Stromal R-Spondin orchestrates gastric epithelial homeostasis in health and disease. Mus musculus

Gastric epithelial stem cells are responsible for constant epithelial self-renewal, which is accelerated by infection with the gastric pathogen Helicobacter pylori. However, the mechanism that regulates stem cell turnover in the stomach remains unknown. Here we show that signaling by R-spondin 3 and Wnt hierarchically organizes the stem cell compartment in the antrum, producing two Wnt-responsive populations, which are either Lgr5+ve or Axin2 +ve. The positional identity of the Axin2+ve population relies on R-spondin 3 produced by stromal myofibroblasts. Increased availability of R-spondin induces hyperproliferation through specific expansion of Axin2+ve but not Lgr5+ve cells. Similarly, infection with H. pylori induces an increase in stromal R-spondin 3 expression, resulting in hyperplasia as well as shedding of bacteria that have entered the gland. This identifies a role for stromal cells in environmental sensing to orchestrate epithelial homeostasis via Wnt signaling. Overall design: Antral epithelial cells from R-spondin-treated mice and untreated control mice. Microarray experiments were performed as dual-color hybridizations on Agilent whole mouse catalog 4x44K (Agilent-014868) arrays. To compensate for dye-specific effects, a dye-reversal color-swap was applied.