Hypergastrinemia expands gastric ECL cells through CCK2R+ progenitor cells via ERK activation.

BACKGROUND: Enterochromaffin-like (ECL) cells in the stomach express gastrin/CCK2 receptors and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified.

METHODS: We utilized mice with fluorescent reporter expression in ECL cells (Hdc-GFP) as well as Cck2r-CreERT2 and Hdc-CreERT2 mice combined with R26-tdTomato mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment).

RESULTS: Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2+ isthmus progenitors, but not Hdc+ mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3D spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r+ Hdc- cells, and increased chromogranin A (CgA) and pERK expression in CCK2R-derived organoids. Gastrin activates ERK pathway in vivo and in vitro, and treatment with the MEK1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and CgA expression in vitro.

CONCLUSION: We show here that hypergastrinemia induces ECL cell hyperplasia that is primarily derived from CCK2R+ progenitors in the corpus. Gastrin-dependent function of CCK2R+ progenitors is regulated by the ERK pathway.