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

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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BibTeX RIS

BibTeX

@misc{zheng2026endocrine,
  title = {{Endocrine Neural Interactions Regulate Antral CCK2R+ Stem Cells in Gastric Inflammation and Preneoplasia}},
  author = {B. Zheng and R. Tu and F. Chen and J. Lu and H. Kobayashi and P. Zhang and Y. Zeng and G. Lian and F. Wu and X. Wang and X. Zhi and K. Huang and J. Qian and Q. T. Waterbury and S. Li and J. Lin and X. Xiong and E. Malagola and Y. Ochiai and M. Hata and J. Arai and L. B. Zamechek and T. C. WANG},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.28.747959},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747959v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - Endocrine Neural Interactions Regulate Antral CCK2R+ Stem Cells in Gastric Inflammation and Preneoplasia
AU  - B. Zheng
AU  - R. Tu
AU  - F. Chen
AU  - J. Lu
AU  - H. Kobayashi
AU  - P. Zhang
AU  - Y. Zeng
AU  - G. Lian
AU  - F. Wu
AU  - X. Wang
AU  - X. Zhi
AU  - K. Huang
AU  - J. Qian
AU  - Q. T. Waterbury
AU  - S. Li
AU  - J. Lin
AU  - X. Xiong
AU  - E. Malagola
AU  - Y. Ochiai
AU  - M. Hata
AU  - J. Arai
AU  - L. B. Zamechek
AU  - T. C. WANG
PY  - 2026
DA  - 2026/08/28
PB  - bioRxiv
DO  - 10.64898/2026.08.28.747959
UR  - https://www.biorxiv.org/content/10.64898/2026.08.28.747959v1
AB  - 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.
ER  -

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