Dynamic plasticity of gastric neck cells contributes to regeneration and metaplasia supported by myeloid-mesenchymal interactions

Gastric mucosal homeostasis is maintained by tissue-resident stem cells. Following mucosal injury, both stem cells and a subset of differentiated cell types contribute to regeneration, coinciding with characteristic pathological changes such as atrophic gastritis and metaplasia. To comprehensively understand the cellular dynamics involved in this process, we performed single-cell and spatial transcriptomics using newly generated transgenic mice. In humans, gastric chief cell loss precedes parietal cell loss during the progression of atrophy and metaplasia. In mice, selective ablation of chief cells induces parietal cell loss and accelerates metaplasia development, validating the causal relationship underlying the decrease of these two lineages. Single-cell analysis confirmed robust stemness activity and metaplastic changes in neck cell clusters following either chief or parietal cell ablation, and lineage-tracing experiments revealed that neck cells serve as a source of metaplasia and regeneration. Mechanistically, mucosal injury recruits IL-1-expressing myeloid cells, which stimulates NRG1 production in stromal fibroblasts, leading to mucosal proliferation and regeneration mediated by activated neck cells. These findings highlight the plasticity and facultative stem cell function of gastric neck cells, which play a critical role in mucosal homeostasis and disease progression.