Endocrine Neural Interactions Regulate Antral CCK2R+ Stem Cells in Gastric Inflammation and Preneoplasia
Zheng, B.; Tu, R.; Chen, F.; Lu, J.; Kobayashi, H.; Zhang, P.; Zeng, Y.; Lian, G.; Wu, F.; Wang, X.; Zhi, X.; Huang, K.; Qian, J.; Waterbury, Q. T.; Li, S.; Lin, J.; Xiong, X.; Malagola, E.; Ochiai, Y.; Hata, M.; Arai, J.; Zamechek, L. B.; WANG, T. C.
Show abstract
Antral CCK2R+ stem cells are regulated by gastrin, but how endocrine and neural cues integrate under chronic injury remains unclear. Here we show that inducible hypogastrinemia shifts from asymmetric renewal to symmetric expansion of CCK2R+ stem cells. With carcinogenic stress, these cells acquire a cycling, injury responsive progenitor state revealed by single-cell RNA profiling. Acute gastrin loss activates a CCK2R+ nodose DMV vagal reflex that increases acetylcholine release, NGF production, cholinergic innervation, and Chrm3 expression, driving ERK and YAP signaling in CCK2R+ stem cells. Vagotomy, Trk inhibition, or Chrm3 deletion each suppressed stem cell expansion. In H. pylori and MNU injury models, hypogastrinemia amplified inflammation, dysplasia, and CCK2R+ clone expansion, whereas gastrin suppressed these responses. Human scRNA seq and spatial profiling confirmed G cell depletion and progenitor state enrichment. These findings define an endocrine neural epithelial axis in which gastrin loss boosts vagal M3R signaling to initiate antral preneoplasia, highlighting this pathway for early interception.
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