A role of hepatocyte growth factor in regulation of hepatic development and differentiation

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Induction of hepatic differentiation of iPS cells requires multiple steps including induction of endodermal, hepatic endodermal, and hepatic progenitor cells, and maturation of hepatocytes. In this study, we found that, HGF increased albumin and alpha-fetoprotein expression in hepatic endodermal cells, which were induced in embryoid bodies of iPS cells treated with Activin A, bFGF, followed by BMP-2 and FGF-4 exposure. These results indicate that HGF plays an essential role in hepatic differentiation of hepatic endodermal cells. Conversely, hepatic endodermal cells expressed Dlk1, but not EpCAM, meaning the possibility that hepatoblast-like cells exist in the hepatic endodermal cells. The findings in this study contribute to establishment of novel cell transplantation therapies for intractable liver diseases using HGF-induced high efficient hepatic differentiation. Conversely, HGF is also essential for repair and regeneration of various injured tissues. Actually, HGF stimulated migration of gastric epithelial cells through modification of tight junction proteins, resulting in increased epithelial restitution in an in vitro ulcer model. Additionally, administration of HGF decreased pulmonary arterial pressure in a rat model of pulmonary arterial hypertension, resulting in prolonged animal survival. These results also indicate that HGF itself is a potent therapeutic agent for various intractable diseases.