Stricturing Crohn's Disease Single-Cell RNA Sequencing Reveals Fibroblast Heterogeneity and Intercellular...

Area of Science:

• Gastroenterology
• Immunology
• Molecular Biology

Background:

• Crohn's disease (CD) pathogenesis involves fibroblast activation and extracellular matrix deposition, leading to intestinal strictures.
• Understanding fibroblast heterogeneity and function is crucial for identifying novel therapeutic targets in CD strictures.

Purpose of the Study:

• To generate a single-cell RNA sequencing (scRNAseq) atlas of fibroblasts in strictured CD bowel.
• To characterize fibroblast heterogeneity and intercellular communication in CD strictures.
• To validate potential therapeutic targets for CD stricture formation.

Main Methods:

• Performed scRNAseq on 99 tissue samples from 13 CD resections and 7 normal controls, analyzing 409,001 cells.
• Separated samples into mucosa/submucosa and muscularis propria for distinct analysis.
• Validated cadherin-11 (CDH11) as a therapeutic target using molecular and in vivo models.

Main Results:

• Revealed significant fibroblast heterogeneity in strictured CD, primarily in the mucosa/submucosa.
• Identified CXCL14+ and MMP/WNT5A+ fibroblasts as key players in CD stricture signaling.
• Demonstrated broad expression and upregulation of CDH11, confirming its profibrotic role and validating it as a therapeutic target.

Conclusions:

• The study provides a comprehensive scRNAseq atlas of fibroblasts in CD strictures, uncovering novel cellular interactions.
• Cadherin-11 (CDH11) is validated as a promising therapeutic target for mitigating fibrosis in Crohn's disease strictures.
• This resource aids in understanding CD stricture pathogenesis and developing new treatment strategies.