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

Minnis-Lyons, S. E. et al. (2021) Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation. Science Signaling, 14(688), eaay9185. (doi: 10.1126/scisignal.aay9185) (PMID:34158399)

Abstract

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.

• Item Type: Articles
• Additional Information: Funding: S.E.M.-L. is funded by a personal Medical Research Council (MRC) Clinical Fellowship. L.B. is funded by the AMMF and the Wellcome Trust (207793/Z/17/Z) and Cancer Research UK (C52499/A27948). R.V.G. is funded by a personal Wellcome Trust fellowship. J.M., W.-Y.L., B.J.D., and S.J.F. are funded by the MRC (MR/K017047/1) and UK Regenerative Medicine Platform (MR/M007588/1). F.P.L. is supported by the Fondation contre le Cancer (2014-125), by the Interuniversity Attraction Pole Programme (Belgian Science Policy, PVII-47), and the FRS-FNRS (Belgium; T.0072.14). N.V.H. and I.A.L. are funded by the Fund for Scientific Medical Research (FRS-FNRS, Belgium), the Fondation contre le Cancer (PDR T.1067.14-P and C/2014/207), and the Belgian Federal Science Policy Office (Interuniversity Attraction Poles program, network P7/83-HEPRO2). CRUK and the European Research Council fund O.J.S. and T.J.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nixon, Mr Colin and Jamieson, Mr Thomas
• Authors: Minnis-Lyons, S. E., Ferreira-González, S., Aleksieva, N., Man, T. Y., Gadd, V. L., Williams, M. J., Guest, R. V., Lu, W.-Y., Dwyer, B. J., Jamieson, T., Nixon, C., Van Hul, N., Lemaigre, F. P., McCafferty, J., Leclercq, I. A., Sansom, O. J., Boulter, L., and Forbes, S. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Science Signaling
• Publisher: American Association for the Advancement of Science
• ISSN: 1945-0877
• ISSN (Online): 1937-9145
• Published Online: 22 June 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Science Signaling 14(688): eaay9185
• Publisher Policy: Reproduced in accordance with the publisher copyright policy