Modeling trajectories of severe early-onset COPD using human induced pluripotent stem cells (iPSC).

Half of the Chronic Obstructive Pulmonary Disease (COPD) patients started in early adulthood from a low lung function. In utero maternal smoking is associated with increased adult COPD risk. iPSCs offer an opportunity to model human development of the lung system. This project aimed to model  COPD trajectories related to a developmental origin through two extreme groups i) patients with an early onset of COPD, and ii) patients free of COPD despite heavy smoking. Paired cultures of airway epithelium were established at air-liquid interface (ALI) from hiPSC (iALI) and bronchial primary epithelial cells (ALI) of one healthy control, one healthy smoker, and 4 COPD patients [NCT03181204]. We characterized cigarette smoke extract (CSE) effects on human airway epithelial cell cultures using bulk RNA and DNA methylome sequencing. Unsupervised clustering analysis and Lasso regression showed that iALI samples formed a distinct cluster from ALI samples. GO biological process and function analysis showed upregulation of morphogenesis, development, and extracellular matrix processes in iALI versus epithelial differentiation, cilium organization, and innate immune response in ALI system. We found that CSE exposure induced a specific signature in iALI but not in paired ALI, suggesting a higher susceptibility of iALI to CSE. iALI culture upregulated reactive oxygen species, and xenobiotic metabolism genes in response to CSE (cytochrome P450 [CYP]1B, NADPH oxidase-1) and aryl hydrocarbon receptor signaling. Our results demonstrate that iALI cultures are less mature than paired ALI culture, and enables modeling early exposure of human fetal airway epithelium in response to environmental exposures.