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Cystine/Glutamate Antiporter (xCT) Is Required for Chief Cell Plasticity After Gastric InjurySummary
- 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
- Subjects :
- 0301 basic medicine
Small interfering RNA
Chief Cell
Oxyntic Atrophy
xCT, cystine/glutamate transporter
Cell
GSII, Griffonia simplicifolia
PCR, polymerase chain reaction
xCTKO, xCT knockout
0302 clinical medicine
TFF2, trefoil factor 2
LAMP2, lysosomal associated membrane protein-2
CD44
Original Research
MAP1LC3B, Microtubule-associated proteins 1A/1B light chain 3B
SPEM, spasmolytic polypeptide-expressing metaplasia
biology
Chemistry
Gastroenterology
ESRP1, epithelial splicing regulatory protein 1
mRNA, messenger RNA
3. Good health
Cell biology
Gastric chief cell
medicine.anatomical_structure
SPEM
UEA1, Ulex Europaeus Agglutinin I
Clu, clusterin
030211 gastroenterology & hepatology
FITC, fluorescein isothiocyanate
ATPase, adenosine triphosphatase
Reprogramming
CD44v9, CD44 variant isoform 9
SLC7A11, solute carrier family 7 member 1
PBS, phosphate-buffered saline
PAS, periodic acid–Schiff
03 medical and health sciences
ROS, reactive oxygen species
Autophagy
medicine
Chief cell
IFN, interferon
ImChief, Immortalized Chief
lcsh:RC799-869
TEM, transmission electron microscopy
Metaplasia
Hepatology
xCT
Sulfasalazine
030104 developmental biology
siRNA, small interfering RNA
Apoptosis
CD, cluster-of-differentiation
biology.protein
Cellular Plasticity
lcsh:Diseases of the digestive system. Gastroenterology
GIF, gastric intrinsic factor
PFA, paraformaldehyde
Reactive Oxygen Species
ImSPEM, Immortalized SPEM
Muc6, mucin 6
DHE, dihydroethidium
Subjects
Details
- Language :
- English
- Volume :
- 8
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cellular and Molecular Gastroenterology and Hepatology
- Accession number :
- edsair.doi.dedup.....6bd0136f7dbda9df64091f80a6a368c5