Induction and Evolution of Metaplasia in the Stomach

胃化生的诱导和进化

• 批准号: 10667645
• 负责人: Eunyoung Choi
• 金额: $ 53.53万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667645
• 关键词: Acute; Antral; Atrophic; Cancerous; Cell Lineage; Cell secretion; Cells; Chief Cell; Chronic; Coculture Techniques; Development; Dysplasia; Elements; Evolution; Fibroblasts; Gastric Parietal Cells; Gastric mucosa; Gland; Goblet Cells; Helicobacter pylori; Human; Immune; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-13; Intestinal Metaplasia; Intestines; Investigation; Lesion; Lymphocyte; Lymphoid Cell; Maintenance; Malignant Neoplasms; Mediating; Metaplasia; Metaplastic Cell; Mucous Membrane; Mucous body substance; Mus; Neoplasms; Patients; Physiological; Population; Protein Secretion; STAT6 gene; Sensory; Smooth Pursuit; Stomach; System; Tissues; Transcriptional Regulation; base; chronic infection; gastric cancer prevention; gastric corpus; gastric organoids; human disease; malignant stomach neoplasm; neoplastic; premalignant; repaired; response; spasmolytic polypeptide; stem cell niche; transdifferentiation

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.

在胃中，在壁细胞丢失或含氧酸萎缩的情况下出现化生。两种类型的 人的胃发生化生：肠化生(存在肠杯状细胞系 胃部)和痉挛多肽表达的化生或SPEM(存在深胃窦腺 胃体中的粘液细胞)。过去十年的调查导致了 认识到SPEM谱系实质上来源于蛋白质分泌主干的转分化 细胞分化为分泌粘液的SPEM谱系。此外，越来越多的证据表明，SPEM代表着一种 生理性局部修复血统，旨在促进局部恢复，然后被正常 血统。重要的是，从主细胞诱导SPEM是通过ILC2释放IL-13来协调的 粘膜固有免疫细胞。ILC2s的清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背景下，除了炎症细胞的变化 在化生环境中，间质成纤维细胞可能支持改变的 化生干细胞的位置。我们已经确定了端粒细胞成纤维细胞群重新定位到碱基 小鼠急性氧合萎缩后化生腺体的变化。此外，我们还确定了四个不同的 正常人和疾病人胃中成纤维细胞的数量。总而言之，这些发现表明 化生壁龛实质内固有的粘膜炎症细胞和成纤维细胞可能 促进化生细胞谱系的维持及其向更具增殖性和 肠化的肿瘤前谱系。我们假设了固有免疫细胞群和改变 成纤维细胞促进重塑的组织环境，从而促进胃部肿瘤的进展。 为了评估这一假设，我们将检验两个具体目标：首先，我们将确定 ILC2s促进化生及其进展。具体来说，我们将研究IL-13和/或ILC2的影响- 与化生胃液共培养促进化生进展。此外，我们还将定义 IL-13介导的STAT6激活对转录调控的影响 化生进展。第二，我们将定义特定的成纤维细胞群体，以促进 胃粘膜癌前环境的改变。我们将评估端粒细胞种群的动态 小鼠化生环境的建立及其促化生能力的评价 共培养的体外研究进展。我们将进一步将成纤维细胞亚群从正常、 化生和癌变的人胃粘膜定义成纤维细胞亚群的变化 促进癌前病变在化生黏膜中的定位。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部癌前环境的发展 并将允许确定可以阻止或逆转从化生到癌症的进展的策略。

项目成果

miR-30-HNF4γ and miR-194-NR2F2 regulatory networks contribute to the upregulation of metaplasia markers in the stomach.

• DOI: 10.1136/gutjnl-2014-308759
• 发表时间: 2016-06
• 期刊: Gut
• 影响因子: 24.5
• 作者: Sousa JF;Nam KT;Petersen CP;Lee HJ;Yang HK;Kim WH;Goldenring JR
• 通讯作者: Goldenring JR

Spasmolytic polypeptide-expressing metaplasia (SPEM) cell lineages can be an origin of gastric cancer.

表达解痉多肽的化生（SPEM）细胞谱系可能是胃癌的起源。

• DOI: 10.1002/path.6089
• 发表时间: 2023
• 期刊: The Journal of pathology
• 作者: Goldenring,JamesR

What Ever Happened to the Scientific Conversation?

科学对话发生了什么？

• DOI: 10.1016/j.jcmgh.2016.03.003
• 发表时间: 2016
• 期刊: Cellular and molecular gastroenterology and hepatology
• 影响因子: 7.2
• 作者: Goldenring,JamesR

No H. pylori, no adenocarcinoma for patients with autoimmune gastritis.

• DOI: 10.1136/gutjnl-2022-328068
• 发表时间: 2023-01
• 期刊: GUT
• 影响因子: 24.5
• 作者: Goldenring, James

WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury.

• DOI: 10.1053/j.gastro.2021.05.058
• 发表时间: 2021-09
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Jeong H;Lee B;Kim KH;Cho SY;Cho Y;Park J;Lee Y;Oh Y;Hwang BR;Jang AR;Park JH;Park JH;Jeong SH;Lee D;Lee YC;Lim KM;Goldenring JR;Nam KT
• 通讯作者: Nam KT