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 Stem cells

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 1

RSPO3 controls secretory cell differentiation in corpus glands.

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RSPO3 controls secretory cell differentiation in corpus glands. (A) qPCR...
(A) qPCR for expression of Rspo1–4 in Bl6 mice (n = 4). (B) ISH of Rspo3 (red) in corpus tissue of a nontreated MYH11-CreERT2; Rspo3WT/WT control mouse. (C) qPCR for Rspo3 expression in Rspo3-KO mice (n = 3) versus littermate controls (n = 4) and MYH11CreERT2-Rosa26CagRspo3 (Rspo3 KI) (n = 6) versus littermate controls (n = 6). (D) Immunofluorescence labeling for Ki67 (white) representative of Rspo3-KO and Rspo3-KI mice and littermate controls. (E) Location and relative size of the Ki67-positive gland compartment. (F) Quantification of the number of Ki67+ nuclei per gland in Rspo3-KO and Rspo3-KI mice and corresponding littermate controls (n = 3 mice per group). (G) Immunofluorescence labeling for GIF (green) representative of Rspo3-KO and Rspo3-KI mice and littermate controls. (H) Location and relative size of GIF-positive gland compartment. (I) Quantification of the number of GIF+ cells per gland in Rspo3-KO and Rspo3-KI mice and corresponding littermate controls (n = 3 mice per group). (J) Immunofluorescence labeling for GSII (red) representative of Rspo3-KO and Rspo3-KI mice and littermate controls. (K) Location and relative size of the GSII-positive gland compartment. (L) Quantification of the number of GSII+ cells per gland in Rspo3-KO and Rspo3-KI mice and corresponding littermate controls (n = 3 mice per group). (M) Immunofluorescence images of H/K-ATPase labeling (gray) in sections representative of Rspo3-KO and Rspo3-KI mice and corresponding littermate controls. (N) Quantification of parietal cells per gland in Rspo3-KO and Rspo3-KI mice and corresponding littermate controls (n = 3 mice per group). Mice were treated with tamoxifen 2 weeks before euthanasia. Scale bars: 100 μm. Enlargements in M equal 8:1 magnification. Unpaired parametric t test (C, E, F, H, and K); 1-way ANOVA with Tukey’s multiple-comparison test (A, I, and L).