Submitted on February 8, 2007
Accepted on April 2, 2007
Hepatocyte Growth Factor Promotes Colonic Epithelial Regeneration via Akt Signaling
Masami Kanayama1, Terumi Takahara1*, Yutaka Yata1, Feng Xue1, Eiji Shinno2, Kazunobu Nonome2, Hiroshi Kudo1, Kengo Kawai3, Takahiko Kudo3, Yoshiaki Tabuchi4, Akiharu Watanabe5, and Toshiro Sugiyama3
1 Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Toyama, Japan
2 Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Toyama, Japan; Toyama, Toyama, Japan
3 Toyama, Toyama, Japan; Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Toyama, Japan
4 Life Science Research Center, University of Toyama, Toyama, Toyama, Japan
5 Kawasaki University of Medical Welfare, Okayama, Okayama, Japan
* To whom correspondence should be addressed. E-mail: terutaka-tym{at}umin.ac.jp.
Background and Aims: Hepatocyte growth factor (HGF) can promote the regeneration of injured organs, including HGF gene therapy by electroporation (EP) for liver injury. In this study, we investigated the effect of HGF on dextran sulfate sodium (DSS)-induced colitis, and tried to clarify the regenerative mechanisms of colonic epithelial cells and the signaling pathway involved.
Methods: 1) Colitis was induced by DSS in mice, together with HGF gene transfer by EP. On day 10, the colitis was evaluated histologically and by Western blot analysis. 2) The colonic epithelial cell line MCE301 was exposed to HGF protein, and its proliferation and activated signaling pathway were analyzed.
Results: 1) In vivo, the histological score improved and the number of Ki-67 positive epithelial cells increased in the HGF-treated mice compared to the controls. Western blot analysis showed enhanced expression of phospho-Akt in the HGF-treated mice compared to the controls. 2) In vitro, HGF stimulated the proliferation of MCE301 cells. There was enhanced phospho-Akt expression for more than 48 hours after HGF stimulation, although phospho-ERK1/2 was enhanced for only 10 minutes. LY294002 or Akt siRNA suppressed cell proliferation induced by HGF. Thus, HGF induces the proliferation of colonic epithelial cells via the PI3K/Akt signaling pathway.
Conclusions: HGF gene therapy can attenuate acute colitis via epithelial cell proliferation through the PI3K/Akt pathway. These data suggested that HGF gene therapy by EP may be effective for the regeneration and repair of injured epithelial cells in inflammatory bowel disease (IBD).
