title: Maximizing ventricular function with multimodal cell-based gene therapy.
abstract: BACKGROUND
  Angiogenesis is enhanced after transplantation of vascular endothelial growth factor (VEGF)-expressing cells into a myocardial scar. Insulin-like growth factor I (IGF-I) may induce hypertrophy and inhibit apoptosis. We evaluated the effect of cell-based IGF-I and VEGF multigene therapy on left ventricular (LV) function, cell survival, and apoptosis after bone marrow cell (BMC) transplantation.
  
  
  RESULTS
  Female Lewis rats underwent left anterior descending ligation 3 weeks before transplantation with male donor BMC, BMC transfected with VEGF (BMC+VEGF), IGF-I (BMC+IGF-I), VEGF and IGF-I (BMC+VEGF+IGF-I), or medium without cells (control) (n=4 per group x 5 groups x 4 time points). Three days and 1, 2, and 4 weeks after transplantation, VEGF and IGF-I expression was quantitated by real-time polymerase chain reaction, cell survival by polymerase chain reaction for sry2, apoptosis by TUNEL staining, LV function by echocardiography and myosin heavy chain, and light chain and troponin I by Western blot. One week after transplantation, IGF-I expression in the scar and border zone was greatest in BMC+IGF-I and BMC+VEGF+IGF-I rats (P<0.05). VEGF expression in the scar and border zone was greatest in BMC+VEGF and BMC+VEGF+IGF-I hearts (P<0.05). Transplanted cell survival was lowest in BMC, intermediate in BMC+VEGF and BMC+IGF-I, and greatest in BMC+VEGF+IGF-I (P<0.05). Apoptotic indices were significantly reduced in BMC+VEGF+IGF-I, BMC+VEGF, and BMC+IGF-I (P<0.05). Two and 4 weeks after transplantation, LV ejection fraction was lowest in control, intermediate in BMC, BMC+VEGF, and BMC+IGF-I, and greatest in BMC+VEGF+IGF-I (P<0.05).
  
  
  CONCLUSIONS
  Transplantation of VEGF- and IGF-I-expressing BMC reduced apoptosis, maximized transplanted cell survival, and enhanced LV function. Multimodal cell-based gene therapy may maximize the benefits of cell transplantation.
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Hospital, Department of Surgery, University of Toronto, Heart & Stroke Foundation/Richard Lewar Centre of Excellence, Toronto, Ontario, Canada. terry.yau@utoronto.ca
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Yau
authors.forename: Christopher
authors.initials: C
authors.lastname: Kim
authors.forename: Guangming
authors.initials: G
authors.lastname: Li
authors.forename: Yaoguang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D024722:Cardiac Myosins / Q000096:biosynthesis / Q000235:genetics; D002470:Cell Survival; D002478:Cells, Cultured / Q000637:transplantation; D002921:Cicatrix / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D006085:Graft Survival; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D018994:Myosin Light Chains / Q000096:biosynthesis / Q000235:genetics; D018919:Neovascularization, Physiologic; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D013318:Stroke Volume; D014162:Transfection; D019210:Troponin I / Q000096:biosynthesis / Q000235:genetics; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D016277:Ventricular Function, Left
chemical_list: D018994:Myosin Light Chains; D011993:Recombinant Fusion Proteins; D019210:Troponin I; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains