Development of the Intrahepatic and Extrahepatic Biliary Tract: A Framework for Understanding Congenital Diseases

Abstract

The involvement of the biliary tract in the pathophysiology of liver diseases and the increased attention paid to bile ducts in the bioconstruction of liver tissue for regenerative therapy have fueled intense research into the fundamental mechanisms of biliary development. Here, I review the molecular, cellular and tissular mechanisms driving differentiation and morphogenesis of the intrahepatic and extrahepatic bile ducts. This review focuses on the dynamics of the transcriptional and signaling modules that promote biliary development in human and mouse liver and discusses studies in which the use of zebrafish uncovered unexplored processes in mammalian biliary development. The review concludes by providing a framework for interpreting the mechanisms that may help us understand the origin of congenital biliary diseases.

NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocyte reprogramming into intrahepatic cholangiocarcinoma

“…Given that SB-HDTVI induces HC-driven ICC in AKT-NICD and AKT-YAP mouse models (8,11), we first explored if any of these ICC driver genes are actually evident in HCs of patients with chronic liver diseases that are known ICC risk factors. By immunohistochemistry (IHC), we examined any evidence of active AKT signaling (phospho-Ser473-AKT or p-AKT) and nuclear localization of SOX9 and YAP, both known targets of NICD (15,18), in liver samples from patients with non-alcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC), known risk factors for CCA (10,19). We identified significant aberrant induction of cytoplasmic and nuclear p-AKT (p=0.024), nuclear SOX9 (p=0.0008) or nuclear YAP (p=0.047) in subsets of HCs in all patients (n=20), whereas these markers were rarely detected in hepatocytes of healthy controls (Fig.1A, Fig.S1A and S1B, Table S1).…”

“…In Akt-NICD-ICC formation, YAP, but not SOX9, appears to be essential for completion of HC-to-BEC reprogramming since its deletion resulted in incomplete repression of HNF4. Indeed, YAP has been shown to be critical for biliary lineage commitment (15,43) as well as malignant HC-to-BEC trans-differentiation through the regulation of Notch-SOX9 cascade in the absence of Notch activity (27). However, in Akt-NICD-driven ICC development, we revealed a novel molecular mechanism: YAP regulates DNMT1 provoking HC-to-BEC conversion when Notch signaling is active, indicating the context-dependent diverse molecular mechanisms and crosstalk of these well studied biliary drivers in committing biliary fate in diseased liver.…”

“…Sox9 and Yap are well known biliary-specific Notch target genes or regulators of Notch signaling, and hence critical in BEC maturation and bile duct morphogenesis in murine development (15). Expression of YAP or SOX9 is prevalent in human ICC and positively correlates with clinical grade (16,17).…”

A fully defined pluripotent stem cell derived multi-liver-cell model for steatohepatitis and fibrosis

“…Finally, we also detected 13.4% of cells with a cholangiocyte phenotype, suggesting the creation of biliary ducts from the d8-PSC-hepatoblasts. Cholangiocyte differentiation from bipotent hepatoblasts is governed by a number of cell-extrinsic signals emanating from mesenchymal structures adjacent to bile ducts (reviewed in (Lemaigre, 2020)). This includes signaling by TGFβ derived from the periportal mesenchyme to commit hepatoblasts to ductal plate cells, and JAGGED1, also expressed in the periportal mesenchyme, which activates the NOTCH2 signaling pathway to support cholangiocyte differentiation.…”

Hepatobiliary Differentiation: Principles from Embryonic Liver Development

“…The morphological changes underlying bile duct formation have been reviewed extensively. 45 Intrahepatic biliary specification is spatially restricted, occurring in close proximity to the hepatic portal vein in response to inductive signaling molecules (►Fig. 2C).…”