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

Zhi-Feng Miao; Jing-Xu Sun; Xuan-Zhang Huang; Shi Bai; Min-Jiao Pang; Jia-Yi Li; Han-Yu Chen; Qi-Yue Tong; Shi-Yu Ye; Xin-Yu Wang; Xiao-Hai Hu; Jing-Ying Li; Jin-Wei Zou; Wen Xu; Jun-Hao Yang; Xi Lu; Jason C Mills; Zhen-Ning Wang

doi:10.1016/j.devcel.2024.03.002

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

Dev Cell. 2024 Mar 19:S1534-5807(24)00142-4. doi: 10.1016/j.devcel.2024.03.002. Online ahead of print.

Authors

Zhi-Feng Miao¹, Jing-Xu Sun², Xuan-Zhang Huang², Shi Bai², Min-Jiao Pang², Jia-Yi Li², Han-Yu Chen², Qi-Yue Tong², Shi-Yu Ye², Xin-Yu Wang², Xiao-Hai Hu², Jing-Ying Li², Jin-Wei Zou², Wen Xu², Jun-Hao Yang², Xi Lu², Jason C Mills³, Zhen-Ning Wang⁴

Affiliations

¹ Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China. Electronic address: zfmiao@cmu.edu.cn.
² Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China.
³ Section of Gastroenterology & Hepatology, Department of Medicine, Departments of Pathology & Immunology, Molecular and Cellular Biology, Baylor College of Medicine, 535E Anderson-Jones Building, One Baylor Plaza, Houston, TX, USA. Electronic address: jason.mills@bcm.edu.
⁴ Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China. Electronic address: znwang@cmu.edu.cn.

PMID: 38521055
DOI: 10.1016/j.devcel.2024.03.002

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.