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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/H1329    most recent 00321.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yamamoto, Y. Articles by Hisatome, I. PubMed PubMed Citation Articles by Yamamoto, Y. Articles by Hisatome, I.

Synergistic effects of autologous cell and hepatocyte growth factor gene therapy for neovascularization in a murine model of hindlimb ischemia

¹Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, ²Division of Molecular Biology, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, and ³Division of Molecular and Genetic Medicine, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Tottori, Japan

Submitted April 2, 2009 ; accepted in final form August 6, 2009

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 10⁵ aMNCs produced significantly higher amounts of VEGF and FGF-2 and stimulated the number of arterioles in ischemic muscle compared with 1 x 10⁸ 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 10⁵ 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 10⁵ aMNCs or 1 x 10⁸ 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.

angiogenesis; apoptosis