Elucidating the Mechanobiology of COPD Fibroblasts: The Role of Yes-Associated Protein (YAP)

Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory disorder characterized by progressive inflammation and remodeling within lung tissue. Therefore, COPD microenvironment is drastically transformed, displaying changes in ECM architecture, tissue stiffening and mechanical stretch. The Hippo pathway effector, Yes-associated protein (YAP), has emerged as a crucial mediator linking mechanical cues to gene expression, cellular proliferation, and tissue remodeling. Despite these insights, YAP's involvement in COPD pathophysiology and mechanotransduction remains insufficiently understood. In this study, we explored the mechanobiology of human lung fibroblasts from healthy and GOLD IV COPD donors. Fibroblasts from 8 different healthy and COPD donors were treated with a YAP activator (Truli) and inhibitor (LB-100), and changes in YAP nuclear-to-cytoplasmic ratio and focal adhesion area were measured. Results show a significant (2-way ANOVA) response in healthy fibroblasts, where YAP nuclear translocation was significantly altered, in comparison to COPD fibroblasts, suggesting a possible dormancy or impairment in mechanosensing capabilities. Additionally, we examined focal adhesion area via paxillin (PAX) fluorescence staining. Unlike healthy cells, COPD fibroblasts exhibited marked changes in focal adhesion structures, potentially reflecting a dysregulated response to mechanical stress. Ongoing efforts involves the transcriptional by RNA sequencing, aiming to reveal molecular cues of the mechanobiology. Understanding these pathways and their dysregulation in COPD may highlight new therapeutic targets to address fibroblast dormancy and dysfunctional mechanotransduction.