{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:48:35Z","timestamp":1790639315670,"version":"4.1.0"},"reference-count":58,"publisher":"Portland Press Ltd.","issue":"19","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 \u03b21 (TGF\u03b2) signalling pathways, and assesses the therapeutic potential of small-molecule Wnt inhibitors.<\/jats:p>\n                  <jats:p>\u03b2-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, TGF\u03b2 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 \u03b2-catenin-positive cells. In vitro, activation of Wnt-\u03b2-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of \u03b2-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGF\u03b2 increased \u03b2-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGF\u03b2 up-regulated WNT5B, a noncanonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a \u03b2-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 TGF\u03b2 signalling pathways in CD intestinal fibrosis.<\/jats:p>","DOI":"10.1042\/cs20210889","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T05:00:54Z","timestamp":1664168454000},"page":"1405-1423","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease"],"prefix":"10.1042","volume":"136","author":[{"given":"Amy","family":"Lewis","sequence":"first","affiliation":[{"name":"1Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saray","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"2Cancer Heterogeneity Lab, CIC bioGUNE, 48160 Derio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Berti","sequence":"additional","affiliation":[{"name":"1Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belen","family":"Pan-Castillo","sequence":"additional","affiliation":[{"name":"1Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Nijhuis","sequence":"additional","affiliation":[{"name":"1Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shameer","family":"Mehta","sequence":"additional","affiliation":[{"name":"1Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliane","family":"Eleid","sequence":"additional","affiliation":[{"name":"1Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Gordon","sequence":"additional","affiliation":[{"name":"3Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radha","family":"Gadhok","sequence":"additional","affiliation":[{"name":"3Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Kimberley","sequence":"additional","affiliation":[{"name":"1Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Minicozzi","sequence":"additional","affiliation":[{"name":"4Department of Colorectal Surgery, Division of Surgery & Perioperative Care, The Royal London Hospital, Whitechapel, London E1 1BB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Chin-Aleong","sequence":"additional","affiliation":[{"name":"5Department of Histopathology, The Royal London Hospital, London E1 1BB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Feakins","sequence":"additional","affiliation":[{"name":"6Department of Cellular Pathology, Royal Free London NHS Foundation Trust, 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