Subepithelial myofibroblasts enhance stem cell regeneration after intestinal epithelial damage

When intestinal stem cells (ISCs) are damaged, other epithelial cells de-differentiate to restore the ISC compartment. Immune, nerve and lymphatic endothelial cells contribute signals that promote this response, but it is unclear whether or how the native mesenchymal niche senses and responds to ISC loss. In homeostasis, trophocytes and smooth muscle beneath intestinal crypts secrete BMP inhibitors (BMPi) and R-spondins to foster ISC self-renewal, whereas sub-epithelial myofibroblasts (SEMFs) concentrated at crypt tops promote differentiation through bone morphogenetic proteins (BMPs). We assessed transcriptional responses in mouse sub-epithelial populations after ablating ISCs with whole-body irradiation and treating Lgr5DTR mice with diphtheria toxin. More than any other cell type, SEMFs modulated expression of genes related to ISC expansion. However, the BMPi gene Smoc1 and non-canonical Wnt signals, both expressed in SEMFs after whole-body irradiation, were dispensable for ISC restoration. Instead, SEMFs appear to support ISC regeneration through factors that are not induced by ISC attrition per se but by local inflammation. These findings reveal unexpectedly limited transcriptional modulation of the native niche after ISC losses and context-dependent signaling functions for SEMFs.