Single-cell transcriptomics uncovers EGFR signaling-mediated gastric progenitor cell differentiation in stomach homeostasis

Hitomi Takada, Yohei Sasagawa, Mika Yoshimura, Kaori Tanaka, Yoshimi Iwayama, Tetsutaro Hayashi, Ayako Isomura-Matoba, Itoshi Nikaido () and Akira Kurisaki ()
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Hitomi Takada: Graduate School of Science and Technology, Nara Institute of Science and Technology
Yohei Sasagawa: Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research
Mika Yoshimura: Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research
Kaori Tanaka: Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research
Yoshimi Iwayama: Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research
Tetsutaro Hayashi: Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research
Ayako Isomura-Matoba: Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research
Itoshi Nikaido: Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research
Akira Kurisaki: Graduate School of Science and Technology, Nara Institute of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Defects in gastric progenitor cell differentiation are associated with various gastric disorders, including atrophic gastritis, intestinal metaplasia, and gastric cancer. However, the mechanisms underlying the multilineage differentiation of gastric progenitor cells during healthy homeostasis remain poorly understood. Here, using a single-cell RNA sequencing method, Quartz-Seq2, we analyzed the gene expression dynamics of progenitor cell differentiation toward pit cell, neck cell, and parietal cell lineages in healthy adult mouse corpus tissues. Enrichment analysis of pseudotime-dependent genes and a gastric organoid assay revealed that EGFR-ERK signaling promotes pit cell differentiation, whereas NF-κB signaling maintains gastric progenitor cells in an undifferentiated state. In addition, pharmacological inhibition of EGFR in vivo resulted in a decreased number of pit cells. Although activation of EGFR signaling in gastric progenitor cells has been suggested as one of the major inducers of gastric cancers, our findings unexpectedly identified that EGFR signaling exerts a differentiation-promoting function, not a mitogenic function, in normal gastric homeostasis.

Date: 2023
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DOI: 10.1038/s41467-023-39113-0

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