Cardiac regeneration: repopulating the heart.

Many forms of pediatric and adult heart disease result from a deficiency in cardiomyocyte number. Through repopulation of the heart with new cardiomyocytes (that is, induction of regenerative cardiac growth), cardiac disease potentially can be reversed, provided that the newly formed myocytes structurally and functionally integrate in the preexisting myocardium. A number of approaches have been utilized to effect regenerative growth of the myocardium in experimental animals. These include interventions aimed at enhancing the ability of cardiomyocytes to proliferate in response to cardiac injury, as well as transplantation of cardiomyocytes or myogenic stem cells into diseased hearts. Here we review efforts to induce myocardial regeneration. We also provide a critical review of techniques currently used to assess cardiac regeneration and functional integration of de novo cardiomyocytes.

[1]  M. Burnett,et al.  Local Delivery of Marrow-Derived Stromal Cells Augments Collateral Perfusion Through Paracrine Mechanisms , 2004, Circulation.

[2]  Rona Shofti,et al.  Electromechanical integration of cardiomyocytes derived from human embryonic stem cells , 2004, Nature Biotechnology.

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

[4]  S. Ogawa,et al.  Effect of granulocyte-macrophage colony-stimulating factor inducer on left ventricular remodeling after acute myocardial infarction. , 2004, Journal of the American College of Cardiology.

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

[6]  R. Weisel,et al.  Cardiomyocyte transplantation improves heart function. , 1996, The Annals of thoracic surgery.

[7]  P. Zandstra,et al.  Scalable production of embryonic stem cell-derived cardiomyocytes. , 2003, Tissue engineering.

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

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

[10]  L. Field Modulation of the Cardiomyocyte Cell Cycle in Genetically Altered Animals , 2004, Annals of the New York Academy of Sciences.

[11]  W. Baumgartner,et al.  Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. , 2002, The Annals of thoracic surgery.

[12]  V. Centonze,et al.  Multiphoton excitation provides optical sections from deeper within scattering specimens than confocal imaging. , 1998, Biophysical journal.

[13]  P. Anversa,et al.  Chimerism of the transplanted heart. , 2002, The New England journal of medicine.

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

[15]  J. Saffitz,et al.  Evidence for Cardiomyocyte Repopulation by Extracardiac Progenitors in Transplanted Human Hearts , 2002, Circulation research.

[16]  W. Baumgartner,et al.  Fluorescence in situ hybridization for the Y-chromosome can be used to detect cells of recipient origin in allografted hearts following cardiac transplantation. , 1993, The American journal of pathology.

[17]  Peter W. Laird,et al.  Rebuilding a Damaged Heart: Long-Term Survival of Transplanted Neonatal Rat Cardiomyocytes After Myocardial Infarction and Effect on Cardiac Function , 2002, Circulation.

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

[19]  Q. Li,et al.  Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. , 1997, The Journal of clinical investigation.

[20]  S. Silver,et al.  Heart Failure , 1937, The New England journal of medicine.

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

[22]  H. Johnsen,et al.  Effect of mobilization of bone marrow stem cells by granulocyte colony stimulating factor on clinical symptoms, left ventricular perfusion and function in patients with severe chronic ischemic heart disease. , 2005, International journal of cardiology.

[23]  M. Soonpaa,et al.  Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. , 1997, The American journal of physiology.

[24]  P. Menasché,et al.  Cell-based cardiac repair: reflections at the 10-year point. , 2005, Circulation.

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

[26]  T. Jung Growth and Hyperplasia of Cardiac Muscle Cells , 1994 .

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

[28]  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.

[29]  Daniel J Garry,et al.  Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. , 2004, Developmental biology.

[30]  L. Field,et al.  Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice. , 1988, Science.

[31]  C. Catton,et al.  Cardiac tumours: diagnosis and management. , 2005, The Lancet. Oncology.

[32]  M. Ikeda,et al.  Critical Role of Cyclin D1 Nuclear Import in Cardiomyocyte Proliferation , 2003, Circulation research.

[33]  Giulio Cossu,et al.  Isolation and Expansion of Adult Cardiac Stem Cells From Human and Murine Heart , 2004, Circulation research.

[34]  O. Simonetti,et al.  Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. , 1999, Circulation.

[35]  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.

[36]  K. Chien,et al.  Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages , 2007, Nature.

[37]  G. Koh,et al.  Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. , 1994, Science.

[38]  J. Ingwall,et al.  Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells , 2005, Nature Medicine.

[39]  E. Wu,et al.  Cyclin A2 Mediates Cardiomyocyte Mitosis in the Postmitotic Myocardium* , 2004, Journal of Biological Chemistry.

[40]  D. Zipes,et al.  Stable fetal cardiomyocyte grafts in the hearts of dystrophic mice and dogs. , 1995, The Journal of clinical investigation.

[41]  Robert Zweigerdt,et al.  Differentiation and lineage selection of mouse embryonic stem cells in a stirred bench scale bioreactor with automated process control. , 2005, Biotechnology and bioengineering.

[42]  Robert A. Kloner,et al.  Systemic Delivery of Bone Marrow–Derived Mesenchymal Stem Cells to the Infarcted Myocardium: Feasibility, Cell Migration, and Body Distribution , 2003, Circulation.

