The intestinal stem cell (ISC) niche is responsible for coordinating the ongoing maintenance and regeneration of the adult gut. Wnt signalling is crucial for stem cell maintenance in the ISC niche, but the source of Wnts remains unclear. Now, on p. , David Virshup and colleagues show that epithelial production of Wnt is dispensable for intestinal homeostasis in the murine gut in vivo, contrary to in vitro observations. The authors use genetic ablation studies to eliminate either Porcn or Wls, two crucial components of Wnt signalling, specifically in intestinal epithelial cells. The resulting mice from these experiments are phenotypically normal, but cannot form intestinal organoids in vitro when epithelial-derived Wnt is abolished. The authors show that the latter phenotype can be rescued by co-culturing the cells with purified intestinal stromal cells that endogenously produce both Wnt and R-spondin 3, suggesting a requirement for stromal-produced Wnt in gut homeostasis. Inhibition of Wnt signalling with the pan-Wnt inhibitor C59 results in impaired proliferation and regeneration following radiation injury in mice where epithelial Wnt is already ablated, confirming the importance of stromal-derived Wnts.
