A single-cell atlas of the airway wall in patients with asthma reveals novel cellular mechanisms of disease.

Asthma is a chronic inflammatory disease of the airways characterized by wheezing, dyspnea, and shortness of breath. Asthma is a complex and heterogeneous disease, caused by mechanisms that are not fully known. To better characterize the cellular mechanisms in asthma, we performed single-cell RNA sequencing (scRNA-seq) analysis on bronchial biopsies from patients with asthma and healthy controls. We recruited 29 controls and 26 patients with asthma for bronchoscopy and scRNA-seq analysis. We performed quality control, then integrated and annotated the data using consensus labels from the Human Lung Cell Atlas. We compared composition, transcriptional phenotypes, trajectories of cell-state transitions and cell-cell communication patterns between the airway wall of patients with asthma and controls. Ex vivo cultured primary bronchial epithelial cells (PBECs) were used to further study mechanisms of epithelial differentiation. We find that composition of the airway epithelium and immune cell subsets such as myeloid and T cells is altered in patients with asthma. The airway epithelial changes reflect an altered transition from basal cells into club/goblet and multiciliated cells. Ex vivo PBEC cultures show that these changes are cell-autonomous. Differential gene expression analysis reveals cell-type specific changes in immune and epithelial cells, including a more activated state of innate and adaptive immune cell subsets, and the response of the epithelium to their mediators. In conclusion, we report extensive changes in the airway epithelium and the tissue-resident immune cell subsets in the airways of patients with asthma, including altered cell-cell communication patterns.