SMOC2 mediates GLI1+ mesenchymal cell-driven fibrostenosis and predicts postoperative recurrence in Crohn's disease.

BACKGROUND

Fibrostenosis is a common and disabling complication of Crohn's disease (CD) with no reliable early biomarkers, limited treatment options and high postoperative recurrence.

OBJECTIVE

To investigate the contribution of glioma-associated oncogene homolog 1 (GLI1+) mesenchymal cells to fibrostenotic progression and their potential as a therapeutic target.

DESIGN

Fibrotic and non-fibrotic tissue samples were collected from patients with CD undergoing surgery for fibrostenotic obstruction. Chronic colitis was induced in mice using dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Single-cell RNA sequencing was performed on human and murine intestinal tissues. Gli1-CreERT2; R26-tdTomato and Gli1-CreERT2; R26-iDTR mice were used for lineage tracing and targeted cell ablation. GLI1+ mesenchymal cells were isolated to identify pathogenic determinants. A surgical CD fibrostenosis cohort was analysed.

RESULTS

Single-cell transcriptomics and immunofluorescence revealed enrichment of GLI1+ mesenchymal cells at fibrotic sites. Lineage tracing showed that these cells expanded and adopted a myofibroblast phenotype in chronic colitis, whereas their ablation alleviated fibrosis. GLI1+ mesenchymal cells exhibited a distinct transcriptional expression profile with prominent expression of SPARC-related modular calcium-binding protein 2 (SMOC2). SMOC2 was upregulated in human and murine fibrosis, and its knockdown in vivo and in vitro attenuated fibrosis. Mechanistically, GLI1+ mesenchymal cells secreted SMOC2, promoting extracellular matrix deposition and fibroblast activation. In surgical CD cohorts, high SMOC2 expression in intestinal tissue correlated with postoperative recurrence, confirmed in the validation cohort.

CONCLUSION

GLI1+ mesenchymal cells drive intestinal fibrostenosis through SMOC2-mediated niche formation. SMOC2 may serve as a predictive biomarker for postoperative recurrence and a potential therapeutic target for CD.