Gastrin-dependent expansion of Cck2rcorpus 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 Cck2rprogenitors during homeostasis and injury, under conditions of hypogastrinaemia and hypergastrinaemia. Injury models included acute ulceration, chronicgastritis and N-Nitroso-N-Methylurea (MNU) exposure. RESULTS: Hypergastrinaemia significantly expanded Cck2risthmus 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 (p0.05). The vagus nerve, through the muscarinic receptor 3, mediated both gastrin elevations and Cck2rprogenitor expansion during ulcer healing. G-cell ablation in-infected mice increased colonisation and exacerbated inflammation, atrophy, metaplasia and dysplasia (p0.05), 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.