Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis

The constant regeneration of stomach epithelium is driven by long-lived stem cells(1-3), but the mechanism that regulates their turnover is not well understood. We have recently found that the gastric pathogen Helicobacter pylori can activate gastric stem cells and increase epithelial turnover(4), while Wnt signalling is known to be important for stem cell identity and epithelial regeneration in several tissues(5). Here we find that antral Wnt signalling, marked by the classic Wnt target gene Axin2, is limited to the base and lower isthmus of gastric glands, where the stem cells reside. Axin2 is expressed by Lgr5(+) cells, as well as adjacent, highly proliferative Lgr(5-) cells that are able to repopulate entire glands, including the base, upon depletion of the Lgr5(+) population. Expression of both Axin2 and Lgr5 requires stroma-derived R-spondin 3 produced by gastric myofibroblasts proximal to the stem cell compartment. Exogenous R-spondin administration expands and accelerates proliferation of Axin2(+)/Lgr5(-) but not Lgr5(+) cells. Consistent with these observations, H. pylori infection increases stromal R-spondin 3 expression and expands the Axin2(+) cell pool to cause hyperproliferation and gland hyperplasia. The ability of stromal niche cells to control and adapt epithelial stem cell dynamics constitutes a sophisticated mechanism that orchestrates epithelial regeneration and maintenance of tissue integrity.