Structure-function relationships of mucociliary clearance in human airways.

Mucociliary 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 drive MCC mainly stem from animal models, limiting our understanding and in vitro modeling 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 ciliary beat properties that vary between species, and (3) quantitatively links these structural differences to differences in particle clearance function using a combination of experimental approaches and physics-based modeling. Finally, we leverage these structure-function relationships to develop metrics of organotypic tissue composition and clearance function in human airway epithelia, leading to the establishment of human-specific benchmarks for in vitro respiratory cultures, and allowing us to quantitatively compare the mucociliary machinery of different model systems, in vitro culture conditions, and disease states.