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Nat Cell Biol. 2019 Jul;21(7):812-823. doi: 10.1038/s41556-019-0339-9. Epub 2019 Jun 24.

R-spondin-3 induces secretory, antimicrobial Lgr5+ cells in the stomach.

Author information

1
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany. michael.sigal@charite.de.
2
Department of Hepatology and Gastroenterology, Charité University Medicine, Berlin, Germany. michael.sigal@charite.de.
3
Berlin Institute of Health, Berlin, Germany. michael.sigal@charite.de.
4
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
5
Department of Hepatology and Gastroenterology, Charité University Medicine, Berlin, Germany.
6
Max Delbrück Center for Molecular Medicine (BIMSB) and BIH, Berlin, Germany.
7
Department of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
8
Division of Gastroenterology, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA.
9
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany. meyer@mpiib-berlin.mpg.de.

Abstract

Wnt signalling stimulated by binding of R-spondin (Rspo) to Lgr-family members is crucial for gastrointestinal stem cell renewal. Infection of the stomach with Helicobacter pylori stimulates increased secretion of Rspo by myofibroblasts, leading to an increase in proliferation of Wnt-responsive Axin2+Lgr5- stem cells in the isthmus of the gastric gland and finally gastric gland hyperplasia. Basal Lgr5+ cells are also exposed to Rspo3, but their response remains unclear. Here, we demonstrate that-in contrast to its known mitogenic activity-Rspo3 induces differentiation of basal Lgr5+ cells into secretory cells that express and secrete antimicrobial factors, such as intelectin-1, into the lumen. The depletion of Lgr5+ cells or the knockout of Rspo3 in myofibroblasts leads to hypercolonization of the gastric glands with H. pylori, including the stem cell compartment. By contrast, systemic administration or overexpression of Rspo3 in the stroma clears H. pylori from the gastric glands. Thus, the Rspo3-Lgr5 axis simultaneously regulates both antimicrobial defence and mucosal regeneration.

PMID:
31235935
DOI:
10.1038/s41556-019-0339-9

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