Hepatocyte growth factor promotes colonic epithelial regeneration via Akt signaling.
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-induced colitis and tried to clarify the regenerative mechanisms of colonic epithelial cells and the signaling pathway involved. Colitis was induced by dextran sulfate sodium in mice, together with HGF gene transfer by EP. On day 10, the colitis was evaluated histologically and by Western blot analysis. The colonic epithelial cell line MCE301 was exposed to HGF protein, and its proliferation and activated signaling pathway were analyzed. In vivo, the histological score improved and the number of Ki-67-positive epithelial cells increased in the HGF-treated mice compared with the controls. Western blot analysis showed enhanced expression of phospho-Akt in the HGF-treated mice compared with the controls. In vitro, HGF stimulated the proliferation of MCE301 cells. There was enhanced phospho-Akt expression for more than 48 h after HGF stimulation, although phospho-ERK1/2 was enhanced for only 10 min. LY-294002 or Akt small interfering RNA suppressed cell proliferation induced by HGF. Thus HGF induces the proliferation of colonic epithelial cells via the phosphatidylinositol 3-kinase/Akt signaling pathway. 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.
Kanayama
Masami
M
Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Takahara
Terumi
T
Yata
Yutaka
Y
Xue
Feng
F
Shinno
Eiji
E
Nonome
Kazunobu
K
Kudo
Hiroshi
H
Kawai
Kengo
K
Kudo
Takahiko
T
Tabuchi
Yoshiaki
Y
Watanabe
Akiharu
A
Sugiyama
Toshiro
T
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D016264:Dextran Sulfate; D018274:Electroporation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015316:Genetic Therapy; D017228:Hepatocyte Growth Factor / Q000494:pharmacology* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects*; D015398:Signal Transduction
D002867:Chromones; D005419:Flavonoids; D007093:Imidazoles; D009025:Morpholines; D011725:Pyridines; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017228:Hepatocyte Growth Factor; D016264:Dextran Sulfate; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one