An integrated atlas of multiciliated cells across the human airway reveals regional heterogeneity and disease-associated remodeling

Multiciliated cells (MCCs) are essential for airway innate defense through mucociliary clearance, yet the diversity of MCCs in the healthy human airway remains poorly defined, hindering the understanding of their dysfunction in chronic respiratory diseases. In this study, we first profiled multiple anatomical regions of the healthy airway, including the turbinate, nasal sinus, nasopharynx, trachea, proximal bronchi, distal bronchi, and bronchioles. Morphological evaluation of MCCs revealed a progressive proximal-to-distal decline in their coverage, ciliary length, and axonemal diameter in the lower respiratory tract. Single-cell RNA sequencing further identified five distinct MCC subtypes whose distribution exhibited marked heterogeneity across airway anatomical regions. At the molecular level, proximal bronchial MCCs exhibited enrichment of antioxidant pathways with up-regulation of NQO1 and TXN compared with bronchiolar MCCs, a finding validated by spatial transcriptomics and immunofluorescence. Organoid experiments functionally confirmed that bronchiolar organoids accumulated significantly higher levels of reactive oxygen species than bronchial organoids upon cigarette smoke extract stimulation. In diseased conditions (nasal polyps, asthma, and COPD), we identified 22 commonly up-regulated and 4 commonly down-regulated genes in MCCs relative to matched control regions, pointing to shared injury features across chronic respiratory diseases. Moreover, we discovered that FTO and IRF9 were significantly up-regulated in MCCs from COPD patients but markedly down-regulated in those from asthma patients, highlighting disease-specific ciliary alterations. This atlas delineates the regional morphological and molecular landscape of airway MCCs, identifies the antioxidant deficiency of distal MCCs as a previously unrecognized feature, and reveals novel targets for therapeutic intervention in chronic respiratory diseases.