Dio2+Il11+ fibroblasts constitute a local stromal-endocrine niche that promotes intestinal stem cell regeneration after immune-mediated injury

Abstract Immune-mediated damage depletes intestinal stem cells (ISCs) and their homeostatic niche. Whether inflammatory injury induces an alternative niche that promotes regeneration remains unknown. Using single-cell spatial transcriptomics in murine gastrointestinal graft-versus-host disease, we identified cytotoxic CD8⁺ T cells accumulated near intestinal crypts coinciding with ISC, Paneth cell depletion, and epithelial death pathway activation. A distinct Dio2⁺ Il11⁺ fibroblast population emerged in regions of maximal intestinal damage between the epithelial progenitors and stromal cells. These fibroblasts expressed cAMP-response and immune-recruitment programs, suggesting niche reorganization. Thyroid hormone receptor antagonism reduced organoid budding, whereas enhancing thyroid hormone signaling promoted morphogenesis, particularly with IL-11, linking local T3 and IL-11 secretion by these Dio2⁺ Il11⁺ cells to ISC regeneration. Similar niches were observed in DSS-induced colitis model and in biopsies from patients with Crohn’s disease. Our data identify Dio2⁺ Il11⁺ fibroblasts as a stromal-endocrine niche at the site of immune injury that supports ISC regeneration.