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

D.H. Wilson, E.J. Jarman, R.P. Mellin, M.L. Wilson, S.H. Waddell, P. Tsokkou, N.T. Younger, A. Raven, S.R. Bhalla, A.T.R. Noll, S.W.O. Damink, F.G. Schaap, P. Chen, D.O. Bates, J.M. Banales, C.H. Dean, D.J. Henderson, O.J. Sansom, T.J. Kendall, L. Boulter*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Web of Science)

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. In fibrotic biliary disease, portal fibroblasts promote both biliary scarring and bile duct regeneration. Here, the authors report that the non-canonical Wnt-PCP signalling promotes bile duct scarring in mice, and inhibition of Wnt-ligands reduces the scarring without impairing regeneration.
Original languageEnglish
Article number445
Number of pages13
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 23 Jan 2020

Keywords

  • components
  • fibrosis
  • liver-injury
  • model
  • mutations
  • pathway
  • repair
  • stem-cells
  • tissue growth-factor
  • vangl2 phosphorylation
  • FIBROSIS
  • STEM-CELLS
  • COMPONENTS
  • MODEL
  • VANGL2 PHOSPHORYLATION
  • REPAIR
  • TISSUE GROWTH-FACTOR
  • LIVER-INJURY
  • PATHWAY
  • MUTATIONS

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