Bronchioalveolar organoids as a tool to study transforming growth factor-β and cigarette smoke–induced lung pathology

Abstract

Background Respiratory medicine has high barriers to new drug development, with fewer approved new treatments and candidate drugs and a higher failure rate than other common disease fields. Most of the major candidate drugs identified in preclinical animal studies fail in the clinical setting because of differences between animal models and humans. Therefore, the rapid development of 3-dimensional (3D) organoid-based disease models that recapitulate human pathological development has attracted increasing attention in drug development and personalized medicine. Methods In the present study, we generated bronchoalveolar organoids (BAOs) from human pluripotent stem cells (hPSCs) and assessed their potential as a pulmonary disease model. Results Derived BAOs contained the expected spectrum of differentiated cells, including alveolar progenitors, type 1 and 2 alveolar epithelial cells, basal cells, secretory cells, ciliated cells, and mesenchymal cells. When the BAOs were exposed to transforming growth factor-beta, both fibrosis- and inflammation-related transcripts were significantly upregulated compared to the control. In addition, the exposure of BAOs to cigarette smoking extract induced increased levels of nitric oxide in a dose-dependent manner, as well as upregulating oxidative stress-related and pro-inflammatory genes. Conclusion These findings suggest that hPSC-derived BAOs could be a promising platform for modeling pulmonary fibrosis and chronic obstructive pulmonary disease and testing drug efficacy.

Keywords

• human pluripotent stem cells
• bronchioalveolar organoids
• pulmonary fibrosis
• chronic obstructive pulmonary disease
• disease modeling