R-spondin/YAP axis promotes gastric oxyntic gland regeneration and Helicobacter pylori–associated metaplasia in mice
Anne-Sophie Fischer, … , Frank Tacke, Michael Sigal
Anne-Sophie Fischer, … , Frank Tacke, Michael Sigal
Published September 13, 2022
Citation Information: J Clin Invest. 2022;132(21):e151363. https://doi.org/10.1172/JCI151363.
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Research Article Gastroenterology

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

Abstract

The stomach corpus epithelium is organized into anatomical units that consist of glands and pits. Mechanisms that control the cellular organization of corpus glands and enable their recovery upon injury are not well understood. R-spondin 3 (RSPO3) is a WNT-signaling enhancer that regulates stem cell behavior in different organs. Here, we investigated the function of RSPO3 in the corpus during homeostasis, upon chief and/or parietal cell loss, and during chronic Helicobacter 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 toward 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 regeneration was maintained long term, promoting severe glandular hyperproliferation and the development of premalignant metaplasia.

Authors

Anne-Sophie Fischer, Stefanie Müllerke, Alexander Arnold, Julian Heuberger, Hilmar Berger, Manqiang Lin, Hans-Joachim Mollenkopf, Jonas Wizenty, David Horst, Frank Tacke, Michael Sigal

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Figure 6

RSPO3 causes glandular proliferation upon H. pylori infection.

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RSPO3 causes glandular proliferation upon H. pylori infection. (A) H&amp...
(A) H&E staining of 2-month–infected Rspo3-KI mice. (B) Representative immunofluorescence images of costaining for GSII (red) and GIF (green) of sections from noninfected and 2-month–infected Rspo3-WT and Rspo3-KI mice. (C) Representative immunofluorescence images of Ki67 staining (white) and MUC5AC (red) of sections from noninfected and 2-month infected Rspo3-WT and Rspo3-KI mice. (D) Quantification of Ki67+ cells per gland of infected Rspo3-WT (n = 4 mice) and Rspo3-KI mice (n = 5) and noninfected littermate controls (n = 3–4). (E) Quantification of proliferating cells per gland base of infected Rspo3-WT (n = 7) and Rspo3-KI mice (n = 5) and noninfected littermate controls (n = 4–5). (F and H) GSEA of microarray data comparing the expression profile of the corpus tissue from 2-month–infected Rspo3-KI mice and infected littermate controls treated with tamoxifen 2 months before euthanasia with a published data set for (F) SPEM (28). (H) Early gastric cancer (GC) signature (29). (G and I) GSEA of microarray data comparing the expression profile of the corpus tissue from noninfected Rspo3-KI mice and noninfected littermate controls treated with tamoxifen 14 days before euthanasia with a published data set for (G) SPEM (28). (I) Early gastric cancer signature (29). ES, enrichment score; NES, normalized enrichment score. For GSEA, n = 2 mice per group. Scale bars: 100 μm. One-way ANOVA with Tukey’s multiple-comparison test.