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Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells
  1. Ki Taek Nam1,
  2. Ryan L O'Neal1,
  3. Robert J Coffey2,
  4. Paul E Finke3,
  5. Nick Barker4,5,
  6. James R Goldenring1
  1. 1Nashville VA Medical Center and the Departments of Surgery and Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  2. 2Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  3. 3Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey, USA
  4. 4Hubrecht Institute and University Medical Centre, Utrecht, The Netherlands
  5. 5Institute of Medical Biology, Singapore
  1. Correspondence to Dr James R Goldenring, Vanderbilt University School of Medicine, Epithelial Biology Center, 10435G MRBIV, 2213 Garland Ave., Nashville, TN 37232-2733, USA; jim.goldenring{at}vanderbilt.edu

Abstract

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-CreERT2/+;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-CreERT2/+;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.

  • SPEM
  • chief cell
  • Lgr5
  • TFF2
  • oxyntic atrophy
  • gastric cancer
  • gastrointestinal cancer
  • molecular pathology
  • stem cells
  • trefoil peptides

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Footnotes

  • Funding The study was supported by grants to JRG from a Department of Veterans Affairs Merit Review Award 1I01BX000930, RO1 DK071590 and the AGA Funderburg Award in Gastric Biology Related to Cancer. This work was supported by core resources of the Vanderbilt Digestive Disease Center (P30 DK058404) and the Vanderbilt-Ingram Cancer Center.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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