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

Abstract

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. To study the role of gastrin-Cck2r axis and corpus progenitors during gastric injury and regeneration. 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 <i>H. pylori</i> gastritis and N-Nitroso-N-Methylurea (MNU) exposure. 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<i><</i>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 <i>H. pylori</i>-infected mice increased colonisation and exacerbated inflammation, atrophy, metaplasia and dysplasia (p<i><</i>0.05), while hypergastrinaemia was protective. Similarly, in the MNU model, G-cell ablation worsened gastric pathology while hypergastrinaemia mitigated it. 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.