TNF signaling drives expansion of Reg4+ epithelial cells in colitis.

Gadeock, S.; Girish, N.; Liu, C. Y.; Huang, Y.; Grikscheit, T. C.; Polk, D. B.

doi:10.1101/2025.09.08.674949

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bioRxiv · 10.1101/2025.09.08.674949

TNF signaling drives expansion of Reg4+ epithelial cells in colitis.

Gadeock, S.·Girish, N.·Liu, C. Y.·Huang, Y.·Grikscheit, T. C.·Polk, D. B.

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Abstract

Reg4+ secretory cells are upregulated in colitis and promote epithelial repair, but their regulation is poorly understood. We show that TNF-TNFR1 signaling controls Reg4+ cell numbers in mouse and human colonoids and in vivo, with TNFR1 deficiency reducing these cells and TNF restoring them dose-dependently. In UC patients and DSS-colitis, REG4+ cells mark regenerating crypts, and persistent REG4, DUOX2, and TNFR1 expression identifies non-responders to anti-TNF therapy. These findings reveal a TNFR1-dependent mechanism regulating Reg4+ cells and suggest potential strategies to improve therapeutic responses in IBD.

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Gadeock, S., Girish, N., Liu, C. Y., Huang, Y., Grikscheit, T. C., Polk, D. B.. 2025-09-09. TNF signaling drives expansion of Reg4+ epithelial cells in colitis.. https://doi.org/10.1101/2025.09.08.674949

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