A novel in vitro tubular model to recapitulate features of distal airways: The bronchioid

Abstract

BackgroundAirflow limitation is the hallmark of obstructive pulmonary diseases. While numerousin vitroairway models already exist, chronic obstructives diseases currently lack an 3D culture system enabling to understand how airway remodelling and the associated constrictive limitation develop. Here, the objective was to build a model of small airways, which would overcome the limitations of current culture systems.MethodsWorking with the Cellular Capsule Technology, we developed a so-called bronchioid model, using an innovative tubular cell-based assay and human bronchial adult stem cells derived from clinical samples.ResultsWe produced a tubular scaffold made of alginate gel, that drives the spontaneous self-organisation of lung epithelial cells. Fine control of the level of contraction is required to obtain a model of distal bronchiole, with physiologically relevant shape and size. 3D imaging and gene expression analysis of bronchioids made of primary bronchial epithelial cells demonstrates the tubular organization, the formation of epithelial junctions, as well as differentiation into ciliated and goblet cells. Ciliary beating is observed, at a decreased frequency in bronchioids made of cells from COPD patients. The bronchioid can be infected by rhinovirus. An air-liquid interface is introduced, that modulates gene expression.ConclusionWe provide here a proof of concept of a perfusable bronchioid, with proper mucociliary and contractile functions. Key advantages of our approach, such as the air-liquid interface, the lumen accessibility, the recapitulation of pathological features and possible assessment of clinically pertinent endpoints, will make our pulmonary organoid-like model a powerful tool for pre-clinical studies.