Objective: Gastric carcinogenesis is still relatively poorly understood， because of the lack of knowledge of stem cells in stomach.  We attempted to molecularly identify gastric stem cells. 

 

Methodology: We reported earlier the 270 bp Runx1 enhancer element that drives the expression of Runx1 in hematopoietic stem cells， termed eR1 (Stem Cells 28:1869-81， 2010). We generated mice harboring eR1-GFP and looked for GFP positive cells. We also generated eR1-CreERT2 mice for lineage tracing as well as for activating oncogenic K-ras. 

 

Results: In stomach， rapidly growing cells are known to be located in the isthmus of both corpus and antrum.  We found that GFP+ cells at isthmus of both the corpus and the antrum of mice (Gastroenterology， 2016， PMID27670082).  A stem cell marker， Lgr5， was reported to identify stem cells in antrum at the base but never in the isthmus (Cell Stem Cell 6:25-36， 2010).  Both Lgr5+ cells and eR1+ cells have the ability to form organoids which are considered to develop only from stem cells.  I will discuss about the presence of more than one type of stem cell activities in a given tissue.  When oncogenic K-ras was expressed in eR1+ cells， dramatic morphological changes occurred to convert corpus epithelium to become antrum-like epithelium by eliminating parietal cells and chief cells.  This phenomenon resembles the antralization observed in chronic gastritis after H pylori infection in human stomach.  About 10% of eR1+ cells are also detected in fully differentiated chief cells that express pepsinogen located at the base of corpus.  They only rarely proliferate without stress. When oncogenic K-ras is expressed， chief cells can also showed stem cell activity as well as to induce SPEM.  

 

Conclusion: We identified gastric stem cells by eR1 at the predicted location both in corpus and antrum. A subset of chief cells may function as reserve stem cells.  Expression of oncogenic K-ras in stem cells induced metaplasia.