Roles of Hepatoma-derived growth factor(HDGF) on the proliferation and differentiation of hepatic stem cells and liver development

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Hepatoma-derived growth factor(HDGF) is a heparin-binding protein, which has been purified the conditioned media of HuH-7 hepatoma cells. Recent studies suggest that HDGF is significantly involved in the development of the liver, cardiovascular system, gut and kidney. In the present study, we investigated the roles of HDGF in the cellular proliferation and differentiation of hepatic progenitor cells, including oval cells, and in the hepatic ontogeny. Hepatic oval cells are one of bipotential hepatic progenitor cells, which can differentiate to both parenchymal hepatocytes and bile duct cells. We analyzed the expression of HDGF in rat liver after acetoaminofluorene/partial hepatectomy treatment by Western blot, Northern blot, immunohistochemisry and in situ hybridization. The expression levels of HDGF by Northern blot and Western blot are parallel to the number of oval cells appeared in the liver. HDGF was expressed in oval cells by in situ hybridization, and more strongly in the nucleu … More s than the cytoplasm by immunohistochemistry. In rat oval cell line, Oct15-5,HDGF was also prominently expressed both in the nucleus and cytoplasm, but in dominantly in the nucleus. Recombinant HDGF mildly stimulated the proliferation of Oct15-5 cells. PPAR-γ ligand, 15d-prostaglandins(PG) J2 inhibited the proliferation of Oct15-5 cells, and significantly suppressed the expression of HDGF. Thus, these data suggest that HDGF plas an important roles on the proliferation of oval cells.We generated HDGF transgenic mouse using albumin promoter. In normal liver, the expression of glucose-6-phoshatase(G-6-Pase) decreases and tryptophan oxygenase(TO) is significantly induced through hepatocyte maturation after birth, however in the liver of HDGF transgenic mouse, the expression of G-6-Pase was not suppressed and TO was not induced at 12 weeks after birth. These findings suggest that the continuous over-expression of HDGF may suppress the differentiation of hepatocytes.Present findings suggest that HDGF should play important roles on the proliferation and differentiation of hepatic progenitor cells in liver ontogeny. Less