Mature chief cells are cryptic progenitors for metaplasia in the stomach

Ki Taek Nam, Hyukjoon Lee, Josane F. Sousa, Victoria G. Weis, Ryan L. O'Neal, Paul E. Finke, Judith Romerogallo, Guanglu Shi, Jason C. Mills, Richard M. Peek, Stephen F. Konieczny, James R. Goldenring

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191 Citations (Scopus)


Background & Aims Gastric cancer evolves in the setting of a pathologic mucosal milieu characterized by both loss of acid-secreting parietal cells and mucous cell metaplasias. Indeed, mucous cell metaplasia is considered the critical preneoplastic lesion for gastric cancer. Previous investigations have shown that infection of mice with Helicobacter felis or induction of acute parietal cell loss with the drug DMP-777 leads to the emergence of a type of metaplasia designated spasmolytic polypeptide-expressing metaplasia (SPEM). We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells. Methods Taking advantage of the chief cell-restricted expression of Mist1-Cre-ERT2, we used lineage mapping to examine whether SPEM lineages were derived from chief cells in 3 independent models of induction by DMP-777 treatment, L-635 treatment, or H felis infection. Results Treatment of mice with L-635 for 3 days led to rapid parietal cell loss, induction of a prominent inflammatory infiltrate, and emergence of SPEM. In all 3 models, SPEM developed, at least in part, from transdifferentiation of chief cells. We further found that acute parietal cell loss in the setting of inflammation (L-635 treatment) led to more rapid induction and expansion of SPEM derived from transdifferentiation of chief cells. Conclusions These studies provide direct evidence by lineage tracing that SPEM evolves from differentiated chief cells. Thus, mature gastric chief cells have the ability to act as cryptic progenitors and reacquire proliferative capacity within the context of mucosal injury and inflammation.

Original languageEnglish
Pages (from-to)2028-2037.e9
Issue number6
Publication statusPublished - 2010 Dec

Bibliographical note

Funding Information:
Funding These studies were supported by grants from a Department of Veterans Affairs Merit Review Award ( RO1 DK071590 ) and the AGA Funderburg Award in Gastric Biology Related to Cancer (J.R.G.); by National Institutes of Health grant RO1 DK079798 (J.C.M.), by National Institutes of Health grant RO1 DK55489 and RO1 CA124586 (S.F.K.), and by National Institutes of Health grants R01 DK58587 , R01 CA77955 , and P01 CA116087 (R.M.P.). This work was supported by core resources of the Vanderbilt Digestive Disease Center ( National Institutes of Health P30 DK058404 ).

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology


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