In vivo enhancement of angiogenesis by adenoviral transfer of HIF-1alpha-modified endothelial progenitor cells (Ad-HIF-1alpha-modified EPC for angiogenesis).
Hypoxia inducible factor (HIF)-1alpha over-expression may have beneficial effects in cell therapy of hypoxia-induced pathophysiological processes, such as ischemic disease. Our previous study showed the feasibility of ex vivo modification of endothelial progenitor cells (EPCs) by HIF-1alpha transfection. In this study, we sought to determine if such ex vivo modified EPCs facilitated functional therapeutic neovascularization. Ad-HIF-1alpha was transduced in human EPC in vitro. HIF-1alpha-transduced EPCs were administered to nude mice with hindlimb ischemia. BrdU-labeling of these EPCs showed that they enhanced neovascularization in vivo. Limb and toe necrosis was significantly reduced in HIF-1alpha-EPC group compared to GFP-EPC group and medium control group at 14 days after transplantation (both P<0.05). A statistically significant difference was still observed in the HIF-1alpha group until 1 and 2 months of follow-up. Neovascularization was improved by both histological and physiological assessments. Exogenous EPC homing was observed. HIF-1alpha over-expression enhanced its mRNA and protein expression in the ischemia zone. The expression of genes downstream of HIF-1alpha was examined to explore the possible mechanism of EPC homing. In conclusion, HIF-1alpha-EPC gene transfer augments impaired neovascularization in experimentally induced mouse hindlimb ischemia in vivo.
Jiang
Meng
M
Department of Cardiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Wang
Binyao
B
Wang
Changqian
C
He
Ben
B
Fan
Huahua
H
Shao
Qin
Q
Gao
Li
L
Liu
Yan
Y
Yan
Guofeng
G
Pu
Jun
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D017186:Titrimetry; D014161:Transduction, Genetic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit