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

Chronic Obstructive Pulmonary Disease (COPD) is characterized by progressive irreversible limitation of expiratory airflow, primarily affecting distal airways, which show early signs of remodelling, inflammation and obliteration. The limited relevance of 2D cell models and lack of 3D models mimicking small airway features hinder early pathophysiological understanding and drug discovery. We have previously developed a 3D mesenchyme-free “bronchioid” model using an innovative tubuloid cell-based assay and human bronchial epithelial adult stem cells derived from clinical samples [1]. Here, we aimed at integrating mesenchymal cells into the bronchioid model to investigate epithelial-mesenchymal interactions and their role in COPD development. Fine-tuning the composition of the scaffold is required to obtain a bronchioid with mesenchymal cells. Epithelial and mesenchymal cells were viable and organized from lumen to periphery, akin to bronchial topology. Adding this mesenchymal component improved the robustness of the system, highlighting their pivotal role in adhesion and contraction balance. Flow cytometry analysis and 3D imaging shows interactions between both compartments, strongly affecting epithelial differentiation. We conclude that the bi-component bronchioid enables modeling of the distal lung's epithelial–mesenchymal unit and represents a powerful tool for a comprehensive grasp of the disease processes in COPD.