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TWIST1+FAP+ fibroblasts in the pathogenesis of intestinal fibrosis in Crohn’s disease
Yao Zhang, … , Duowu Zou, Bing Su
Yao Zhang, … , Duowu Zou, Bing Su
Published July 18, 2024
Citation Information: J Clin Invest. 2024;134(18):e179472. https://doi.org/10.1172/JCI179472.
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Research Article Gastroenterology Article has an altmetric score of 3

TWIST1+FAP+ fibroblasts in the pathogenesis of intestinal fibrosis in Crohn’s disease

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Abstract

Intestinal fibrosis, a severe complication of Crohn’s disease (CD), is characterized by excessive extracellular matrix (ECM) deposition and induces intestinal strictures, but there are no effective antifibrosis drugs available for clinical application. We performed single-cell RNA sequencing (scRNA-Seq) of fibrotic and nonfibrotic ileal tissues from patients with CD with intestinal obstruction. Analysis revealed mesenchymal stromal cells (MSCs) as the major producers of ECM and the increased infiltration of its subset FAP+ fibroblasts in fibrotic sites, which was confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomic profiling of chronic dextran sulfate sodium salt murine colitis model revealed that CD81+Pi16– fibroblasts exhibited transcriptomic and functional similarities to human FAP+ fibroblasts. Consistently, FAP+ fibroblasts were identified as the key subtype with the highest level of ECM production in fibrotic intestines. Furthermore, specific knockout or pharmacological inhibition of TWIST1, which was highly expressed by FAP+ fibroblasts, could significantly ameliorate fibrosis in mice. In addition, TWIST1 expression was induced by CXCL9+ macrophages enriched in fibrotic tissues via IL-1β and TGF-β signal. These findings suggest the inhibition of TWIST1 as a promising strategy for CD fibrosis treatment.

Authors

Yao Zhang, Jiaxin Wang, Hongxiang Sun, Zhenzhen Xun, Zirui He, Yizhou Zhao, Jingjing Qi, Sishen Sun, Qidi Yang, Yubei Gu, Ling Zhang, Chunhua Zhou, Youqiong Ye, Ningbo Wu, Duowu Zou, Bing Su

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Figure 5

The interaction between FAP+ fibroblasts and CXCL9+ macrophages.

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The interaction between FAP+ fibroblasts and CXCL9+ macrophages.
(A) Rep...
(A) Representative multiplex immunofluorescence (mIF) staining of human fibrotic (right) and nonfibrotic (left) intestinal tissue (original magnification, ×20). DAPI (blue), FAP (red), TWIST1 (green), vimentin (white), CD68 (orange), and CXCL9 (purple) in individual and merged channels are shown. Scale bar: 100 μm. A high-power field (bottom) showing close colocalization between FAP+ fibroblasts (red arrows) and CXCL9+ macrophages (green arrows). The experiment was performed in 4 patients. (B) Quantitative analysis of mIF staining. Proportion of CXCL9+ macrophages to CD68+ cells between fibrotic and nonfibrotic intestinal samples (left); the proportion of CXCL9+ macrophages near to FAP+ fibroblasts (within 30 μm) and far from FAP+ fibroblasts (of 30 μm) per field in fibrosis states (right) was calculated by HALO software (n = 12, 4 patients with 3 fields). Statistical differences were determined by t test. (C) Heatmap showing the activity of the top-ranked ligands inferred to regulate FAP+ fibroblasts by CXCL9+ macrophages according to NicheNet (left), the ligand–receptor interaction between them ordered by ligand activity (middle), and the downstream target genes in FAP+ fibroblasts (right).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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