Spatial fibroblast niches define Crohn's fistulae

Area of Science:

• Gastroenterology
• Cell Biology
• Tissue Engineering

Background:

• Crohn's disease frequently causes fistulae, abnormal intestinal tracts impacting patient morbidity.
• The molecular mechanisms underlying fistula formation are poorly understood due to challenges in studying these complex structures.

Purpose of the Study:

• To create a detailed spatial atlas of intestinal fistulae in Crohn's disease.
• To identify and characterize cellular states and molecular pathways involved in fistula development and persistence.

Main Methods:

• Construction of a subcellular-resolution spatial atlas of 68 intestinal fistulae.
• Analysis of epithelial, immune, and stromal cell populations within fistula tracts.
• Examination of growth factor zonation, extracellular matrix architecture, and fibroblast behavior.

Main Results:

• Identification of distinct fistula-associated stromal (FAS) fibroblast populations organized in concentric layers.
• Characterization of abnormal growth factor zonation linked to the development of tunnelling anatomy.
• Association of FAS fibroblasts with specific collagen structures, showing diverse functional properties from proliferation to fibrosis.
• Definition of niches supporting fistula epithelialization and identification of similar cells in Crohn's disease ulcers.

Conclusions:

• Common molecular pathways and cellular niches underlie fistulae across different intestinal locations.
• Fistula-associated stromal (FAS) fibroblasts are key cellular players in the establishment and persistence of Crohn's disease fistulae.
• This spatial atlas provides a resource for developing improved model systems and therapeutic interventions targeting fibroblast activity.