Background and challenges: Mucociliary clearance (MCC) is a crucial defense mechanism in human airways that relies on coordinated ciliary beating and mucus production to remove harmful particles and pathogens. Although MCC-failure is linked to several severe respiratory diseases including asthma, cystic fibrosis or chronic obstructive pulmonary disease (COPD), our current understanding of disease-linked MCC impairment is limited due to (a) an over-reliance on murine models, which don't accurately reflect human airway physiology, and (b) the lack of quantitative benchmarks for human airway function. Adding to this challenge, transcriptional profiling - though useful for assessing cellular heterogeneity - lacks the capacity to determine spatial cell arrangement, quantify protein expression and predict mechanical functions. However, such crucial knowledge is key to understand and adequately model human MCC to increase the clinical relevance of these in vitro models for studying MCC-related diseases and therapeutic interventions.
Strategy: The recently published Nature Communications study by Pioneer Campus PI Janna Nawroth’s team , together with their US collaborators around Amy Ryan’s group, established a quantitative map of ciliated and secretory cells in both human and rat airways, revealing significant species-specific differences. Some of these differences were expected, such as the absence of goblet cells in healthy rodent specimens, but some came as a surprise, such as the much higher levels of ciliation in human compared to rodent large airways.
Subsequently, they assessed species-specific variations in particle clearance and used this information to build quantitative metrics and physics-based computational models that accurately predict mucociliary clearance (MCC) performance from ciliated cell organization and beat activity. Ultimately, they applied this comprehensive quantitative framework to compare the structural and functional features of diverse in vitro human airway epithelial cultures with those of native human airway epithelia. This analysis demonstrated that commonly used culture protocols result in poor mucociliary clearance performance and revealed exactly which ciliary parameters were causing the divergence.
Taken as a whole, the study underscored key structural differences between human airways, animal models and lab-grown cultures, emphasizing once more the need for and importance of improved in vitro models that better reflect human physiology.
Outlook: This important study paves the way for more accurate and effective research into human respiratory health. The benchmarks and tools established here have the potential to enhance the clinical applicability of in vitro models for respiratory disease research as they can help assessing the effectiveness of treatments for improving/restoring human MCC.