PECAM2-CD38 Signaling Drives Crohn's Disease Fibrosis — A New Therapeutic Target

Crohn's disease (CD) affects millions globally and frequently progresses to fibrostenotic complications requiring surgery. Despite the prevalence of intestinal strictures — occurring in over 50% of patients — no medical therapy exists to prevent or reverse fibrosis. Understanding the precise molecular and cellular transitions from chronic inflammation to fibrosis has remained elusive, partly because prior bulk and single-cell RNA sequencing lacked spatial context.

To address this gap, the authors performed spatial transcriptomics (10x Visium) on 13 FFPE surgical specimens from CD ileocecal resections, strategically sampling healthy margins, intermediate inflammatory-fibrotic zones, and maximally strictured areas from each specimen. These spatial datasets were integrated with published single-cell RNA sequencing data, enabling cellular deconvolution and the mapping of specific cell-type transitions across disease stages. Pseudotime analysis with Monocle 3 traced lineage trajectories, while CellChat v2 reconstructed ligand–receptor communication networks across the inflammation-to-fibrosis continuum.

The central finding was the identification of PECAM2 signaling — operating through the PECAM1–CD38 ligand–receptor axis — as the primary driver of mesenchymal fibrotic remodeling in CD. As inflammation progressed toward fibrosis, this pathway became progressively activated within the stromal compartment, reshaping intestinal cytoarchitecture. In parallel, ApoA signaling (specifically APOA1–ABCA interactions) was found to maintain epithelial and stromal homeostasis in healthy tissue, with its downregulation correlating with fibrotic transition. These computational findings were independently validated by CD38 immunohistochemistry in a separate cohort of CD patients processed at the University of Brescia.

To test therapeutic relevance, the team employed a TNBS-induced chronic colitis mouse model. Female C57BL/6 mice received escalating TNBS doses over 7 weeks, with or without a CD38 inhibitor (15 mg/kg intraperitoneally, three times weekly starting at week 4). CD38 inhibition significantly reduced disease activity index scores, colitis symptoms, and colon thickening compared to TNBS-only controls, providing in vivo proof-of-concept that blocking this pathway can attenuate fibroinflammatory disease.

These findings reframe CD-associated fibrosis as a process with identifiable, targetable molecular checkpoints. The PECAM2–CD38 axis represents a novel therapeutic avenue for stricture prevention, and the study demonstrates that spatiotemporal transcriptomics is a powerful discovery platform for complex inflammatory diseases. Caveats include the relatively small human cohort, use of FFPE tissue (which can affect RNA quality), and the need for further validation in human fibroblast systems and larger clinical studies.