Genetic vulnerability to Crohn's disease reveals a spatially resolved epithelial restitution program

Area of Science:

• Gastroenterology
• Molecular Biology
• Regenerative Medicine

Background:

• Effective tissue repair relies on intricate intercellular communication to manage damage and restore function.
• Understanding these communication pathways is crucial for addressing diseases like Crohn's, which involve impaired healing.

Purpose of the Study:

• To investigate the role of a Crohn's disease risk variant, HGFAC R509H, in intestinal mucosal healing.
• To map intercellular communication during wound healing at single-cell and spatial resolution.

Main Methods:

• Single-cell and spatial transcriptomics to analyze gene expression and cell interactions.
• Genetic manipulation in mice (Hgfac R509H) to study the variant's impact on healing.
• In vitro organoid coculture models to dissect specific cell signaling circuits.

Main Results:

• The HGFAC R509H variant impairs the activation of macrophage-stimulating protein (MSP), a key growth factor.
• Reduced MSP activation leads to defective wound-associated epithelial (WAE) cell differentiation and delayed colon healing in mice.
• WAE cells produce a localized retinoic acid (RA) gradient that directs fibroblast-mediated tissue remodeling.

Conclusions:

• The HGFAC R509H variant disrupts a critical damage-sensing pathway, linking coagulation to growth factor signaling and RA gradients.
• This genetic defect impairs WAE cell induction and fibroblast remodeling, leading to delayed intestinal wound healing.
• The study provides a spatially resolved mechanistic model of tissue healing, informed by a human disease-associated genetic variant.