Study on the differentiation of oval cells for the development of liver-targeted regenerative medicine

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Oval cells of the liver participate in liver regeneration when hepatocytes are prevented from proliferating in response to liver damage. To clarify the role of hepatoma-derived growth factor (HDGF) in the liver regeneration involving oval cells, we examined the expression of HDGFmRNA in the liver undergoing regeneration in the 2-acetylaminofluorene/partial hepatectomy model. Expression levels of HDGFmRNA changed in correlation to the number of oval cells, and its expression was exclusively observed in oval cells. These results suggest that HDGF may play an important role in the proliferation of oval cells, thereby promoting liver regeneration.To assess the usefulness of Oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of osm cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of osm cDNA in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM … More protein in Kupffer cells of the liver, which accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferaion. The apoptosis of hepatocytes and the fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy prior to or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and antiapoptosis of hepatocytes and suggest that osm gene therapy is useful, as preventive and curative means, for the treatment of patients with liver damage. Less