Journal of Crohn's & colitis · 2025
Spatiotemporal analysis of Crohn's disease reveals PECAM2 signaling at the basis of the inflammation-to-fibrosis transition.
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Massimino Luca, Parigi Tommaso Lorenzo, Riva Matteo, Nicolò Sabrina, Errico Carmela, Spanò Salvatore, Mino Sara, Bugatti Mattia, Frontali Alice, Scarfò Federico, Vignali Andrea, Municchi Andrea, Villanacci Vincenzo, Albarello Luca, Ponzoni Maurilio, Solitano Virginia, Malesci Alberto, Jairath Vipul, Peyrin-Biroulet Laurent, Sileri Pierpaolo, Danese Silvio, Ungaro Federica
Аннотация
BACKGROUND AND AIMS: Crohn's disease (CD) is a chronic inflammatory disease of the bowel, often complicated by fibrotic strictures, for which medical treatment is lacking, and surgery is commonly required. The mechanisms underlying the progression from chronic inflammation to fibrosis are not yet defined. We aim to unravel CD pathogenesis using a cutting-edge computational pipeline combining several available tools.
METHODS: Spatial transcriptomics was performed on 13 surgical specimens, including inflamed and fibrotic CD tissues and healthy controls. The resulting spatial data were integrated with single-cell RNA sequencing to trace the cellular and molecular transitions from healthy intestine to fibrotic tissue. Ligand-receptor interaction and pseudotime analyses were employed to infer dynamic cell-cell communication networks and lineage trajectories. Key computational findings were validated through immunostaining in an independent cohort of CD patients. Finally, the therapeutic relevance of the identified target was evaluated in a TNBS-induced chronic colitis mouse model upon CD38 inhibitor administration.
RESULTS: We demonstrated that intestinal cytoarchitecture was rearranged while chronic inflammation progressed. CD-associated fibrosis evolved within the mesenchymal compartment, driven by PECAM2 signaling through the PECAM1-CD38 interaction. In parallel, ApoA signaling, particularly the APOA1-ABCA interaction, emerged as relevant for maintaining epithelial and stromal homeostasis, while its downregulation was associated with fibrosis development. Moreover, inhibition of CD38 signaling effectively reduced colitis symptoms and colon thickening in the experimental TNBS-induced model of chronic inflammation.
CONCLUSIONS: Our results provide insights into CD38-driven fibrosis and indicate that blockade of PECAM2 signaling could reduce the development of strictures in patients with CD, potentially offering a new treatment target.
METHODS: Spatial transcriptomics was performed on 13 surgical specimens, including inflamed and fibrotic CD tissues and healthy controls. The resulting spatial data were integrated with single-cell RNA sequencing to trace the cellular and molecular transitions from healthy intestine to fibrotic tissue. Ligand-receptor interaction and pseudotime analyses were employed to infer dynamic cell-cell communication networks and lineage trajectories. Key computational findings were validated through immunostaining in an independent cohort of CD patients. Finally, the therapeutic relevance of the identified target was evaluated in a TNBS-induced chronic colitis mouse model upon CD38 inhibitor administration.
RESULTS: We demonstrated that intestinal cytoarchitecture was rearranged while chronic inflammation progressed. CD-associated fibrosis evolved within the mesenchymal compartment, driven by PECAM2 signaling through the PECAM1-CD38 interaction. In parallel, ApoA signaling, particularly the APOA1-ABCA interaction, emerged as relevant for maintaining epithelial and stromal homeostasis, while its downregulation was associated with fibrosis development. Moreover, inhibition of CD38 signaling effectively reduced colitis symptoms and colon thickening in the experimental TNBS-induced model of chronic inflammation.
CONCLUSIONS: Our results provide insights into CD38-driven fibrosis and indicate that blockade of PECAM2 signaling could reduce the development of strictures in patients with CD, potentially offering a new treatment target.