Structure-function relationships of mucociliary clearance in human airways

Abstract

ABSTRACTMucociliary clearance (MCC) is a key mechanical defense mechanism of the human airways, and MCC failure is linked to major respiratory diseases. While single-cell transcriptomics have unveiled the cellular complexity of the human airway epithelium, our insights into the mechanical structure-function relationships that link tissue organization to MCC mainly stem from animal models, limiting our understanding andin vitromodeling of human airway barrier function and disease. This study addresses these knowledge gaps and (1) reveals key differences in abundance and proportion of ciliated and secretory cell types at the luminal surface along the proximo-distal axis of the human and rat airway epithelium, (2) identifies species-specific differences in ciliary beat properties, and (3) quantitatively links these structural differences to species-specific airway clearance using a wide variety of experimental approaches and physics-based modeling. Finally, we leverage these structure-function relationships to establish human-specific benchmarks forin vitrorespiratory cultures, allowing us to quantitatively compare the mucociliary machinery of different model systems,in vitroculture conditions, and disease states.