Aleksieva, Niya

Boulter, Luke

Dwyer, Benjamin

Ferreira-Gonzalez, Sofía

Forbes, Stuart J

Gadd, Victoria

Guest, Rachel V

Jamieson, Tam

Leclercq, Isabelle

Lemaigre, Frederic P.

Lu, Wei-Yu

Man, Janet

McCafferty, John

Minnis-Lyons, Sarah

NIxon, Colin

Sansom, O.J.

Van Hul, Noémi

Williams, Michael

English

Edinburgh Research Explorer

Notch-IGF1 signalling in biliary epithelial cells drives their expansion and inhibits hepatocyte differentiation

In the adult liver, a population of facultative progenitor cells called biliary epithelial cells (BECs) proliferate and differentiate into cholangiocytes and hepatocytes after injury, thereby restoring liver function. In mammalian models of chronic liver injury, Notch signaling is essential for bile duct formation from these cells. However, the continual proliferation of BECs and differentiation of hepatocytes in these models have limited their use for determining whether Notch signaling is required for BECs to replenish hepatocytes after injury in the mammalian liver. Here, we used a temporally restricted model of hepatic repair in which large-scale hepatocyte injury and regeneration are initiated through the acute loss of Mdm2 in hepatocytes, resulting in the rapid, coordinated proliferation of BECs. We found that transient, early activation of Notch1- and Notch3-mediated signaling and entrance into the cell cycle preceded the phenotypic expansion of BECs into hepatocytes. Notch inhibition reduced BEC proliferation, which resulted in failure of BECs to differentiate into hepatocytes, indicating that Notch-dependent expansion of BECs is essential for hepatocyte regeneration. Notch signaling increased the abundance of the insulin-like growth factor 1 receptor (IGF1R) in BECs, and activating IGFR signaling increased BEC numbers but suppressed BEC differentiation into hepatocytes. These results suggest that different signaling mechanisms control BEC expansion and hepatocyte differentiation

Minnis-Lyons, Sarah E.

Ferreira-González, Sofía

Man, Tak Yung

Gadd, Victoria L.

Williams, Michael J.

Guest, Rachel V.

Dwyer, Benjamin J.

Nixon, Colin

Van Hul, Noemi

Leclercq, Isabelle A.

Sansom, Owen J.

Forbes, Stuart J.

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Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation

Minnis-Lyon, Sarah E

Ferreira-Gonzalez, Sofia

Williams, Michael J

Dwyer, Benjamin J

Lemaigre, Frédéric

Sansom, Owen J

DIAL UCLouvain

https://www.pure.ed.ac.uk/ws/files/206648387/Minnis_Lyons_et_al_Final_Manuscript_Submission_Final_2021_for_Pure.pdf

Notch-IGF1 signalling in biliary epithelial cells drives their expansion and inhibits hepatocyte differentiation

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