Language

English

Publication Date

5-6-2024

Journal

Developmental Cell

DOI

10.1016/j.devcel.2024.03.002

PMID

38521055

Abstract

In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which is critical in lipid radical detoxification through glutathione peroxidase 4 (GPX4), also increases ferroptosis. Finally, we show that PGC1α-mediated ROS and mitochondrial changes also underlie the paligenosis of pancreatic acinar cells. Altogether, the results detail how metabolic and mitochondrial changes are necessary for injury response, regeneration, and metaplasia in the stomach.

Keywords

Animals, Reactive Oxygen Species, Mice, Ferroptosis, Stomach, Regeneration, Amino Acid Transport System y+, Metaplasia, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Mitochondria, NF-E2-Related Factor 2, Gastric Mucosa, Mice, Inbred C57BL, Chief Cells, Gastric, Acinar Cells, Mice, Knockout, Phospholipid Hydroperoxide Glutathione Peroxidase, Intercellular Signaling Peptides and Proteins, DMP777, cerulein, ferroptosis, gastric metaplasia, high-dose tamoxifen, metabolic reprogramming, mitochondria, paligenosis, pancreatic acinar-ductal metaplasia.

Published Open-Access

yes

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