@article{d2f7c0a4997946c4847d5409b34043e6,
title = "Cystine/Glutamate Antiporter (xCT) Is Required for Chief Cell Plasticity After Gastric Injury",
abstract = "Background & Aims: Many differentiated epithelial cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic chief cells into a metaplastic cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in chief cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of chief cells into SPEM. Methods: Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed. Results: xCT was up-regulated early as chief cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for chief cell reprogramming into SPEM after gastric injury in vivo. Chief cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development. Conclusions: The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for chief cell plasticity and ROS detoxification.",
keywords = "Autophagy, CD44, Cellular Plasticity, Chief Cell, Metaplasia, Oxyntic Atrophy, Reactive Oxygen Species, Reprogramming, SPEM, Sulfasalazine, xCT",
author = "Meyer, {Anne R.} and Engevik, {Amy C.} and Willet, {Spencer G.} and Williams, {Janice A.} and Yong Zou and Massion, {Pierre P.} and Mills, {Jason C.} and Eunyoung Choi and Goldenring, {James R.}",
note = "Funding Information: Funding These studies were supported by grants from a Department of Veterans Affairs Merit Review Award IBX000930, National Institutes of Health RO1 DK101332, and Department of Defense CA160479 (J.R.G.); National Institutes of Health R01s DK094989, DK105129, and DK110406 (J.C.M.); by Department of Defense CA160399, American Association of Cancer Research-Debbie's Dream Foundation grant 17-20-41-CHOI, pilot grants from National Institutes of Health P30 DK058404, and ACS IRG-15-169-56 (E.C.); by an American Association of Cancer Research-Debbie's Dream Foundation Grant (S.G.W.); by National Institutes of Health T32 GM008554 and F31 DK117592 (A.R.M.); by National Institutes of Health F32 DK111101 (A.C.E.); by National Cancer Institute grant CA102353 and Department of Defense W81XWH-11-2-0161 (Y.Z. and P.P.M.); by core resources of the Vanderbilt Digestive Disease Center (National Institutes of Health P30 DK058404); Washington University Digestive Disease Research Core Center (National Institutes of Health P30 DK052574); Translational Pathology Shared Resource and Cell Imaging Shared Resource (National Cancer Institute/National Institutes of Health Cancer Center Support grant 2P30 CA068485); and imaging was supported by the Vanderbilt Digital Histology Shared Resource supported by a VA shared instrumentation grant (1IS1BX003097). Funding These studies were supported by grants from a Department of Veterans Affairs Merit Review Award IBX000930, National Institutes of Health RO1 DK101332, and Department of Defense CA160479 (J.R.G.); National Institutes of Health R01s DK094989, DK105129, and DK110406 (J.C.M.); by Department of Defense CA160399, American Association of Cancer Research- Debbie's Dream Foundation grant 17-20-41-CHOI, pilot grants from National Institutes of Health P30 DK058404, and ACS IRG-15-169-56 (E.C.); by an American Association of Cancer Research- Debbie's Dream Foundation Grant (S.G.W.); by National Institutes of Health T32 GM008554 and F31 DK117592 (A.R.M.); by National Institutes of Health F32 DK111101 (A.C.E.); by National Cancer Institute grant CA102353 and Department of Defense W81XWH-11-2-0161 (Y.Z. and P.P.M.); by core resources of the Vanderbilt Digestive Disease Center (National Institutes of Health P30 DK058404); Washington University Digestive Disease Research Core Center (National Institutes of Health P30 DK052574); Translational Pathology Shared Resource and Cell Imaging Shared Resource (National Cancer Institute/National Institutes of Health Cancer Center Support grant 2P30 CA068485); and imaging was supported by the Vanderbilt Digital Histology Shared Resource supported by a VA shared instrumentation grant (1IS1BX003097). Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
doi = "10.1016/j.jcmgh.2019.04.015",
language = "English",
volume = "8",
pages = "379--405",
journal = "CMGH",
issn = "2352-345X",
number = "3",
}