Development of a 3D « bronchioid » to model Chronic Obstructive Pulmonary disease – BRONCHIOLE

Chronic obstructive pulmonary disease (COPD) is a major public health disease (i.e., 3rd cause of death worldwide) characterized by persistent airflow limitation, which responds minimally to bronchodilators and corticosteroid therapy. In COPD, both mesenchymal and epithelial cells undergo pathological remodeling in the distal airways, that leads to this constrictive limitation. These profound changes are driven by a complex multistep cascade, including epithelial production of cytokines, mucus hyperproduction, neutrophil infiltration and activation of bronchial smooth muscle cells and fibroblasts with disproportionate extracellular matrix deposition. However, the lack of physiological relevance of current cell-based assays, as well as the limited predictability of tests performed in animal models, strongly limit the study of disease-relevant cell-cell interactions and complex tissue remodeling processes.
In the present project, we aim to develop a 3D “bronchioid” model recapitulating the morphological and functional characteristics of distal airway, using an innovative tubuloid cell-based assay and primary bronchial cells derived from clinical samples. Working with the unique Cellular Capsule Technology developed by our collaborators (team ‘Bioimaging and Optofluidics’, UMR CNRS 5298), we will produce a tubular scaffold made of alginate gel. This scaffold will drive the spontaneous self-organisation of lung cells, to obtain a model of bronchiole, with physiologically relevant shape and size. By exposing the lumen to cigarette smoke and incorporating neutrophils, we will develop a system able to model COPD. We will evaluate using this bronchioid the efficiency of innovative curative RNA drugs, that could conteract airway remodelling. 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.
This project is intrinsically interdisciplinary, and relies on basic and translational approaches together with a combination of advanced cell imaging and innovative 3D multicellular models. The final objective is to decipher and reverse essential mechanisms governing COPD development.