[43]  P. Anversa,et al.  Insulin-like growth factor-1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart. , 1999, Circulation research.

[44]  J A Pearce,et al.  Development of a multifrequency conductance catheter-based system to determine LV function in mice. , 2000, American journal of physiology. Heart and circulatory physiology.

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

[46]  L. Field,et al.  Enhanced cardiomyocyte DNA synthesis during myocardial hypertrophy in mice expressing a modified TSC2 transgene. , 2000, Circulation research.

[47]  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.

[48]  E. Ryan,et al.  Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. , 2000, The New England journal of medicine.

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

[50]  R. Kim,et al.  Contrast-enhanced magnetic resonance imaging of myocardium at risk: distinction between reversible and irreversible injury throughout infarct healing. , 2000, Journal of the American College of Cardiology.

[51]  D. Kass,et al.  Estimation of parallel conductance by dual-frequency conductance catheter in mice. , 2000, American journal of physiology. Heart and circulatory physiology.

[52]  P. Anversa,et al.  Ventricular myocytes are not terminally differentiated in the adult mammalian heart. , 1998, Circulation research.

[53]  Yibin Wang,et al.  p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. , 2005, Genes & development.

[54]  L. Field,et al.  Cardiomyocyte cell cycle regulation. , 2002, Circulation research.

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

[56]  Fei Ye,et al.  Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. , 2004, The American journal of cardiology.

[57]  E. Willbold,et al.  Generation of confluent cardiomyocyte monolayers derived from embryonic stem cells in suspension: a cell source for new therapies and screening strategies. , 2003, Cytotherapy.

[58]  P. Kang,et al.  Cardiac-Specific Overexpression of Cyclin-Dependent Kinase 2 Increases Smaller Mononuclear Cardiomyocytes , 2001, Circulation research.

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

[60]  T. Strom,et al.  Allogeneic stem cell-derived "repair unit" therapy and the barriers to clinical deployment. , 2004, Journal of the American Society of Nephrology : JASN.

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

[62]  Stefanie Dimmeler,et al.  Unchain my heart: the scientific foundations of cardiac repair. , 2005, The Journal of clinical investigation.

[63]  D. Fiszer,et al.  Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial. , 2005, European heart journal.

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

[65]  L. Field,et al.  Cell Cycle Regulation to Repair the Infarcted Myocardium , 2003, Heart Failure Reviews.

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

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

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

[69]  D. Torella,et al.  Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[70]  I. Komuro,et al.  G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes , 2005, Nature Medicine.

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

[72]  M. Fishbein,et al.  Inducible Activation of c-Myc in Adult Myocardium In Vivo Provokes Cardiac Myocyte Hypertrophy and Reactivation of DNA Synthesis , 2001, Circulation research.

[73]  A. Deten,et al.  Hematopoietic stem cells do not repair the infarcted mouse heart. , 2005, Cardiovascular research.

[74]  G. Koh,et al.  Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice. , 1997, The Journal of clinical investigation.

[75]  R. Ferrari,et al.  Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile. , 2005, European heart journal.

[76]  P. Anversa,et al.  bcl-2 overexpression promotes myocyte proliferation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[77]  F. Prósper,et al.  Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. , 2003, European heart journal.

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

[79]  B. Li,et al.  Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[80]  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.

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

[82]  Steven B. Bradfute,et al.  Cardiac Muscle Plasticity in Adult and Embryo by Heart‐Derived Progenitor Cells , 2004, Annals of the New York Academy of Sciences.

[83]  R. Palmiter,et al.  Heart and bone tumors in transgenic mice. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[84]  J. Epstein,et al.  Smooth Muscle Cells, But Not Myocytes, of Host Origin in Transplanted Human Hearts , 2002, Circulation.

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

[86]  M. Rudnicki,et al.  The post‐natal heart contains a myocardial stem cell population , 2002, FEBS letters.

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

[88]  M. Soonpaa,et al.  Assessment of cardiomyocyte DNA synthesis during hypertrophy in adult mice. , 1994, The American journal of physiology.

[89]  E. B. Katz,et al.  Cardiomyocyte proliferation in mice expressing alpha-cardiac myosin heavy chain-SV40 T-antigen transgenes. , 1992, The American journal of physiology.

[90]  L. Kedes,et al.  Transplantation of fetal myocardial tissue into the infarcted myocardium of rat. A potential method for repair of infarcted myocardium? , 1996, Circulation.

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

[92]  L. Field,et al.  Expression of Mutant p193 and p53 Permits Cardiomyocyte Cell Cycle Reentry After Myocardial Infarction in Transgenic Mice , 2004, Circulation research.

[93]  D. Fiszer,et al.  Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. , 2004, American heart journal.

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

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

[96]  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.

[97]  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.

[98]  M. Soonpaa,et al.  Survey of studies examining mammalian cardiomyocyte DNA synthesis. , 1998, Circulation research.

[99]  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.

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

[101]  Kenneth W Dunn,et al.  Two-photon molecular excitation imaging of Ca2+ transients in Langendorff-perfused mouse hearts. , 2003, American journal of physiology. Cell physiology.

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

[103]  Martin J. Lohse,et al.  Dobutamine-Stress Magnetic Resonance Microimaging in Mice: Acute Changes of Cardiac Geometry and Function in Normal and Failing Murine Hearts , 2001, Circulation research.