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The developmental origins of Notch-driven intrahepatic bile duct disorders.

ABSTRACT: The Notch signaling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, cell fate specification, and maintenance of stem and progenitor cell populations. In the vertebrate liver, an absence of Notch signaling results in failure to form bile ducts, a complex tubular network that radiates throughout the liver, which, in healthy individuals, transports bile from the liver into the bowel. Loss of a functional biliary network through congenital malformations during development results in cholestasis and necessitates liver transplantation. Here, we examine to what extent Notch signaling is necessary throughout embryonic life to initiate the proliferation and specification of biliary cells and concentrate on the animal and human models that have been used to define how perturbations in this signaling pathway result in developmental liver disorders.

SUBMITTER: Martinez Lyons A

PROVIDER: S-EPMC8480193 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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The developmental origins of Notch-driven intrahepatic bile duct disorders.

Martinez Lyons Anabel A Boulter Luke L

Disease models & mechanisms 20210922 9

The Notch signaling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, cell fate specification, and maintenance of stem and progenitor cell populations. In the vertebrate liver, an absence of Notch signaling results in failure to form bile ducts, a complex tubular network that radiates throughout the liver, which, in healthy individuals, transports bile from the liver into the bowel. Loss of a functional biliary network through conge ...[more]

PMID: 34549776

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Project description:BackgroundDuring liver development, intrahepatic bile ducts are thought to arise by a unique asymmetric mode of cholangiocyte tubulogenesis characterized by a series of remodeling stages. Moreover, in liver diseases, cells lining the Canals of Hering can proliferate and generate new hepatic tissue. The aim of this study was to develop protocols for three-dimensional visualization of protein expression, hepatic portal structures and human hepatic cholangiocyte tubulogenesis.ResultsProtocols were developed to digitally visualize portal vessel branching and protein expression of hepatic cell lineage and extracellular matrix deposition markers in three dimensions. Samples from human prenatal livers ranging from 7 weeks + 2 days to 15½ weeks post conception as well as adult normal and acetaminophen intoxicated liver were used. The markers included cytokeratins (CK) 7 and 19, the epithelial cell adhesion molecule (EpCAM), hepatocyte paraffin 1 (HepPar1), sex determining region Y (SRY)-box 9 (SOX9), laminin, nestin, and aquaporin 1 (AQP1).Digital three-dimensional reconstructions using CK19 as a single marker protein disclosed a fine network of CK19 positive cells in the biliary tree in normal liver and in the extensive ductular reactions originating from intrahepatic bile ducts and branching into the parenchyma of the acetaminophen intoxicated liver. In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic biliary tree forms through several developmental stages involving an initial transition of primitive hepatocytes into cholangiocytes shaping the ductal plate followed by a process of maturation and remodeling where the intrahepatic biliary tree develops through an asymmetrical form of cholangiocyte tubulogenesis.ConclusionsThe developed protocols provide a novel and sophisticated three-dimensional visualization of vessels and protein expression in human liver during development and disease.

Dataset Information

The developmental origins of Notch-driven intrahepatic bile duct disorders.

Publications

The developmental origins of Notch-driven intrahepatic bile duct disorders.

Similar Datasets

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