Annalisa Buck, Chiara Writz, Max Umbach, Kristina Widemann, Marie Christine Goess, Florian Jokisch, Kamacay Cira, Stefan Reischl, Chunqiao Li, Shiqian Liu, Julia M Heinze, Tina Krammel, Iana Gadjalova, Dirk Wilhelm, Simon Weidlich, Julia Mergner, Andreas Pichlmair, Helmut Friess, Dirk Haller, Selina J Keppler, Klaus-Peter Janssen, Marie-Christin Weber, Philipp-Alexander Neumann
WISP1 links WNT signaling, cytoskeletal remodeling, and metabolism to drive fibroblast-mediated fibrosis in CD. Its neutralization ameliorates fibrotic and inflammatory features, positioning WISP1 as a promising antifibrotic target.
BACKGROUND & AIMS: Intestinal fibrosis remains a debilitating complication of Crohn's disease (CD). Canonical WNT signaling and WNT1 inducible signaling pathway protein (WISP1) are linked to tissue remodeling, but their role in intestinal fibrosis remains unclear. This study aims to elucidate how WISP1 regulates fibroblast activation, metabolic reprogramming, and extracellular matrix (ECM) remodeling as a novel target for stricturing CD.
METHODS: Matched fibrotic, inflamed and non-fibrotic ileal tissue from CD patients was analyzed using bulk RNA-sequencing, spatial transcriptomics and lipidomics. Primary human intestinal fibroblasts were used for in-vitro assays including fatty acid oxidation (FAO), ECM analysis, metabolic flux profiling, and proteome/secretome analysis with or without WISP1 stimulation. A WISP1-neutralizing antibody was tested in a murine fibrosis model.
RESULTS: WISP1 was highly expressed in fibrotic ileum. Spatial transcriptomics revealed fibroblast heterogeneity, with WISP1+ and WNT-associated subsets enriched in fibrotic regions and displaying pro-fibrotic/glycolytic signatures. Histologically, ECM deposition and lipid accumulation were key features in CD fibrosis. WISP1 treatment in-vitro shifted fibroblast metabolism from FAO to glycolysis, ROS (reactive oxygen species) production, promoted adipokine secretion, and induced lipid accumulation. Inhibition of FAO promoted ECM deposition, while PPARα activation restored FAO and reduced collagen production, linking metabolism to fibrogenesis. WISP1-driven fibrosis involved the RHO/ROCK/MRTFA pathway, supported by increased MRTFA/SRF signatures in fibrotic tissue. In-vivo, WISP1 neutralization reduced collagen deposition, ECM complexity, inflammation, and MRTF target gene expression.
CONCLUSION: WISP1 links WNT signaling, cytoskeletal remodeling, and metabolism to drive fibroblast-mediated fibrosis in CD. Its neutralization ameliorates fibrotic and inflammatory features, positioning WISP1 as a promising antifibrotic target.