| First Author | Li H | Year | 2026 |
| Journal | Exp Mol Med | Volume | 58 |
| Issue | 5 | Pages | 1495-1509 |
| PubMed ID | 42062572 | Mgi Jnum | J:389063 |
| Mgi Id | MGI:8350754 | Doi | 10.1038/s12276-026-01716-0 |
| Citation | Li H, et al. (2026) Tetrameric STAT5 regulates the formation of immune niche cells to protect stem cell regenerative repair against mucosal inflammation. Exp Mol Med 58(5):1495-1509 |
| abstractText | How intestinal stem cells (ISCs) are regulated during inflammation remains largely unexplored, leading to a lack of effective treatments for inflammatory bowel diseases (IBD). ISC-mediated intestinal epithelial regenerative repair can be regulated by intra-epithelial T lymphocytes, whose maturation is controlled by STAT5 dimeric or tetrameric activation. However, the mechanisms by which the T lymphocytes can protect ISCs are unclear. Here we hypothesize that tetrameric STAT5 regulates intra-crypt T cells to act as niche cells for ISC regeneration. Using IBD biospecimens, STAT5-hyperactive, tetramer-deficient mice and organoids, we found IBD-ulcerative colitis exhibited more crypt TCRgammadelta(+)STAT5(+) T cells and less ISC pluripotency than healthy patients. Compared with wild-type mice, depleting tetrameric STAT5 in mice significantly increased ISC-mediated intestinal epithelial hyperplasia, TCR gene signatures, crypt TCRgammadelta(+) T cells with elevated STAT5 tyrosine phosphorylation (pYSTAT5) and IL-17A levels, amplified both Lgr5(hi) and Lgr5(low) ISC proliferation and promoted de novo crypt regeneration with increased TCRgammadelta(+) cell influx post irradiation or colitis. By contrast, depleting tetrameric STAT5 in organoids reduced ISC pluripotency and organoid growth post irradiation. Mechanistically, chromatin immunoprecipitation and single-cell RNA sequencing analyses with crypt cells revealed that depleting STAT5 tetramers decreased STAT5-binding on the Metallothionein 1 (Mt1) locus in crypt T cells and increased Mt1 expression, which leads to T cell migration into crypts and enhanced ISC regeneration. Together, the tetrameric STAT5 suppresses the formation of the crypt T cell niche. Interrupting STAT5 tetramers promotes the expansion of crypt TCRgammadelta cells, providing a target for promoting ISC regenerative repair during IBD-ulcerative colitis. |
