Dataset Information

Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia.

ABSTRACT: Intestinal metaplasia in the esophagus (Barrett's esophagus IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal and gastric adenocarcinoma, respectively. We hypothesize that BE-IM and GIM follow parallel developmental trajectories in response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of the entire gastrointestinal tract spanning physiologically normal and pathologic states including gastric metaplasia in the esophagus (E-GM), BE-IM, atrophic gastritis, and GIM. We demonstrate that BE-IM and GIM share molecular features, and individual cells simultaneously possess transcriptional properties of gastric and intestinal epithelia, suggesting phenotypic mosaicism. Transcriptionally E-GM resembles atrophic gastritis; genetically, it is clonal and has a lower mutational burden than BE-IM. Finally, we show that GIM and BE-IM acquire a protumorigenic, activated fibroblast microenvironment. These findings suggest that BE-IM and GIM can be considered molecularly similar entities in adjacent organs, opening the path for shared detection and treatment strategies.

Significance

Our data capture the gradual molecular and phenotypic transition from a gastric to intestinal phenotype (IM) in the esophagus and stomach. Because BE-IM and GIM can predispose to cancer, this new understanding of a common developmental trajectory could pave the way for a more unified approach to detection and treatment. See related commentary by Stachler, p. 1291. This article is highlighted in the In This Issue feature, p. 1275.

SUBMITTER: Nowicki-Osuch K

PROVIDER: S-EPMC10236154 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia.

Nowicki-Osuch Karol K Zhuang Lizhe L Cheung Tik Shing TS Black Emily L EL Masqué-Soler Neus N Devonshire Ginny G Redmond Aisling M AM Freeman Adam A di Pietro Massimilliano M Pilonis Nastazja N Januszewicz Wladyslaw W O'Donovan Maria M Tavaré Simon S Shields Jacqueline D JD Fitzgerald Rebecca C RC

Cancer discovery 20230601 6

Intestinal metaplasia in the esophagus (Barrett's esophagus IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal and gastric adenocarcinoma, respectively. We hypothesize that BE-IM and GIM follow parallel developmental trajectories in response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of the entire gastrointestinal tract spanning physiologically normal and pathologic states including gast ...[more]

PMID: 36929873

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Project description:The formation of tongue coating is closely related with the differentiation of the lingual dorsal mucosa, and a great deal of evidence shows that the variation of tongue coating reflects the pathological and physiological state of the gastric mucosa. However, the detailed mechanism remains elusive. This study established a rat model of gastric intestinal metaplasia (GIM) with 2% sodium salicylate and 20 mmol/L of deoxycholate sodium, and used single-cell RNA sequencing (scRNA-seq) to reveal the cell landscape of tongue dorsal mucosa. In comparison to the control group, the tongue dorsal mucosa of GIM rats became grayish-white, and the histologic characteristics presented an uneven distribution of tongue papilla with many immune cells in the submucosal layer. The expressive levels of pro-inflammatory factors (IL-1β, IL-6, and IL-17) were significantly higher in GIM rats than in the control group. Stratified analysis revealed the significant downregulation of autophagy marker gene Map1lc3a in neutrophils and T cells, and the significant downregulation of cuproptosis marker gene Dlst in fibroblasts of the tongue dorsal mucosa in GIM rats. These changes were closely related to mucosal inflammation and impaired tissue barrier integrity. Significantly, the expression of several keratin genes (Krt7, Krt8, Krt13, Krt16, and Krt76) was significantly downregulated, as well as the expression of the bitter taste receptor gene Rtp4 and the sweet taste receptor gene Tas1r2 in the GIM rats. The data indicated that fewer cells entered regulated cell death in immune cells of tongue mucosa, a more active inflammatory response occurred, the keratinization of tongue dorsal mucosal cells was inhibited, and the taste perception function was weakened. The results bring new perspectives on tongue coating in the application of gastric disorders. Characteristics of the tongue dorsum mucosal cell landscape in the rats with gastric intestinal metaplasia. The abundances of T cells, neutrophils, and macrophages were upregulated, and the autophagy marker gene Map1lc3a in T cells and neutrophils was downregulated, which indicated an actively inflammatory immune response. Downregulation of cuprotosis marker gene Dlst in fibroblasts suggested potential damage to the mucosal barrier. Meanwhile, the expression of bitter receptor Rtp4 and sweet receptor Tas1r2 in mesenchymal stem cells was downregulated. The cell communication ability was reduced, especially between mesenchymal stem cells and epithelial cells. In a word, the abnormal status of tongue dorsum mucosa may accompany the development of gastric intestinal metaplasia.

Dataset Information

Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia.

Significance

Publications

Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia.

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