BMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation

Marta Kapalczynska, Manqiang Lin, Jeroen Maertzdorf, Julian Heuberger, Stefanie Muellerke, Xiangsheng Zuo, Ramon Vidal, Imad Shureiqi, Anne-Sophie Fischer, Sascha Sauer, Hilmar Berger, Evelyn Kidess, Hans-Joachim Mollenkopf, Frank Tacke, Thomas F. Meyer and Michael Sigal ()
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Marta Kapalczynska: Charité University Medicine
Manqiang Lin: Charité University Medicine
Jeroen Maertzdorf: Max Planck Institute for Infection Biology
Julian Heuberger: Charité University Medicine
Stefanie Muellerke: Charité University Medicine
Xiangsheng Zuo: The University of Texas MD Anderson Cancer Center
Ramon Vidal: Max Delbrück Center for Molecular Medicine
Imad Shureiqi: The University of Texas MD Anderson Cancer Center
Anne-Sophie Fischer: Charité University Medicine
Sascha Sauer: Max Delbrück Center for Molecular Medicine
Hilmar Berger: Charité University Medicine
Evelyn Kidess: Charité University Medicine
Hans-Joachim Mollenkopf: Max Planck Institute for Infection Biology
Frank Tacke: Charité University Medicine
Thomas F. Meyer: Max Planck Institute for Infection Biology
Michael Sigal: Charité University Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Helicobacter pylori causes gastric inflammation, gland hyperplasia and is linked to gastric cancer. Here, we studied the interplay between gastric epithelial stem cells and their stromal niche under homeostasis and upon H. pylori infection. We find that gastric epithelial stem cell differentiation is orchestrated by subsets of stromal cells that either produce BMP inhibitors in the gland base, or BMP ligands at the surface. Exposure to BMP ligands promotes a feed-forward loop by inducing Bmp2 expression in the epithelial cells themselves, enforcing rapid lineage commitment to terminally differentiated mucous pit cells. H. pylori leads to a loss of stromal and epithelial Bmp2 expression and increases expression of BMP inhibitors, promoting self-renewal of stem cells and accumulation of gland base cells, which we mechanistically link to IFN-γ signaling. Mice that lack IFN-γ signaling show no alterations of BMP gradient upon infection, while exposure to IFN-γ resembles H. pylori-driven mucosal responses.

Date: 2022
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DOI: 10.1038/s41467-022-29176-w

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