Back to Search Start Over

Cystine/Glutamate Antiporter (xCT) Is Required for Chief Cell Plasticity After Gastric InjurySummary

Authors :
Pierre P. Massion
James R. Goldenring
Eun-Young Choi
Janice A. Williams
Anne R. Meyer
Jason C. Mills
Yong Zou
Amy C. Engevik
Spencer G. Willet
Source :
Cellular and Molecular Gastroenterology and Hepatology, Vol 8, Iss 3, Pp 379-405 (2019), Cellular and Molecular Gastroenterology and Hepatology
Publication Year :
2019
Publisher :
Elsevier, 2019.

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.<br />Graphical abstract

Details

Language :
English
Volume :
8
Issue :
3
Database :
OpenAIRE
Journal :
Cellular and Molecular Gastroenterology and Hepatology
Accession number :
edsair.doi.dedup.....6bd0136f7dbda9df64091f80a6a368c5