Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation

Using temporal multi-omics, biomechanical profiling, and spatial fate mapping in colitis models, we showed that colonic ECM underwent lasting pathological reprogramming following inflammation, which we termed modified (mod)ECM. Characterized by collagen XVIII accumulation and immune-driven proteolysis, modECM redirected intestinal stem cells (ISCs) toward a wound-associated epithelial state with a pro-inflammatory transcriptional program.

Ex vivo, modECM alone reshaped ISC fate by suppressing Wnt signaling and activating immune recruitment pathways. In vivo, modECM-rich zones sustained T cell infiltration and KRT14⁺ epithelial cell emergence from Lgr5⁺ progenitors. This aberrant epithelial program was mirrored in inflamed rectal biopsies from individuals with ulcerative colitis.