Intercellular interaction between FAP+ fibroblasts and CD150+ inflammatory monocytes mediates fibrostenosis in Crohn’s disease
Bo-Jun Ke, … , Séverine Vermeire, Gianluca Matteoli
Bo-Jun Ke, … , Séverine Vermeire, Gianluca Matteoli
Published July 23, 2024
Citation Information: J Clin Invest. 2024;134(16):e173835. https://doi.org/10.1172/JCI173835.
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Research Article Gastroenterology Inflammation

Intercellular interaction between FAP+ fibroblasts and CD150+ inflammatory monocytes mediates fibrostenosis in Crohn’s disease

Abstract

Crohn’s disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced 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) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.

Authors

Bo-Jun Ke, Saeed Abdurahiman, Francesca Biscu, Gaia Zanella, Gabriele Dragoni, Sneha Santhosh, Veronica De Simone, Anissa Zouzaf, Lies van Baarle, Michelle Stakenborg, Veronika Bosáková, Yentl Van Rymenant, Emile Verhulst, Sare Verstockt, Elliott Klein, Gabriele Bislenghi, Albert Wolthuis, Jan Frič, Christine Breynaert, Andre D’Hoore, Pieter Van der Veken, Ingrid De Meester, Sara Lovisa, Lukas J.A.C. Hawinkels, Bram Verstockt, Gert De Hertogh, Séverine Vermeire, Gianluca Matteoli

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Figure 4

Heterogeneity of myeloid cells in fibrostenotic CD.

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Heterogeneity of myeloid cells in fibrostenotic CD. (A and B) UMAP repre...
(A and B) UMAP representation of reclustered myeloid cells (A) and cell subset composition (B) across different lesions of the terminal ileum. (C) Heatmap showing the expression of the top marker genes of each myeloid subset. (D) Dot plot showing NicheNet-predicted ligands expressed by myeloid cell subsets. (E) Selected GO terms significantly enriched in myeloid cell subsets. (F) CellPhoneDB dot plot showing ligand-receptor interactions between FAP+ fibroblasts and inflammatory monocytes or neutrophils. First and second interacting molecules correspond to first and second cell types on the y axis, respectively. Black circles indicate significant interactions. (G and H) Flow cytometry gating strategy for myeloid cell subpopulations (G) and plot of CD150 (SLAMF1) expression (H) in CD14+ myeloid cells (7-AAD–CD45+CD3–CD19–CD56–HLA-DR+/–) in different lesions of terminal ileum from 19 CD patients and 8 CRC control ilea. Data are shown as box-and-whisker plots. Statistically significant differences were determined using a 1-way ANOVA test corrected with Tukey’s multiple-comparison test (**P <0.01, ***P <0.005, ****P <0.001). (I) Immunofluorescence staining for CD68, CD150, and FAP expression in healthy ileum and CD diseased ileum. Original image composed of stitched ×25 images. Scale bars: 200 μm in top panels, 100 μm in bottom panels. White arrowheads indicate the spot of colocalization.