Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors

• Type of Material: Article
• Authors: D. H. Wilson, Institute for Genetic and Molecular Medicine, Edinburgh, UK; E. J. Jarman, Institute for Genetic and Molecular Medicine, Edinburgh, UK; R. P. Mellin, Institute for Genetic and Molecular Medicine, Edinburgh, UK; M. L. Wilson, Institute for Genetic and Molecular Medicine, Edinburgh, UK; S. H. Waddell, Institute for Genetic and Molecular Medicine, Edinburgh, UK; P. Tsokkou, Institute for Genetic and Molecular Medicine, Edinburgh, UK; N. T. Younger, Institute for Genetic and Molecular Medicine, Edinburgh, UK; A. Raven, Cancer Research UK Beatson Institute, Glasgow, UK; S. R. Bhalla, University of Nottingham; A. T. R. Noll, Maastricht University; S. W. O. Damink, Maastricht University; F. G. Schaap, Maastricht University; Ping Chen, Emory University; D. O. Bates, University of Nottingham; J. M. Banales, Biodonostia HRI, CIBERehd, Ikerbasque, San Sebastian, Spain; C. H. Dean, Imperial College London; D. J. Henderson, University of Newcastle; O. J. Sansom, University of Glasgow; T. J. Kendall, University of Edinburgh; L. Boulter, MRC Human Genetics Unit, Institute for Genetic and Molecular Medicine, Edinburgh, UK
• Language: English
• Date: 2020-01-23
• Publisher: Nature Publishing Groups
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-14283-3
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 445
• End Page: 445
• Grant/Funding Information: This work was funded by Primary Sclerosing Cholangitis (PSC) Support, The Alan Morement Memorial Foundation (AMMF, The Cholangiocarcinoma Charity) and core funding provided to the MRC Human Genetics Unit, by the Medical Research Council and the Wellcome Trust (207793/Z/17/Z).; T.J.K. was partially funded by a Wellcome Trust Intermediate Clinical Fellowship (095898/Z/11/Z).; O.S. and A.R. were funded by CRUK core funding to the CRUK Beatson Institute (A17196).
• Keywords: Science & Technology; VANGL2 Phosphorylation; Repair; Tissue growth factor; Science & Technology - Other Topics; Fibrosis; Stem-cells; Multidisciplinary Sciences; Model; Liver injury; Pathway; Mutations; Components
• Research Categories: Biology, Microbiology; Biology, Cell; Health Sciences, Pathology

Abstract

The number of patients diagnosed with chronic bile duct disease is increasing and in most cases these diseases result in chronic ductular scarring, necessitating liver transplantation. The formation of ductular scaring affects liver function; however, scar-generating portal fibroblasts also provide important instructive signals to promote the proliferation and differentiation of biliary epithelial cells. Therefore, understanding whether we can reduce scar formation while maintaining a pro-regenerative microenvironment will be essential in developing treatments for biliary disease. Here, we describe how regenerating biliary epithelial cells express Wnt-Planar Cell Polarity signalling components following bile duct injury and promote the formation of ductular scars by upregulating pro-fibrogenic cytokines and positively regulating collagen-deposition. Inhibiting the production of Wnt-ligands reduces the amount of scar formed around the bile duct, without reducing the development of the pro-regenerative microenvironment required for ductular regeneration, demonstrating that scarring and regeneration can be uncoupled in adult biliary disease and regeneration.