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.

 

目的：由于缺乏对胃干细胞的了解，人们对于胃癌的发病机理尚不清楚。我们试图在这篇研究中对胃干细胞做分子鉴定。

 

方法：我们早些时候报道了造血干细胞中驱动Runx1表达的270bp Runx1增强子元件，称为eR1（Stem Cells 28：1869-81，2010）。我们培育了携带eR1-GFP的小鼠，并寻找GFP阳性细胞。我们还生成eR1-CreERT2小鼠，用于谱系追踪以及激活原癌基因K-ras。

 

结果：在胃中，已知快速生长的细胞主要位于胃体和胃窦的峡部。我们发现在小鼠胃体和胃窦的峡部中均发现了GFP +细胞（Gastroenterology，2016，PMID27670082）。据报道，干细胞标记物Lgr5可以鉴定胃窦基底部的干细胞，但无法鉴定峡部的干细胞（Cell Stem Cell 6：25-36，2010）。 Lgr5 +细胞和eR1 +细胞均具有形成仅从干细胞发育而来的机体器官的能力。我将讨论的是，在既定组织中存在多种类型的干细胞活动。当eR1 +细胞中表达原癌K-ras时，发生了剧烈的形态学变化，通过清除顶叶细胞和主细胞，从而将胃腺上皮转化为窦样上皮细胞。这种现象类似于人胃幽门螺杆菌感染后导致的慢性胃炎中观察到的化生。在位于胃基底部的表达胃蛋白酶原的完全分化主细胞中也检测到了约10％的eR1 +细胞。在没有压力的情况下这些细胞很少增殖。当致癌K-ras被表达时，主细胞也可以显示干细胞活性以及诱导SPEM。

 

结论：我们通过eR1在胃体和胃窦的预期部位鉴定了胃干细胞。主细胞的一个子集可以作为备用干细胞。干细胞中原癌K-ras的表达诱导了化生。