title: Synergistic effects of autologous cell and hepatocyte growth factor gene therapy for neovascularization in a murine model of hindlimb ischemia.
abstract: Autologous cell implantation and angiogenic gene therapy have been evaluated in critical limb ischemic patients. Here, we compared the features of these strategies individually and in combination. C57BL/6J mice with ischemic hindlimbs were injected with adherent mononuclear cells (aMNCs) from bone marrow or adenovirus encoding the hepatocyte growth factor (HGF) gene (Ad-HGF). Under comparable angiogenic conditions, 10 x 10(5) aMNCs produced significantly higher amounts of VEGF and FGF-2 and stimulated the number of arterioles in ischemic muscle compared with 1 x 10(8) plaque-forming units (pfu) of Ad-HGF. Ad-HGF produced 10 times more HGF in ischemic muscle compared with aMNCs. Injection of 0.3 x 10(5) aMNCs previously transfected with Ad-HGF (aMNC/Ad-HGF) increased blood flow and elevated the numbers of capillaries and arterioles to levels comparable with that seen with 10 x 10(5) aMNCs or 1 x 10(8) pfu of Ad-HGF. Hypoxic conditions induced the apoptotic death of aMNCs. However, coincubation with HGF or aMNC/Ad-HGF protected cells against apoptosis. HGF stimulated the migration of aMNCs, and the migration capacity of the aMNC/Ad-HGF group was significantly higher than that in the aMNC/Ad-LacZ group. In conclusion, cell-based HGF gene therapy decreased the number of cells required for neovascularization. This strategy can be an effective angiogenic therapy.
authors: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori Univ, Yonago, Tottori 683-8504, Japan. yasutaka@grape.med.tottori-u.ac.jp
authors: Yasutaka
authors: Y
authors: Yamamoto
authors: Takashi
authors: T
authors: Matsuura
authors: Genta
authors: G
authors: Narazaki
authors: Miyoko
authors: M
authors: Sugitani
authors: Kohei
authors: K
authors: Tanaka
authors: Akihiro
authors: A
authors: Maeda
authors: Goshi
authors: G
authors: Shiota
authors: Kenzo
authors: K
authors: Sato
authors: Akio
authors: A
authors: Yoshida
authors: Ichiro
authors: I
authors: Hisatome
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D006614:Hindlimb; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D020127:Recovery of Function; D012039:Regional Blood Flow; D013997:Time Factors; D014162:Transfection; D014182:Transplantation, Autologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor