Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation
Sarah E. Minnis-Lyons, Sofía Ferreira-González, Niya Aleksieva, Tak Yung Man, Victoria L. Gadd, Michael J. Williams, Rachel V. Guest, Wei‐Yu Lu, Benjamin J. Dwyer, Thomas Jamieson, Colin Nixon, Noémi Van Hul, Frédéric P. Lemaigre, John McCafferty, Isabelle Leclercq, Owen J. Sansom, Luke Boulter, Stuart J. Forbes
Abstract
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.