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.

Guodong Lian

Appearances