Endocrine–Neural Interactions Regulate Antral CCK2R⁺ Stem Cells in Gastric Inflammation and Preneoplasia

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SUMMARY 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. In brief Zheng and colleagues show that gastrin loss is sensed by CCK2R⁺ vagal afferents to engage a nodose–brainstem cholinergic reflex that activates epithelial M3R–ERK/YAP signaling, while lifting gastrin’s cell-intrinsic brake on symmetric division. Together these inputs expand antral CCK2R⁺ +4 stem cells, drive injury-state reprogramming, and promote preneoplastic progression. Highlights CCK2R⁺ vagal afferents sense gastrin loss and engage a nodose–brainstem reflex. Gastrin deficiency induces NGF–TrkA–dependent cholinergic remodeling and elevates epithelial M3R. Cholinergic M3R signaling activates ERK and YAP to drive expansion of antral CCK2R⁺ +4 stem cells. Direct loss of gastrin’s restraint on symmetric division synergizes with indirect neural signaling to promote preneoplasia.

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