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.
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BibTeX
@misc{reddy2026dio2il11,
title = {{Dio2+Il11+ fibroblasts constitute a local stromal-endocrine niche that promotes intestinal stem cell regeneration after immune-mediated injury}},
author = {Pavan Reddy and Takashi Ikeda and Akira Yamamoto and Tyler Leach and Kelli McCord and Lihong Xu and Meng-Chih Wu and Yuichi Sumii and Neelam Bodhale and Yui Kambara and Victoria Ontiveros and Ana Santibanez and Dongchang zhao and Yaping Sun and Laure Maneix and William Hudson},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-11143774/v1},
url = {https://doi.org/10.21203/rs.3.rs-11143774/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Dio2+Il11+ fibroblasts constitute a local stromal-endocrine niche that promotes intestinal stem cell regeneration after immune-mediated injury
AU - Pavan Reddy
AU - Takashi Ikeda
AU - Akira Yamamoto
AU - Tyler Leach
AU - Kelli McCord
AU - Lihong Xu
AU - Meng-Chih Wu
AU - Yuichi Sumii
AU - Neelam Bodhale
AU - Yui Kambara
AU - Victoria Ontiveros
AU - Ana Santibanez
AU - Dongchang zhao
AU - Yaping Sun
AU - Laure Maneix
AU - William Hudson
PY - 2026
DA - 2026/10/16
PB - Research Square
DO - 10.21203/rs.3.rs-11143774/v1
UR - https://doi.org/10.21203/rs.3.rs-11143774/v1
AB - 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.
SN - 2693-5015
ER -