Acetylcholine From Solitary Chemosensory Cell, Not Neuron, Regulates Basal Cell Fate Driving Eosinophilic Chronic Rhinosinusitis With Nasal Polyps

BACKGROUND: Basal cells (BCs) play a crucial role in epithelial remodeling, a hallmark of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP). Single-cell sequencing has revealed an increased number of solitary chemosensory cells (SCCs) alongside BC hyperplasia in eCRSwNP, yet the underlying mechanism of BC hyperplasia in eCRSwNP remains unclear. This study aimed to investigate the role of SCC-derived acetylcholine (Ach) in determining BC fate. METHODS: Tissue samples from healthy individuals, patients with eCRSwNP, and those with non-eCRSwNP (neCRSwNP) were analyzed to investigate BC proliferation, differentiation abnormalities, and the prevalence of SCCs. The relationship between SCC-derived Ach, BC dysfunction, and disease severity was examined. Ach sources and receptor expression patterns were characterized. In vitro studies using submerged cell cultures and air-liquid interface cultures, along with in vivo murine models, were employed to elucidate the mechanisms by which Ach influences BC fate. The inhibitory effects of tiotropium bromide (TB) on Ach-driven processes were also evaluated. RESULTS: Our results indicated that SCC-derived Ach, rather than by parasympathetic nerves, contributed to abnormal BC proliferation and differentiation through muscarinic acetylcholine receptors (mAChRs) and had potential impact on the development of eCRSwNP. These effects were associated with the activation of YAP and could be partially reversed both in vitro and in vivo by blocking mAChRs with TB. CONCLUSION: These results demonstrate that SCC-derived Ach plays a critical role in eCRSwNP by regulating BC fate. This provides a potential translational framework for developing prevention and treatment strategies targeting the cholinergic pathway.