DPR and DM designed the study and reviewed the manuscript. All the authors read and approved the final manuscript.”
“Background 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 this website 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]. In humans, chronic biliary liver diseases (CBLD) characterized by progressive biliary epithelial degeneration are also known to be associated with formation of intermediate hepatobiliary cells expressing both hepatocytic and biliary specific markers [7–9]. However, the mechanisms promoting selleckchem such hepatocyte to BEC transdifferentiation (or vice versa) are not completely understood. In the current study, by repeatedly injuring biliary cells by minimally toxic dose of DAPM administered to rats we established a novel rodent model Neratinib mw resembling CBLD [10]. DAPM selectively injures biliary cells because toxic metabolites of DAPM are excreted in bile [10, 11]. Orchestrated network of liver-enriched transcription factors is known to play an important role in pre- and postnatal liver development as well as in lineage specification of hepatoblasts into
hepatocytes and BECs [12, 13]. Studies with knockout mice have shown that hepatocyte nuclear factor (HNF) 1α and HNF4α regulate transcription of genes essential for the hepatocytic lineage [14–16] whereas HNF1β and HNF6 are involved in development of the gallbladder and bile ducts [17–19]. In the present study, the expression of hepatocyte- and biliary-specific HNFs is examined during reprogramming of cell lineage during transdifferentiation using DAPM + BDL and repeated DAPM treatment models. Gradient of TGFβ expression regulated by Onecut transcription factor HNF6 in ductal plate hepatoblasts during embryonic liver development is crucial for biliary differentiation [20]. In the present study, TGFβ1 and HNF6 expression pattern was studied in order to determine if mTOR inhibitor similar mechanism is recapitulated during hepatocyte to BEC transdifferentiation in the adult liver. The likely source of hepatocytes capable of functioning as progenitor cells in the event of compromised biliary regeneration is investigated by assessing expression of biliary specific keratin CK19.