unexpectedly efficient homing capacity of purified murine hematopoietic stem cells. , 2004, Immunity.

[35]  Haruchika Masuda,et al.  Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization , 1999, Nature Medicine.

[36]  C. Donadoni,et al.  Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues. , 2004, Brain : a journal of neurology.

[37]  Paul D. Kessler,et al.  Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart , 2002, Circulation.

[38]  Stefanie Dimmeler,et al.  Profoundly Reduced Neovascularization Capacity of Bone Marrow Mononuclear Cells Derived From Patients With Chronic Ischemic Heart Disease , 2004, Circulation.

[39]  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.

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

[41]  Chunhui Xu,et al.  Characterization and Enrichment of Cardiomyocytes Derived From Human Embryonic Stem Cells , 2002, Circulation research.

[42]  Hung-Fat Tse,et al.  Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation , 2003, The Lancet.

[43]  M. Keating.  Genetic approaches to disease and regeneration. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[44]  M. Entman,et al.  Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. , 2001, The Journal of clinical investigation.

[45]  C. Heeschen,et al.  Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. , 2003, Blood.

[46]  D. Melton,et al.  "Stemness": Transcriptional Profiling of Embryonic and Adult Stem Cells , 2002, Science.

[47]  S. Mittnacht,et al.  Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes , 2003, Journal of Cell Science.

[48]  William Abraham,et al.  Recovery from heart failure with circulatory assist: a working group of the National, Heart, Lung, and Blood Institute. , 2003, Journal of cardiac failure.

[49]  Doris A Taylor,et al.  Comparison of Benefits on Myocardial Performance of Cellular Cardiomyoplasty with Skeletal Myoblasts and Fibroblasts , 2000, Cell transplantation.

[50]  G. Koh,et al.  Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. , 1996, The Journal of clinical investigation.

[51]  Á. Raya,et al.  Activation of Notch signaling pathway precedes heart regeneration in zebrafish , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Rubart,et al.  Physiological Coupling of Donor and Host Cardiomyocytes After Cellular Transplantation , 2003, Circulation research.

[53]  S. Fichtlscherer,et al.  Number and Migratory Activity of Circulating Endothelial Progenitor Cells Inversely Correlate With Risk Factors for Coronary Artery Disease , 2001, Circulation research.

[54]  Federica Limana,et al.  Mobilized bone marrow cells repair the infarcted heart, improving function and survival , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Bernd Hertenstein,et al.  Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial , 2004, The Lancet.

[56]  W. Hofmann,et al.  HMG-CoA Reductase Inhibitors Reduce Senescence and Increase Proliferation of Endothelial Progenitor Cells via Regulation of Cell Cycle Regulatory Genes , 2003, Circulation research.

[57]  Stefanie Dimmeler,et al.  Transdifferentiation of Blood-Derived Human Adult Endothelial Progenitor Cells Into Functionally Active Cardiomyocytes , 2003, Circulation.

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

[59]  S. Rafii,et al.  Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. , 2001, Blood.

[60]  T. Misteli,et al.  Release of chromatin protein HMGB1 by necrotic cells triggers inflammation , 2002, Nature.

[61]  Erwin Hauser,et al.  Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice , 1999, Anatomy and Embryology.

[62]  A. Mathur,et al.  Stem cells and repair of the heart , 2004, The Lancet.

[63]  Karl-Ludwig Laugwitz,et al.  Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages , 2005, Nature.

[64]  W. Hofmann,et al.  Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. , 2004, Journal of the American College of Cardiology.

[65]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[66]  M. Pittenger,et al.  Mesenchymal stem cells and their potential as cardiac therapeutics. , 2004, Circulation research.

[67]  Winfried Brenner,et al.  Assessment of the Tissue Distribution of Transplanted Human Endothelial Progenitor Cells by Radioactive Labeling , 2003, Circulation.

[68]  A. Hagège,et al.  Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy , 2003, The Lancet.

[69]  Peter Wernet,et al.  Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans , 2002 .

[70]  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.

[71]  G. Koh,et al.  Differentiation and long-term survival of C2C12 myoblast grafts in heart. , 1993, The Journal of clinical investigation.

[72]  A. Hagège,et al.  Myoblast transplantation for heart failure , 2001, The Lancet.

[73]  M. Entman,et al.  Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. , 2004, The American journal of pathology.

[74]  L. Reinlib,et al.  Cell transplantation as future therapy for cardiovascular disease?: A workshop of the National Heart, Lung, and Blood Institute. , 2000, Circulation.

[75]  J. Isner,et al.  VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells , 1999, The EMBO journal.

[76]  Hyun-Jai Cho,et al.  Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial , 2004, The Lancet.

[77]  Eric J Topol,et al.  Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy , 2003, The Lancet.

[78]  E. Topol,et al.  Cellular, but not direct, adenoviral delivery of vascular endothelial growth factor results in improved left ventricular function and neovascularization in dilated ischemic cardiomyopathy. , 2004, Journal of the American College of Cardiology.

