Transdifferentiation of hepatocytes to biliary epithelial cells requires expression of reprogramming factor Oct3/4 (398.8)

Abstract

Transdifferentiation of liver epithelial cells (hepatocytes and biliary cells) into each other provides a rescue mechanism in liver disease under situations where either cell compartment fails to regenerate by itself. The mechanisms underlying such transdifferentiation of terminally differentiated epithelial are not known. Recently we reported that adult rat liver expresses reprogramming factors Oct3/4, Nanog, and KLF4, and their expression is important for hepatocyte proliferation and liver regeneration. To test if reprogramming factor Oct3/4 plays a role in transdifferentiation of hepatocytes to BECs, we used the hepatocyte organoid culture: an in vitro hepatocyte to biliary transdifferentiation model. In this model, primary hepatocytes when plated on collagen coated roller bottles and cultured in presence of HGF, EGF, and dexamethasone, transdifferentiate to form BECs between 6‐8 days in culture. We found that Oct3/4 is upregulated at day 6 in this model as assessed by mRNA and protein levels suggesting its possible involvement in transdifferentiation. When expression of Oct3/4 was blocked in hepatocytes using adenovirus containing Oct shRNA, there was a significant decrease in appearance of biliary cells (compared to controls) as assessed by biliary marker HNF1‐beta, strongly supporting the role of Oct3/4 in transdifferentiation of hepatocyte to biliary epithelial cells. Experiments to investigate mechanisms through which Oct3/4 might regulate transdifferentiation are under way.Grant Funding Source: 1. Pathology Post‐doctoral Research Training grant, 2. Center for chronic diseases of aging grant