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

Dev Cell. 2024 May 6;59(9):1175-1191.e7. doi: 10.1016/j.devcel.2024.03.002. Epub 2024 Mar 22.

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: DMP777; cerulein; ferroptosis; gastric metaplasia; high-dose tamoxifen; metabolic reprogramming; mitochondria; paligenosis; pancreatic acinar-ductal metaplasia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acinar Cells / metabolism
  • Amino Acid Transport System y+* / genetics
  • Amino Acid Transport System y+* / metabolism
  • Animals
  • Chief Cells, Gastric / metabolism
  • Ferroptosis* / physiology
  • Gastric Mucosa / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Metaplasia* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / metabolism
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Reactive Oxygen Species* / metabolism
  • Regeneration* / physiology
  • Stomach* / pathology

Substances

  • Reactive Oxygen Species
  • Amino Acid Transport System y+
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Slc7a11 protein, mouse
  • NF-E2-Related Factor 2
  • Ppargc1a protein, mouse
  • Nfe2l2 protein, mouse
  • glutathione peroxidase 4, mouse
  • spasmolytic polypeptide
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Intercellular Signaling Peptides and Proteins