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 2

Heterogeneity of stromal cells in fibrostenotic CD.

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Heterogeneity of stromal cells in fibrostenotic CD. (A) UMAP representat...
(A) UMAP representation of reclustered mesenchymal cells across different lesions of the terminal ileum. (B) Heatmap showing relative expression of top marker genes in each subset. (C) Cell subset composition across different lesions of the terminal ileum. (D) Bar plot showing gene set module score for core matrisome collagen genes in each stromal cell subset in different lesions. Horizontal lines indicate medians of respective lesions. (E) Enrichment analysis for Reactome biological pathways in FAP+ fibroblasts (log fold change > 0.5; FDR < 0.1). (F and G) Flow cytometry gating strategy for fibroblast subsets (F) and plot of FAP expression in pan-fibroblasts (7-AAD–CD45–CD31–CD326–PDPN+THY1+) (G) 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). (H) Immunofluorescence staining for PDPN, ADAMDEC1 (indicated by white arrowheads), CD34, and FAP expression in healthy ileum and CD diseased ileum. CD34 and FAP colocalization is indicated by orange arrowheads (scale bars: 200 μm). (I) Heatmap showing relative transcription factor activity in each stromal cell subset based on single-cell regulatory network inference and clustering (SCENIC) analysis. (J) Heatmap showing selected terms after functional enrichment analysis of top 5 regulons using GO terms and core ECM gene set from MatrisomeDB (*statistically significant terms after 1-sided Fisher’s exact test and multiple correction by Benjamini-Hochberg method). (K) Immunofluorescence staining for TWIST1 and CD34 expression in FAP+ fibroblasts in CD diseased ileum (indicated by arrowheads; scale bar: 50 μm).