Induction and Evolution of Metaplasia in the Stomach

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In the stomach, metaplasia arises in the setting of parietal cell loss or oxyntic atrophy. Two types of metaplasia occur in the human stomach: intestinal metaplasia (the presence of intestinal goblet cell lineages in the stomach) and Spasmolytic Polypeptide-Expressing Metaplasia or SPEM (the presence of deep antral gland type mucus cells in the corpus of the stomach). Investigations over the past decade have led to the recognition that SPEM lineages are substantially derived from transdifferentiation of protein secreting chief cells into mucus-secreting SPEM lineages. In addition, increasing evidence suggests that SPEM represents a physiological local repair lineage that is meant to promote local restitution and then be replaced by normal lineages. Importantly, the induction of SPEM from chief cells is orchestrated by release of IL-13 from ILC2 intrinsic mucosal immune cells. Elimination of ILC2s blocks the development of SPEM following acute parietal cell loss. In the setting of chronic injury and inflammation, in addition to alterations in the inflammatory cells within the metaplastic milieu, there is a resculpting of the stromal fibroblasts that likely supports the altered metaplastic stem cell niche. We have identified the relocalization of telocyte fibroblast populations to the bases of metaplastic glands following acute oxyntic atrophy in mice. In addition, we have identified four distinct populations of fibroblast in the normal and diseased human stomach. Together these findings suggest that intrinsic mucosal inflammatory cells and fibroblasts within the parenchyma of the metaplastic niche may promote the maintenance of metaplastic cell lineages as well as their progression to more proliferative and intestinalized pre-neoplastic lineages. We have hypothesized that intrinsic immune cell populations and altered fibroblasts promote a remodeled tissue milieu that promotes progression towards neoplasia in the stomach. To evaluate this hypothesis, we will examine two specific aims: First, we will determine how expansion of ILC2s promotes metaplasia and its progression. Specifically, we will examine the effects of IL-13 and or ILC2- co-culture with metaplastic gastroids to promote progression of metaplasia. Additionally, we will define the transcriptional regulation initiated by IL-13 mediated activation of STAT6 that accounts for induction of metaplasia progression. Second, we will define specific fibroblast populations that promote the development of an altered pre-neoplastic milieu in the gastric mucosa. We will assess the dynamics of telocyte populations in the establishment of the metaplastic milieu in mice and evaluate their ability to promote metaplastic progression in vitro in co-culture. We will further isolate fibroblast sub-populations from regions of normal, metaplastic, and cancerous human gastric mucosa to define alterations in fibroblast sub-populations that may promote a pre-neoplastic niche in the metaplastic mucosa. These studies will establish in greater detail how immune cell and fibroblast populations contribute to the development of a pre-cancerous milieu in the stomach and will allow the identification of strategies that can arrest or reverse progression from metaplasia to cancer.