Intercellular interaction between FAP fibroblasts and CD150 inflammatory monocytes mediates fibro-stenosis in Crohn's disease

Ke, B.-J.; Abdurahiman, S.; Biscu, F.; Dragoni, G.; Santhosh, S.; De Simone, V.; Zouzaf, A.; van Baarle, L.; Stakenborg, M.; Bosakova, V.; Van Rymenant, Y.; Verhulst, E.; Verstockt, S.; Bislenghi, G.; Wolthuis, A.; Fric, J.; Breynaert, C.; D'Hoore, A.; Van Der Veken, P.; De Meester, I.; Verstockt, B.; de Hertogh, G.; Vermeire, S.; Matteoli, G.

doi:10.1101/2023.05.04.539383

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bioRxiv · 10.1101/2023.05.04.539383

Intercellular interaction between FAP fibroblasts and CD150 inflammatory monocytes mediates fibro-stenosis in Crohn's disease

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Abstract

Crohns disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibro-stenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate complex intercellular interactions leading to fibro-stenosis in CD, we analysed the transcriptome of cells isolated from the transmural ileum of CD patients, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from non-CD patients. Our computational analysis revealed that pro-fibrotic signals from a subset of monocyte-derived cells expressing CD150 induce a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) production. Therapeutic inhibition of TWIST1 inhibits fibroblast activation, reducing ECM production and deposition. These findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibro-stenosis in CD.

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Ke, B.-J., Abdurahiman, S., Biscu, F., Dragoni, G., Santhosh, S., De Simone, V., Zouzaf, A., van Baarle, L., Stakenborg, M., Bosakova, V., Van Rymenant, Y., Verhulst, E., Verstockt, S., Bislenghi, G., Wolthuis, A., Fric, J., Breynaert, C., D'Hoore, A., Van Der Veken, P., De Meester, I., Verstockt, B., de Hertogh, G., Vermeire, S., Matteoli, G.. 2023-05-04. Intercellular interaction between FAP fibroblasts and CD150 inflammatory monocytes mediates fibro-stenosis in Crohn's disease. https://doi.org/10.1101/2023.05.04.539383

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