Metaplastic regeneration in the mouse stomach requires a reactive oxygen species pathway

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. [Display omitted] •scRNA-seq tracked gastric chief-cell mRNA changes during injury-induced metaplasia•Three distinct stages of chief-cell metaplastic reprogramming (paligenosis) were seen•Pgc1α controls late-stage paligenotic cell mitochondrial activity and metabolism•PGC1α-NRF2-xCT-GPX4 axis helps paligenotic cells suppress ferroptotic death Miao et al. provide a single-cell transcriptomic atlas of metaplastic regeneration in the stomach (paligenosis), identifying transcriptional signatures of three distinct stages. Paligenotic cells must control mitochondrial activity in response to ROS using a PGC1α-xCT-GPX4 axis, and failed ROS scavenging blocks paligenosis and promotes cell death by ferroptosis.