Heart infarct in NOD‐SCID mice: Therapeutic vasculogenesis by transplantation of human CD34+ cells and low dose CD34+KDR+ cells

Hematopoietic (Hem) and endothelial (End) lineages derive from a common progenitor cell, the hemangioblast: specifically, the human cord blood (CB) CD34+KDR+ cell fraction comprises primitive Hem and End cells, as well as hemangioblasts. In humans, the potential therapeutic role of Hem and End progenitors in ischemic heart disease is subject to intense investigation. Particularly, the contribution of these cells to angiogenesis and cardiomyogenesis in myocardial ischemia is not well established. In our studies, we induced myocardial infarct (MI) in the immunocompromised NOD‐SCID mouse model, and monitored the effects of myocardial transplantation of human CB CD34+ cells on cardiac function. Specifically, we compared the therapeutic effect of unseparated CD34+ cells vs. PBS and mononuclear cells (MNCs); moreover, we compared the action of the CD34+KDR+ cell subfraction vs. the CD34+KDR– subset. CD34+ cells significantly improve cardiac function after MI, as compared with PBS/MNCs. Similar beneficial actions were obtained using a 2‐log lower number of CD34+KDR+ cells, while the same number of CD34+KDR– cells did not have any effects. The beneficial effect of CD34+KDR+ cells may mostly be ascribed to their notable resistance to apoptosis and to their angiogenic action, since cardiomyogenesis was limited. Altogether, our results indicate that, within the CD34+ cell population, the CD34+KDR+ fraction is responsible for the improvement in cardiac hemodynamics and hence represents the candidate active CD34+ cell subset.

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

[2]  E. Gao,et al.  Post-ischemic myocardial fibrosis occurs independent of hemodynamic changes. , 2003, Cardiovascular research.

[3]  M. Latronico,et al.  ‘Advanced’ generation lentiviruses as efficient vectors for cardiomyocyte gene transduction in vitro and in vivo , 2003, Gene Therapy.

[4]  Arjun Deb,et al.  Bone Marrow–Derived Cardiomyocytes Are Present in Adult Human Heart: A Study of Gender-Mismatched Bone Marrow Transplantation Patients , 2003, Circulation.

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

[6]  Y. Yoon,et al.  Intramyocardial Transplantation of Autologous Endothelial Progenitor Cells for Therapeutic Neovascularization of Myocardial Ischemia , 2003, Circulation.

[7]  C. Peschle,et al.  Identification of the hemangioblast in postnatal life. , 2002 .

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

[9]  N. Ferrara,et al.  VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism , 2002, Nature.

[10]  G. Spangrude,et al.  Chimerism of the transplanted heart. , 2002, The New England journal of medicine.

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

[12]  G. Cossu,et al.  Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: Implications for myocardium regeneration , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  ToyoakiMurohara,et al.  Implantation of Bone Marrow Mononuclear Cells Into Ischemic Myocardium Enhances Collateral Perfusion and Regional Function via Side Supply of Angioblasts, Angiogenic Ligands, and Cytokines , 2001 .

[14]  A. Kosaki,et al.  Implantation of Bone Marrow Mononuclear Cells Into Ischemic Myocardium Enhances Collateral Perfusion and Regional Function via Side Supply of Angioblasts, Angiogenic Ligands, and Cytokines , 2001, Circulation.

[15]  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.

[16]  M. Todaro,et al.  Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function , 2001, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[19]  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.

[20]  J. Isner,et al.  Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor Cells for Myocardial Ischemia , 2001, Circulation.

[21]  J. Isner,et al.  Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Rafii,et al.  Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. , 2000, Blood.

[23]  C. Peschle,et al.  KDR receptor: a key marker defining hematopoietic stem cells. , 1999, Science.

[24]  G. Stassi,et al.  Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. , 1999, Circulation.

[25]  J. Isner,et al.  Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. , 1999, The Journal of clinical investigation.

[26]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.