Angiogenic gene cell therapy using suicide gene system regulates the effect of angiogenesis in infarcted rat heart.
BACKGROUND
Although angiogenic gene therapy has been reported to be effective in restoring ischemic heart function, there are several obstacles to its clinical application, such as unreliable efficiency of transfection and uncontrollable expression. We developed human HGF (hHGF)-producing cells that regulated hHGF production using the thymidine kinase gene of Herpes Simplex Virus (TK) and the Ganciclovir (GCV) system. We tested whether these cells induced and regulated angiogenic effects in infarcted myocardium.


METHODS
NIH3T3 cells were stably transfected with an hHGF cDNA expression plasmid (NIH/HGF). Next, the NIH/HGF cells were stably transfected with TK (NIH/HGF/TK). The left anterior descending artery was ligated in the heart of severe combined immunodeficiency rats, and four materials were transplanted: 1) NIH/HGF (n=10), 2) NIH/HGF/TK, with orally administered GCV (n=10), 3) NIH3T3 (n=10), and 4) culture medium (n=10).


RESULTS
In vitro, the proliferation of NIH/HGF/TK cells was suppressed by GCV. In vivo, significant increases in cardiac performance and angiogenesis were observed in the NIH/HGF and NIH/HGF/TK groups 4 weeks after transplantation. Although tumorous lesions were detected in the NIH/HGF group, their growth was completely controlled in the NIH/HGF/TK group.


CONCLUSIONS
Angiogenic gene cell therapy using the TK-GCV suicide gene system induces and regulates angiogenesis under the control of cell growth, suggesting it as a promising system for therapeutic angiogenesis.
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0071, Japan.
Shigeru
S
Miyagawa
Yoshiki
Y
Sawa
Keiichi
K
Fukuda
Yasuyo
Y
Hisaka
Satoshi
S
Taketani
Imran Ahmed
IA
Memon
Hikaru
H
Matsuda
D000818:Animals; D005347:Fibroblasts / Q000637:transplantation*; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics*; D014162:Transfection
D017228:Hepatocyte Growth Factor; D013937:Thymidine Kinase; D015774:Ganciclovir