982
GASTRIN-DEPENDENT EXPANSION OF CCK2R+ CORPUS PROGENITORS ACCELERATES ULCER HEALING AND INHIBITS GASTRIC ATROPHY
Date
May 21, 2024
Explore related products in the following collection:
Background
The cholecystokin-2/gastrin receptor (CCK2R) is expressed in corpus isthmus progenitor cells and parietal/ECL cells, and can regulate their homeostatic cellular turnover. While gastrin elevations induce ECL cells expansion from CCK2R+ progenitors (Cell Mol Gastroenterol Hepatol. 2020; 10(2): 434–449.e1.), the role of gastrin signaling in CCK2R+ isthmus progenitor cells during mucosal regeneration remains unexplored.
Methods
We generated CCK2R-CreERT2; Gastrin-BAC-DTR-P2A-TdTomato; Rosa26-ZsGreen mice in a C57BL/6 background. Hypogastrinemia was induced through antral G cell ablation with diphtheria toxin, and hypergastrinemia via gastrin infusion or intraperitoneal PPI injection. Lineage tracing from corpus CCK2R+ isthmus progenitor cells was assessed quantitatively during homeostasis and injury using acute acetic acid ulcer model, chronic H. pylori infection and MNU injury models.
Results
Hypergastrinemia promoted CCK2R+ isthmus progenitor cells, while hypogastrinemia had the opposite effects. After acute ulcerative damage, both G cells numbers (135±11.13 vs 93±19 (control) per 50 glands) and gastrin levels (47.94±10.59 vs 28.97±6.47(control) pg/ml) increased. Gastrin infusion effectively increased gastrin levels (74.31±4.22pg/ml), associated with enhanced expansion of CCK2R+ progenitors. Conversely, G-cell ablation reduced gastrin levels (16.39±1.87pg/ml) and hindered this process. The degree of progenitor cells expansion correlated with tissue regeneration: control group ulcer sizes on day 14 were 1.78±0.46 mm2, gastrin infused group 0.53±0.38 mm2, and DT group 2.56±0.80 mm2 (P<0.05). In ongoing studies, PPI treatment also increased gastrin levels and enhanced ulcer healing through the expansion of CCK2R+ progenitors, while PPI with G-cell ablation hindered this process. In the chronic H. pylori infection model, after 3 months, G cell ablation led to increased mucinous metaplasia, proliferation (Ki67+ cells), higher CD45 expression, and significantly fewer chief and parietal cells compared to the control group (P<0.05). Conversely, gastrin infusion for 3 months in HP infected mice exerted some protective effects, reducing inflammation and parietal cell loss, but also increasing mucinous metaplasia and chief cell loss. In ongoing MNU injury studies, the G cell ablation group at 36 weeks showed significantly greater tumor number and size than the control groups.
Conclusions.
Our results unveil a novel role for G cells during gastric regeneration. Hypogastrinemia is a risk factor for gastric ulcer healing, atrophy and potentially cancer, while hypergastrinemia is a protective factor in this C57BL/6 background. This may suggest a contribution by PPI-induced hypergastrinemia in the healing of gastric ulcers, and that maintainence of normal or possibly increased gastrin signaling may be beneficial in the prevention of gastric preneoplasia.
The cholecystokin-2/gastrin receptor (CCK2R) is expressed in corpus isthmus progenitor cells and parietal/ECL cells, and can regulate their homeostatic cellular turnover. While gastrin elevations induce ECL cells expansion from CCK2R+ progenitors (Cell Mol Gastroenterol Hepatol. 2020; 10(2): 434–449.e1.), the role of gastrin signaling in CCK2R+ isthmus progenitor cells during mucosal regeneration remains unexplored.
Methods
We generated CCK2R-CreERT2; Gastrin-BAC-DTR-P2A-TdTomato; Rosa26-ZsGreen mice in a C57BL/6 background. Hypogastrinemia was induced through antral G cell ablation with diphtheria toxin, and hypergastrinemia via gastrin infusion or intraperitoneal PPI injection. Lineage tracing from corpus CCK2R+ isthmus progenitor cells was assessed quantitatively during homeostasis and injury using acute acetic acid ulcer model, chronic H. pylori infection and MNU injury models.
Results
Hypergastrinemia promoted CCK2R+ isthmus progenitor cells, while hypogastrinemia had the opposite effects. After acute ulcerative damage, both G cells numbers (135±11.13 vs 93±19 (control) per 50 glands) and gastrin levels (47.94±10.59 vs 28.97±6.47(control) pg/ml) increased. Gastrin infusion effectively increased gastrin levels (74.31±4.22pg/ml), associated with enhanced expansion of CCK2R+ progenitors. Conversely, G-cell ablation reduced gastrin levels (16.39±1.87pg/ml) and hindered this process. The degree of progenitor cells expansion correlated with tissue regeneration: control group ulcer sizes on day 14 were 1.78±0.46 mm2, gastrin infused group 0.53±0.38 mm2, and DT group 2.56±0.80 mm2 (P<0.05). In ongoing studies, PPI treatment also increased gastrin levels and enhanced ulcer healing through the expansion of CCK2R+ progenitors, while PPI with G-cell ablation hindered this process. In the chronic H. pylori infection model, after 3 months, G cell ablation led to increased mucinous metaplasia, proliferation (Ki67+ cells), higher CD45 expression, and significantly fewer chief and parietal cells compared to the control group (P<0.05). Conversely, gastrin infusion for 3 months in HP infected mice exerted some protective effects, reducing inflammation and parietal cell loss, but also increasing mucinous metaplasia and chief cell loss. In ongoing MNU injury studies, the G cell ablation group at 36 weeks showed significantly greater tumor number and size than the control groups.
Conclusions.
Our results unveil a novel role for G cells during gastric regeneration. Hypogastrinemia is a risk factor for gastric ulcer healing, atrophy and potentially cancer, while hypergastrinemia is a protective factor in this C57BL/6 background. This may suggest a contribution by PPI-induced hypergastrinemia in the healing of gastric ulcers, and that maintainence of normal or possibly increased gastrin signaling may be beneficial in the prevention of gastric preneoplasia.
Tracks
Related Products
Basic Mechanism of Tissue Repair and Injury
TFF2+ GASTRIC CORPUS PROGENITORS DIRECTLY CONTRIBUTE TO THE DEVELOPMENT OF METAPLASIA/SPEM
A PROSPECTIVE, MULTI-INSTITUTIONAL STUDY REVEALS THE COMBINATION OF RNA ANALYSIS WITH DNA-BASED NEXT-GENERATION SEQUENCING (NGS) IMPROVES THE PREOPERATIVE CLASSIFICATION OF PANCREATIC CYSTS AND IDENTIFICATION OF ADVANCED NEOPLASIA
BACKGROUND: As outlined by the Kyoto guidelines, targeted DNA-based NGS of pancreatic cyst fluid (PCF) is an important adjunct to the evaluation of pancreatic cyst patients…
INCREASED REFLUX SECONDARY BILE ACIDS ARE ASSOCIATED WITH SHIFTS TO THE MICROBIOME AND TRANSCRIPTOME IN BARRETT’S ESOPHAGUS
Background: Bile acids comprise a major component of refluxate in GERD, the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Bile acids are metabolized by bacteria, and bacterial composition is also impacted by exposure to bile acids…
