Recapitulating morphological and functional characteristics of distal airways in tubular organoids to model post-viral obstructive diseases

Post-viral lung obstructive diseases such as chronic obstructive pulmonary disease (COPD) are major public health diseases characterized by chronic inflammation and remodelling. The lack of physiological relevance of traditional 2D cell culture models, as well as the limited predictibility of tests performed in animal models, strongly limit drug discovery. In the present project, we aim to develop a 3D “bronchioid” model using an innovative tubuloid cell-based assay and human bronchial adult stem cell cells derived from clinical samples. Working with the unique Cellular Capsule Technology, we produced a tubular scaffold made of alginate gel, that drives the spontaneous self-organisation of lung cells. Our results show that fine tuning the balance between adhesion and contraction is required to obtain a model of bronchiole, with physiologically relevant shape and size. 3D imaging of organoids made of primary bronchial epithelial cells demonstrates the tubular organization and the existence of a lumen, as well as proper differentiation into ciliated and mucous cells. The bronchioid is perfusable, with medium or with air. It is also easily infectable with respiratory viruses. We provide here a proof of concept that we are able to build a perfusable bronchioid, with proper mucociliary and contractile functions. Key advantages of our approach, such as the air-liquid interface, the lumen accessibility, and possible assessment of clinically pertinent endpoints, will make our pulmonary organoid a powerful tool for pre-clinical studies.