Abstract
Background Airflow limitation is the hallmark of obstructive pulmonary diseases, with the distal airways representing a major site of obstruction. Although numerous in vitro models of bronchi already exist, there is currently no culture system for obstructive diseases that reproduces the architecture and function of small airways. Here, we aimed to engineer a model of distal airways to overcome the limitations of current culture systems.
Methods We developed a so-called bronchioid model by encapsulating human bronchial adult stem cells derived from clinical samples in a tubular scaffold made of alginate gel.
Results This template drives the spontaneous self-organization of epithelial cells into a tubular structure. Fine control of the level of contraction is required to establish a model of the bronchiole, which has a physiologically relevant shape and size. 3D imaging, gene expression and single-cell RNA-seq analysis of bronchioids made of bronchial epithelial cells revealed tubular organization, epithelial junction formation and 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.
Conclusion Here, we provide a proof of concept of a perfusable bronchioid with proper mucociliary and contractile functions. The key advantages of our approach, such as the air-liquid interface, lumen accessibility, recapitulation of pathological features and possible assessment of clinically relevant endpoints, will make our pulmonary organoid-like model a powerful tool for preclinical studies.
Competing Interest Statement
ID and PB has 2 patents delivered (EP 3050574 and EP 20173595). ID, PH and MZ report grants from the Fondation Bordeaux Universite. MZ reports personal fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Novartis, Chiesi, GlaxoSmithKline and non-financial support Lilly. PB reports grants and personal fees from Novartis, personal fees and non-financial support from Chiesi, Boehringer Ingelheim, AstraZeneca and Sanofi, personal fees from Menarini and TEVA, outside the submitted work. All other authors declare they have no competing interests.
Footnotes
A novel tubular engineered lung model called a “bronchioid” exhibits mucociliary function and is compatible with the establishment of an air-liquid interface.
methodology of ciliary beating frequency analysis characterization of COPD-derived bronchioids
