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Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease

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Title: Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease
Authors: Lewis, A
Sánchez, S
Berti, G
Pan-Castillo, B
Nijhuis, A
Mehta, S
Eleid, L
Gordon, H
Gadhok, R
Kimberley, C
Minicozzi, A
Chin-Aleong, J
Feakins, R
Kypta, R
Lindsay, JO
Silver, A
Item Type: Journal Article
Abstract: Intestinal fibrosis and stricture formation is an aggressive complication of Crohns disease (CD), linked to increased morbidity and costs. The present study investigates the contribution of Wingless-Int-1 (Wnt) signalling to intestinal fibrogenesis, considers potential cross-talk between Wnt and transforming growth factor β1 (TGFβ) signalling pathways, and assesses the therapeutic potential of small-molecule Wnt inhibitors. β-catenin expression was explored by immunohistochemistry (IHC) in formalin-fixed paraffin embedded (FFPE) tissue from patient-matched nonstrictured (NSCD) and strictured (SCD) intestine (n=6 pairs). Functional interactions between Wnt activation, TGFβ signalling, and type I collagen (Collagen-I) expression were explored in CCD-18Co cells and primary CD myofibroblast cultures established from surgical resection specimens (n=16) using small-molecule Wnt inhibitors and molecular techniques, including siRNA-mediated gene knockdown, immunofluorescence (IF), Wnt gene expression arrays, and western blotting. Fibrotic SCD tissue was marked by an increase in β-catenin-positive cells. In vitro, activation of Wnt-β-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of β-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGFβ increased β-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGFβ up-regulated WNT5B, a noncanonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a β-catenin-independent mechanism. Treatment of CCD-18Co fibroblasts and patient-derived myofibroblasts with the FZD8 inhibitor 3235-0367 reduced extracellular matrix (ECM) expression. Our data highlight small-molecule Wnt inhibitors of both canonical and noncanonical Wnt signalling, as potential antifibrotic drugs to treat SCD intestinal fibrosis. They also highlight the importance of the cross-talk between Wnt and TGFβ signalling pathways in CD intestinal fibrosis.
Issue Date: 14-Oct-2022
Date of Acceptance: 23-Sep-2022
URI: http://hdl.handle.net/10044/1/100280
DOI: 10.1042/cs20210889
ISSN: 0143-5221
Publisher: Portland Press Ltd.
Start Page: 1405
End Page: 1423
Journal / Book Title: Clinical Science
Volume: 136
Issue: 19
Copyright Statement: © 2022 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
Keywords: Cardiovascular System & Hematology
11 Medical and Health Sciences
Publication Status: Published
Open Access location: https://portlandpress.com/clinsci/article/136/19/1405/231861/Small-molecule-Wnt-inhibitors-are-a-potential
Online Publication Date: 2022-10-14
Appears in Collections:Department of Surgery and Cancer

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