PECAM2 Signaling Drives Fibrosis Transition in Crohn's Disease

Overview

This study identifies PECAM2 signaling, particularly via PECAM1–CD38 interaction, as a key driver in the progression from inflammation to fibrosis in Crohn's disease (CD). Spatial transcriptomics combined with single-cell RNA sequencing revealed molecular and cellular changes across disease stages, and CD38 inhibition reduced fibrosis and colitis symptoms in a mouse model.

Background

Crohn's disease is a chronic inflammatory bowel disorder often complicated by fibrotic strictures, which currently lack effective medical treatments and frequently require surgery. Fibrosis arises from chronic inflammation-induced tissue injury, but the molecular mechanisms driving this transition remain poorly understood. Advances in spatial transcriptomics allow mapping of gene expression within tissue architecture, providing new insights into CD pathogenesis. This study leverages spatial transcriptomics and computational analyses to elucidate the cellular and molecular pathways underlying fibrosis development in CD.

Data Highlights

Spatial transcriptomics was performed on 13 surgical specimens from CD patients, including healthy, inflamed, and fibrotic intestinal regions. Integration with single-cell RNA sequencing enabled tracing of cellular transitions. Ligand–receptor interaction and pseudotime analyses identified PECAM2 signaling as a key pathway in fibrosis progression. Immunostaining validated computational findings in an independent patient cohort. In a TNBS-induced chronic colitis mouse model, CD38 inhibition significantly reduced colitis symptoms and colon thickening.

Key Findings

• Intestinal cytoarchitecture is progressively rearranged during chronic inflammation in CD, culminating in fibrosis within the mesenchymal compartment.
• PECAM2 signaling, mediated by PECAM1–CD38 interaction, is identified as a central driver of the transition from inflammation to fibrosis.
• ApoA signaling (APOA1–ABCA interaction) supports epithelial and stromal homeostasis, and its downregulation correlates with fibrosis development.
• Inhibition of CD38 signaling in a TNBS-induced chronic colitis mouse model ameliorates colitis symptoms and reduces colon thickening.
• Spatial transcriptomics combined with single-cell RNA sequencing provides a powerful approach to map disease progression and identify therapeutic targets in CD.

Clinical Implications

Targeting PECAM2 signaling, specifically through CD38 inhibition, represents a promising therapeutic strategy to prevent or reduce fibrotic strictures in Crohn's disease. This approach could potentially reduce the need for invasive surgical interventions. Furthermore, spatial transcriptomics may aid in identifying biomarkers and pathways relevant for early intervention in CD fibrosis.

Conclusion

This study elucidates the pivotal role of PECAM2 signaling in driving fibrosis in Crohn's disease and demonstrates that CD38 blockade can mitigate disease progression in experimental models. These findings offer a novel therapeutic target to address fibrotic complications in CD.

References

1. Original Article 2024 -- Temporal and Spatial Examination of Crohn's Disease Identifies PECAM2 Signaling as a Key Factor in the Transition from Inflammation to Fibrosis