title: Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration.
abstract: Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31- cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31- cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD) ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV) function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31- cells formed viable grafts and improved LV ejection fraction (EF) (Control, 54.5+/-2.4; MI, 17.6+/-3.1; Cell, 28.2+/-4.2, n = 9, P<0.01). IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/-2.2; n = 9, P<0.01) and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31- cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31- cells revealed that Sca-1+/CD31- cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.
authors.affiliation: Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Qinglu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Piradeep
authors.initials: P
authors.lastname: Suntharalingam
authors.affiliation: Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Arthur H L
authors.initials: AH
authors.lastname: From
authors.affiliation: Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics*; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006335:Heart Injuries / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000235:genetics*; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012038:Regeneration / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I