Expression of hepatocytic- and biliary-specific transcription factors in regenerating bile ducts during hepatocyte-to-biliary epithelial cell transdifferentiation

In addition to previously examined DAPM + BDL model, an experimental model resembling chronic biliary damage was established by repeated administration of DAPM. Hepatocyte to BEC transdifferentiation was tracked using dipetidyl dipeptidase IV (DDPIV) chimeric rats that normally carry DPPIV only in hepatocytes. Following DAPM treatment, ~20% BEC population turned DPPIV-positive, indicating that they are derived from DPPIV-positive hepatocytes. New ductules emerging after DAPM + BDL and repeated DAPM exposure expressed hepatocyte-associated transcription factor hepatocyte nuclear factor (HNF) 4α and biliary specific transcription factor HNF1β. In addition, periportal hepatocytes expressed biliary marker CK19 suggesting periportal hepatocytes as a potential source of transdifferentiating cells. Although TGFβ1 was induced, there was no considerable reduction in periportal HNF6 expression, as observed during embryonic biliary development.Taken together, these findings indicate that gradual loss of HNF4α and acquisition of HNF1β by hepatocytes, as well as increase in TGFβ1 expression in periportal region, appear to be the underlying mechanisms of hepatocyte-to-BEC transdifferentiation.Transdifferentiation of the liver epithelial cells (hepatocytes and biliary cells) into each other provides a rescue mechanism in liver disease under the situations where either cell compartment fails to regenerate by itself. We have previously reported transdifferentiation of hepatocytes into biliary epithelial cells (BEC) both in in vivo rat model using biliary toxicant 4,4'-methylenedianiline [diaminodiphenyl methane, (DAPM)] followed by biliary obstruction induced by bile duct ligation (BDL) [1] and in vitro using hepatocyte organoid cultures treated with hepatocyte growth factor (HGF) and epidermal growth factor (EGF) [2-4]. Other investigators have also demonstrated hepatocyte-to-BEC transdifferentiation in hepatocyte cultures [5] and following hepatocyte transplantation in spleen [6].