Modeling COPD with a complex tubular distal airway model integrating the epithelial and mesenchymal compartments

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease characterized by a progressive decline of lung function. The limitation of expiratory airflow primarily affects distal airways, which show early signs of remodelling, inflammation and obliteration. The limited relevance of 2D cell- and lack of 3D-models mimicking small airway features hinder early pathophysiological understanding and drug discovery. We formerly developed a 3D mesenchyme-free “bronchioid” model using a tubuloid cell-based assay and human bronchial epithelial adult stem cells derived from clinical samples¹. Here, we aimed at integrating bronchial smooth muscle (BSM) cells into the bronchioid model to investigate epithelial-mesenchymal interactions and their role in COPD development. Spatially controling the encapsulation of the two cell types was required to obtain a bronchioid with BSM cells. Both cell types were viable. Adding the BSM cell population improved the robustness of the system. Confocal imaging demonstrated the tubular organization of epithelial cells bordered by a peripheral concentric layer of BSM cells, akin to bronchial topology. Differentiation of the bronchioid was observed, with emergence of ciliated and goblet cells.Calcium imaging following carbachol stimulation confirmed the ability of BSM cells to respond to a cholinergic stimulus. Bronchoconstriction release will be tested in COPD and non-COPD-derived bronchioids. We conclude that the bi-component bronchioid enables modeling of the distal lung’s epithelial–mesenchymal unit and serves as a powerful tool for understanding COPD pathogenesis. ¹Maurat <italic>et al., Eur Respir J.</italic> 2024. DOI: 10.1183/13993003.00562-2024