[79]  Michael D. Schneider,et al.  Sizing up the heart: development redux in disease. , 2003, Genes & development.

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

[81]  Helen M. Blau,et al.  Nuclear reprogramming: A key to stem cell function in regenerative medicine , 2004, Nature Cell Biology.

[82]  J. Isner,et al.  Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells , 2002, Circulation.

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

[84]  K. Mani,et al.  Death begets failure in the heart. , 2005, The Journal of clinical investigation.

[85]  T. Murohara,et al.  Hypoxic Preconditioning Augments Efficacy of Human Endothelial Progenitor Cells for Therapeutic Neovascularization , 2003, Laboratory Investigation.

[86]  L. Naldini,et al.  Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells , 2003, Nature Medicine.

[87]  I. Weissman,et al.  Little Evidence for Developmental Plasticity of Adult Hematopoietic Stem Cells , 2002, Science.

[88]  A M Zeiher,et al.  HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. , 2001, The Journal of clinical investigation.

[89]  N. Rosenthal.  Prometheus's vulture and the stem-cell promise. , 2003, The New England journal of medicine.

[90]  W. Vaughn,et al.  Improved Exercise Capacity and Ischemia 6 and 12 Months After Transendocardial Injection of Autologous Bone Marrow Mononuclear Cells for Ischemic Cardiomyopathy , 2004, Circulation.

[91]  J. Isner,et al.  Stromal Cell–Derived Factor-1 Effects on Ex Vivo Expanded Endothelial Progenitor Cell Recruitment for Ischemic Neovascularization , 2003, Circulation.

[92]  N. Weissman,et al.  Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. , 2001, Journal of the American College of Cardiology.

[93]  T. Papayannopoulou.  Bone marrow homing: the players, the playfield, and their evolving roles , 2003, Current opinion in hematology.

[94]  B. Fleischmann,et al.  Bone marrow–derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation , 2004, Nature Medicine.

[95]  A. Terzic,et al.  Stem cell differentiation requires a paracrine pathway in the heart , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[96]  J. Isner,et al.  Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. , 1999, Circulation research.

[97]  Stefanie Dimmeler,et al.  Antioxidants Inhibit Nuclear Export of Telomerase Reverse Transcriptase and Delay Replicative Senescence of Endothelial Cells , 2004, Circulation research.

[98]  L Gepstein,et al.  Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. , 2001, The Journal of clinical investigation.

[99]  E. Guinan,et al.  Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation , 2003, Transplantation.

[100]  L. Pénicaud,et al.  Spontaneous Cardiomyocyte Differentiation From Adipose Tissue Stroma Cells , 2004, Circulation research.

[101]  P. Wernet,et al.  A New Human Somatic Stem Cell from Placental Cord Blood with Intrinsic Pluripotent Differentiation Potential , 2004, The Journal of experimental medicine.

[102]  Klaus Pfeffer,et al.  Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes , 2003, Nature.

[103]  S. Ogawa,et al.  Cardiomyocytes can be generated from marrow stromal cells in vitro. , 1999, The Journal of clinical investigation.

[104]  W. R. MacLellan,et al.  Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of Rb , 2005, Molecular and Cellular Biology.

[105]  M. Endres,et al.  Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. , 2003, Circulation.

[106]  C. Verfaillie,et al.  Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. , 2002, Experimental hematology.

[107]  Mark A Sussman,et al.  Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 Overexpression , 2004, Circulation research.

[108]  C. Verfaillie.  Adult stem cells: assessing the case for pluripotency. , 2002, Trends in cell biology.

[109]  M. Entman,et al.  Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[110]  S. Rafii,et al.  Platelet-Derived Growth Factor-AB Promotes the Generation of Adult Bone Marrow–Derived Cardiac Myocytes , 2004, Circulation research.

[111]  H. Matsubara.  Risk to the coronary arteries of intracoronary stem cell infusion and G-CSF cytokine therapy , 2004, The Lancet.

[112]  M. Bianchi,et al.  Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation , 2004, The Journal of cell biology.

[113]  Stefanie Dimmeler,et al.  Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. , 2004, Circulation.

[114]  A. S. Conner,et al.  Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo , 1996, The Journal of experimental medicine.

[115]  Geoffrey C Gurtner,et al.  Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 , 2004, Nature Medicine.

[116]  G. Keller,et al.  Hypoxia affects mesoderm and enhances hemangioblast specification during early development , 2004, Development.

[117]  James T. Willerson,et al.  Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure , 2003, Circulation.

[118]  D. Taylor,et al.  Comparison of intracardiac cell transplantation: autologous skeletal myoblasts versus bone marrow cells. , 2007, Handbook of experimental pharmacology.

[119]  M. Cerqueira,et al.  Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. , 2003, Journal of the American College of Cardiology.

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

[121]  H. Waldmann,et al.  Embryonic stem cells and the challenge of transplantation tolerance. , 2004, Trends in immunology.

[122]  M. Marcinkiewicz,et al.  Oxytocin in cardiac ontogeny. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[123]  M. Baiocchi,et al.  The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. , 2002, Development.