Induction and Evolution of Metaplasia in the Stomach

在胃中，化生发生在壁细胞丢失或泌酸萎缩的情况下。两种类型的 化生发生在人的胃：肠化生（肠杯状细胞谱系的存在， 胃）和痉挛性多肽表达化生或SPEM（胃窦深部腺的存在 胃体中的粘液细胞）。过去十年的调查导致了 认识到SPEM谱系基本上来源于蛋白分泌主要的转分化， 细胞转化为分泌粘液的SPEM谱系。此外，越来越多的证据表明，SPEM代表了 生理局部修复谱系，旨在促进局部恢复，然后被正常修复谱系所取代。 血统重要的是，从主细胞诱导SPEM是通过从ILC2释放IL-13来协调的。 内在粘膜免疫细胞。ILC2的消除阻断了急性顶叶后SPEM的发展 细胞丢失。在慢性损伤和炎症的情况下，除了炎性细胞的改变外， 在化生环境中，基质成纤维细胞的再造可能支持改变的 化生干细胞龛我们已经确定了端细胞成纤维细胞群的重新定位的基础上， 小鼠急性泌酸性萎缩后腺体化生。此外，我们还发现了四种不同的 正常和患病的人胃中的成纤维细胞群。这些发现表明， 化生龛实质内的固有粘膜炎性细胞和成纤维细胞可能 促进化生细胞谱系的维持以及它们向更具增殖性和 肿瘤形成前的细胞系。我们假设，内在免疫细胞群和改变 成纤维细胞促进重塑的组织环境，其促进向胃中瘤形成的进展。 为了评估这一假设，我们将研究两个具体的目标：首先，我们将确定如何扩大 ILC2促进化生及其进展。具体来说，我们将检查IL-13和/或ILC2 - 1对IL-13和/或ILC2 - 1的影响。 与化生胃腺共培养以促进化生的进展。此外，我们将定义 由IL-13介导的STAT6激活启动的转录调节，其导致了 化生进展。第二，我们将定义促进成纤维细胞发育的特定成纤维细胞群。 胃粘膜中肿瘤前环境的改变。我们将评估端细胞群体的动态， 在小鼠中建立化生环境并评价其促进化生的能力 在体外共培养中进展。我们将进一步从正常区域分离成纤维细胞亚群， 化生和癌变的人胃粘膜，以确定成纤维细胞亚群的变化， 促进化生粘膜中的肿瘤前小生境。这些研究将更详细地确定 免疫细胞和成纤维细胞群有助于胃中癌前环境的发展 并将允许鉴定可以阻止或逆转从化生到癌症的进展的策略。

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.