Hepatocyte Growth Factor (HGF) for a Cell-Signal-Based Therapy During Acute and Chronic Liver Diseases

Kiyomasa      Oka; Kazuhiro      Fukuta; Shinya      Mizuno

Abstract

It has been more than 25 years since HGF was discovered as a mitogen of adult rat hepatocytes. HGF is produced in stromal cells, and stimulates epithelial cell proliferation, motility, morphogenesis and angiogenesis in various organs via tyrosine phosphorylation of its receptor, c-Met. There is now growing evidence to show that stroma-derived HGF is important for organogenesis in embryo and a recovery from diseased conditions in adults. In the liver, HGF has mitogenic, morphogenic and anti-apoptotic effects on hepatocytes and endothelium. HGF exerts anti-inflammatory functions via direct effect on hepatic macrophages during sepsis. Notably, HGF targets hepatic myofibroblasts and elicits anti-fibrogenic responses, resulting in resolution of liver cirrhosis. Inversely, the inhibition of HGF-c-Met signals by anti-HGF antibody, or c-Met gene destruction, leads to the accelerated progression of hepatitis. These findings demonstrated that HGF-c-Met axis confers a host defense system to “minimize” acute and chronic hepatitis. Under pathological conditions, however, HGF production is insufficient and occasionally retarded, and such a loss in self-repair system allow for progression of hepatic failure. Based on these backgrounds, we emphasized a rationale for exogenous HGF supplement therapy during hepatitis. The present review focuses on both the physiological roles of HGF in liver regeneration and the therapeutic potential of HGF-c-Met signaling to prevent or restore liver diseases. “Growth factor therapy” to treat hepatitis may open up an avenue for the future development of other cell-signal transduction therapies.

Keywords: HGF, c-Met, liver regeneration, hepatitis and cirrhosis, growth factor therapy, anti-apoptosis, anti-necrosis, anti-inflammation, anti-fibrosis, steatosis hepatis, alcholic hepatitis, septic hepatitis, cholestasis, gene therapy, HGF cDNA, stem cell biology, hepatic fibrosis, cirrhosis, TGF-beta, PDGF, Extracellular matrix, Sinusoidal cells, Kupffer cells, Hepatic stellate cells