DOP07 Targeting the canonical WNT signalling pathway as a potential novel therapy in Crohn′s associated fibrosis

Abstract Background Crohn’s disease (CD) is characterized by chronic recurrent intestinal inflammation that leads to progressive fibrotic remodelling of the wall. Despite advances in medical therapy for CD, 50% patients still require surgical treatment after 10 years mainly due fibrosis-associated stenosis formation. A specific anti-fibrotic does not yet exist, underlining need further research this area. The exact mechanism fibrosis development CD understood, but WNT signalling has been shown play a critical role other organs. However, WNT-signalling and its potential druggability well characterized. Methods Bulk RNA sequencing was performed uncover important mechanistic pathways participating specimens from with fibrostenosing CD. Non non-inflamed areas same served as controls. To elucidate functional matrix producing fibroblasts, primary cells were isolated both areas. Their flow cytometry, immunofluorescence, sequencing. Protein levels markers target genes assessed using immunofluorescence imaging techniques. Results Gene set enrichment (GAGE) revealed highly upregulated WNT-pathway (p adj < 0.0029) compared matched normal tissue. Flow cytometry an increased population PDPN+, PDGFRa+ mesenchymal segments non-fibrotic These preserve their phenotype vitro showing elevated expression aSMA COL1 FACS. Functional gene analysis showed migratory production capabilities (VIM, COL1A1, FN1). tissue fibroblasts markedly Wnt1 effector WISP1, which In turn, WISP1 led activation canonical pathway, transcription factors (LEF1, MMP7). Conclusion Fibrosis formation associated activated signalling. One druggable protein, downstream could be WISP1. This will investigated our vivo model, propose novel reducing intervention patients.