R-spondin-YAP axis promotes gastric oxyntic gland regeneration and Helicobacter pylori-associated metaplasia in mice


  • A.S. Fischer
  • S. Müllerke
  • A. Arnold
  • J. Heuberger
  • H. Berger
  • M. Lin
  • H.J. Mollenkopf
  • J. Wizenty
  • D. Horst
  • F. Tacke
  • M. Sigal


  • Journal of Clinical Investigation


  • J Clin Invest 132 (21): e151363


  • The stomach corpus epithelium is organized into anatomical units that consist of glands and pits and contain different specialized secretory cells. Acute and chronic injury of the corpus are associated with characteristic changes of cellular differentiation and proliferation. Processes that control cellular differentiation under homeostatic conditions and upon injury are not well understood. R-spondin 3 (Rspo3) is a Wnt signalling enhancer secreted by gastric stromal cells, which controls stem cell homeostasis in different organs. Here we investigated the function of Rspo3 in the corpus during homeostasis, acute injury, and H. pylori infection.Using organoid culture and conditional mouse models, we demonstrate that RSPO3 is a critical driver of secretory cell differentiation in the corpus gland towards parietal and chief cells, while its absence promoted pit cell differentiation. Acute loss of chief and parietal cells induced by high dose tamoxifen - or merely the depletion of LGR5+ chief cells - caused an upregulation of RSPO3 expression, which was required for the initiation of a coordinated regenerative response via the activation of yes-associated protein (YAP) signaling. This response enabled a rapid recovery of the injured secretory gland cells. However, in the context of chronic H. pylori infection, the R-spondin-driven regeneraton was maintained long-term, promoing severe glandular hyperproliferation and the development of premalignant metaplasia.