Gastrin-dependent expansion of Cck2r+ corpus progenitors accelerates ulcer healing and inhibits gastric dysplasia

Abstract

Background The cholecystokinin-2/gastrin receptor (Cck2r) is expressed in corpus isthmus progenitor, enterochromaffin-like and parietal cells, regulating acid secretion and cell turnover. However, the role of gastrin on Cck2r progenitors during mucosal regeneration remains unexplored. Objective To study the role of gastrin-Cck2r axis and corpus progenitors during gastric injury and regeneration. Design We generated Cck2r-CreERT2; Gastrin-DTR-p2A-TdTomato; Rosa26-ZsGreen mice to trace corpus Cck2r+ progenitors during homeostasis and injury, under conditions of hypogastrinaemia and hypergastrinaemia. Injury models included acute ulceration, chronic H. pylori gastritis and N-Nitroso-N-Methylurea (MNU) exposure. Results Hypergastrinaemia significantly expanded Cck2r+ isthmus progenitors, whereas hypogastrinaemia reduced them. Gastric ulceration induced a twofold elevation in plasma gastrin by day 14, antral G-cell expansion and complete ulcer healing by day 28. Gastrin infusion or proton pump inhibitor (PPI) treatment further elevated gastrin and promoted complete ulcer healing by day 14, whereas G-cell ablation minimised gastrin, impaired healing and abrogated the benefits of PPI (p < 0.05). The vagus nerve, through the muscarinic receptor 3, mediated both gastrin elevations and Cck2r+ progenitor expansion during ulcer healing. G-cell ablation in H. pylori -infected mice increased colonisation and exacerbated inflammation, atrophy, metaplasia and dysplasia (p < 0.05), while hypergastrinaemia was protective. Similarly, in the MNU model, G-cell ablation worsened gastric pathology while hypergastrinaemia mitigated it. Conclusions We report a novel role for G-cell-derived gastrin in ulcer healing. Hypogastrinaemia is a risk factor for poor ulcer healing, corpus atrophy and potentially cancer, while physiological gastrin responses are protective. PPI-induced hypergastrinaemia plays a key role in ulcer healing, and gastrin signalling may prevent gastric preneoplasia. All data relevant to the study are included in the article or uploaded as supplementary information.