Hepatocyte growth factor promotes colonic epithelial regeneration via Akt signaling

Abstract

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.

Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis

“…[29][30][31] Each of these factors has been described earlier as facilitating intestinal mucosa repair, either through enhancement of cell proliferation or inhibition of epithelial cell apoptosis, or by a combination of both. [32][33][34][35] The therapeutic benefit of MSC reported in this study could be the consequence of releases and synergic effects of multiple paracrine factors. Further research is needed to elucidate this complex issue.…”

Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas

“…These results demonstrated that sprouty-2 induces an increase in functional c-Met in colon cancer cells. Important down-stream effectors of c-Met includes phosphatidylinositol-3kinase (PI3K/Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) that mediate proliferative and pro-survival signals (Kanayama et al, 2007). In colon cancer cells Akt and ERK enhance cell cycle progression and inhibit apoptosis (Vaculova et al, 2006).…”

Intramuscular injection of adenoviral hepatocyte growth factor at a distal site ameliorates dextran sodium sulfate-induced colitis in mice

“…For instance, Hanawa et al (22) reported that administration of the naked HGF gene into the liver attenuated acute colitis in mice, and Kanbe et al (23) showed that intrarectal administration of a plasmid carrying the HGF gene ameliorated DSS-induced colitis in mice. Kanayama et al (24) found that colonic epithelial regeneration is promoted by HGF gene transfer via electroporation. Oh et al (43) reported that HVJ liposomes encapsulating the hHGF gene ameliorated TNBS-induced colitis in mice, and that intrarectal administration of an Ad carrying the HGF gene improved colonic damage in TNBS-induced colitis (21).…”

“…Additionally, Hanawa et al (22) demonstrated the attenuation of mouse DSS colitis by naked gene transfer of rat HGF into the liver, and Kanbe et al (23) reported the amelioration of mucosal damage in DSS colitis by the intrarectal administration of the naked HGF gene. In their study, Kanayama et al (24) demonstrated the promotion of colonic epithelial regeneration by HGF gene transfer through electroporation. Findings by those authors suggest that HGF is potentially an important new treatment modality for promoting the repair of intestinal mucosa in patients with IBD.…”