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Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from
Ki Taek Nam1, Ryan L O'Neal, Robert J Coffey
1Nashville VA Medical Center and the Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2733, USA.
Objective:
Metaplastic lineages in the oxyntic mucosa of the stomach are critical preneoplastic precursors of gastric cancer. Recent studies have demonstrated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the mouse oxyntic mucosa arises from transdifferentiation of mature gastric chief cells. Other investigations of intestinal progenitor cells have shown that cells demonstrating transcriptional activity for leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5) in the intestine, colon and gastric antrum function as adult stem cells. We have now investigated whether cells demonstrating Lgr5 transcriptional activity in the oxyntic mucosa of mice might be responsible for development of metaplasia.
Design:
Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice were used to examine the distribution of Lgr5 transcriptionally active cells in the normal oxyntic mucosa as well as after treatment with DMP-777 or L-635 to induce acute SPEM. Lineage mapping was performed to determine if Lgr5-expressing cells gave rise to SPEM.
Results:
Cells expressing transcriptional activity for Lgr5 in the oxyntic mucosa were present as scattered rare cells only along the lesser curvature of the stomach. These cells also stained for markers of chief cells (intrinsic factor and pepsinogen) but never showed any staining for proliferative markers (Ki-67). In Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice induced with tamoxifen, treatment with either DMP-777 or L-635 to induce acute oxyntic atrophy caused induction of SPEM, but no lineage mapping into SPEM from Lgr5-expressing cells was observed.
Conclusion:
The results indicate that, while chief cells with Lgr5 transcriptional activity are present along the lesser curvature of the gastric oxyntic mucosa, they are not responsible for production of metaplasia.
Insights
Gastric chief cells with Lgr5 activity are rare in the oxyntic mucosa and do not generate metaplasia. These findings clarify the cellular origins of gastric metaplasia and cancer precursors.
Area of Science:
- Gastroenterology
- Cell Biology
- Cancer Research
Background:
- Metaplastic lineages in the stomach's oxyntic mucosa are precursors to gastric cancer.
- Spasmolytic polypeptide-expressing metaplasia (SPEM) in mice arises from gastric chief cell transdifferentiation.
- Leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5) marks adult stem cells in various tissues.
Purpose of the Study:
- To investigate if Lgr5-expressing cells in the mouse oxyntic mucosa contribute to metaplasia development.
- To determine the role of Lgr5+ cells in the pathogenesis of gastric metaplasia.
Main Methods:
- Utilized Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice to track Lgr5-expressing cells.
- Induced acute SPEM using DMP-777 or L-635 treatments.
- Performed lineage mapping to trace cell origins after SPEM induction.
Main Results:
- Lgr5 transcriptional activity was found in rare scattered cells along the stomach's lesser curvature.
- These Lgr5+ cells expressed chief cell markers but not proliferative markers.
- Despite SPEM induction, lineage mapping showed no contribution from Lgr5-expressing cells to metaplasia.
Conclusions:
- Chief cells expressing Lgr5 are present in the gastric oxyntic mucosa.
- These Lgr5+ chief cells are not the source of metaplasia development.
- The study refutes Lgr5+ cells as progenitors for SPEM in this context.
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