Angiogenic gene cell therapy using suicide gene system regulates the effect of angiogenesis in infarcted rat heart

Shigeru Miyagawa, Yoshiki Sawa, Keiichi Fukuda, Yasuyo Hisaka, Satoshi Taketani, Imran Ahmed Memon, Hikaru Matsuda

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)902-907
Number of pages6
JournalTransplantation
Volume81
Issue number6
DOIs
Publication statusPublished - 2006 Mar

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Cell- and Tissue-Based Therapy
Genetic Therapy
Suicide
Ganciclovir
Genes
Severe Combined Immunodeficiency
Thymidine Kinase
Simplexvirus
Growth
Transfection
Culture Media
Myocardium
Plasmids
Complementary DNA
Arteries
Transplantation

Keywords

  • Gene therapy
  • Heart failure
  • HGF
  • Myocardial infarction

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Angiogenic gene cell therapy using suicide gene system regulates the effect of angiogenesis in infarcted rat heart. / Miyagawa, Shigeru; Sawa, Yoshiki; Fukuda, Keiichi; Hisaka, Yasuyo; Taketani, Satoshi; Memon, Imran Ahmed; Matsuda, Hikaru.

In: Transplantation, Vol. 81, No. 6, 03.2006, p. 902-907.

Research output: Contribution to journalArticle

Miyagawa, Shigeru ; Sawa, Yoshiki ; Fukuda, Keiichi ; Hisaka, Yasuyo ; Taketani, Satoshi ; Memon, Imran Ahmed ; Matsuda, Hikaru. / Angiogenic gene cell therapy using suicide gene system regulates the effect of angiogenesis in infarcted rat heart. In: Transplantation. 2006 ; Vol. 81, No. 6. pp. 902-907.
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abstract = "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.",
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AU - Memon, Imran Ahmed

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N2 - 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.

AB - 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.

KW - Gene therapy

KW - Heart failure

KW - HGF

KW - Myocardial infarction

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