Language

English

Publication Date

6-6-2024

Journal

Cell Stem Cell

DOI

10.1016/j.stem.2024.04.016

PMID

38733994

PMCID

PMC11162331

PubMedCentral® Posted Date

6-6-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Parietal cells (PCs) produce gastric acid to kill pathogens and aid digestion. Dysregulated PC census is common in disease, yet how PCs differentiate is unclear. Here, we identify the PC progenitors arising from isthmal stem cells, using mouse models and human gastric cells, and show they preferentially express cell-metabolism regulator and orphan nuclear receptor Estrogen-related receptor gamma (Esrrg, encoding ERRγ). Esrrg expression facilitated the tracking of stepwise molecular, cellular, and ultrastructural stages of PC differentiation. EsrrgP2ACreERT2 lineage tracing revealed Esrrg expression commits progenitors to differentiate into mature PCs. scRNA-seq indicated the earliest Esrrg+ PC progenitors preferentially express SMAD4 and SP1 transcriptional targets and the GTPases regulating acid-secretion signal transduction. As progenitors matured, ERRγ-dependent metabolic transcripts predominated. Organoid and mouse studies validated the requirement of ERRγ for PC differentiation. Our work chronicles stem cell differentiation along a single lineage in vivo and suggests ERRγ as a therapeutic target for PC-related disorders.

Keywords

Animals, Cell Differentiation, Receptors, Estrogen, Mice, Parietal Cells, Gastric, Stem Cells, Humans, Gastric Acid, Cell Lineage

Published Open-Access

yes

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