Hepatobiliary Differentiation: Principles from Embryonic Liver Development

Abstract

Hepatocytes and biliary epithelial cells (BECs), the two endodermal cell types of the liver, originate from progenitor cells called hepatoblasts. Based principally on in vitro data, hepatoblasts are thought to be bipotent stem cells with the potential to produce both hepatocytes and BECs. However, robust in vivo evidence for this model has only recently emerged. We examine the molecular mechanisms that stimulate hepatoblast differentiation into hepatocytes or BECs. In the absence of extrinsic cues, the default fate of hepatoblasts is hepatocyte differentiation. Inductive cues from the hepatic portal vein, however, initiate transcription factor expression in hepatoblasts, driving biliary specification. Defining the mechanisms of hepatobiliary differentiation provides important insights into congenital disorders, such as Alagille syndrome, and may help to better characterize the poorly understood hepatic lineage relationships observed during regeneration from liver injury.

Therapeutics Development for Alagille Syndrome

“…Notch signaling is a required feature of biliary genesis during liver development with Notch2 accounting for the majority of Notch receptor expressed in fetal livers. Coordination of contact signaling between JAG1 and Notch2 expressing cells results in terminal differentiation to cholangiocytes in the Notch2 expressing hepatoblasts ( Freeburg and Goessling, 2020 ). In histopathological analysis of ALGS livers, a distinct dearth of staining for cholangiocyte-specific signaling factors is observed ( Fabris et al, 2007 ).…”