Effects of TNFR1 deletion on gene expression in mouse colonoic epithelial organoids

Colonic deep crypt secretory cells are a recently identified population of Paneth-like cells located near the base of the colonic crypt. In mice, these cells express the marker gene Reg4 and contribute to the maintenance of the epithelial stem cell niche during normal cellular turnover and repair. During colitis, the epithelium adopts a regenerative program that involves the upregulation of proliferative activity, reprogramming of stem cells, and increased expression of Reg4. Whether these changes are associated with increased deep crypt secretory cell specification and how they could be linked to the inflammatoy milieu of colonic injury remain to be resolved. Here, we demonstrate in human specimens that inflammatory bowel disease induces a population of Reg4+ cells at the base of the colonic crypt. In mice, murine organoids, and human organoids, we find that tumor necrosis factor (TNF) amplified the specification of deep crypt secretory cells, and that this effect depends on the expression of tumor necrosis factor receptor 1 (TNFR1). Thus, TNF signaling links colonic inflammation to the differentiation of a specialized deep crypt secretory cell type that may promote epithelial regenerative function.