Human iPSC-Derived Vascularised Lung Organoids for Modelling COPD and Pulmonary Hypertension.

Vascularised lung organoids (vLOs) that faithfully mimic human lung tissue architecture and disease pathology are critical for advancing pulmonary research but remain challenging to generate. Here, we developed a robust self-organisation protocol to produce vLOs with cellular heterogeneity and functional vasculature. The engineered blood vessels within vLOs exhibit lung-specific characteristics. As proof of concept, we applied this platform to model chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH). Using patient-derived vLOs, we demonstrated that cigarette smoke extract (CSE) induces pathological features resembling clinical COPD, including epithelial disruption and inflammatory responses. Furthermore, vLOs generated from a PH patient recapitulated disease-associated vascular remodelling, with RNA-seq revealing dysregulated pathways in endothelial dysfunction. Notably, we identified sodium hydrosulfide (NaHS) as a potential therapeutic candidate, as it attenuated aberrant EndoMT in PH-vLOs. In summary, our study establishes a physiologically relevant vLO system that enables modelling of cell-type-specific disease mechanisms and underscores the broad utility of this platform for mechanistic investigations and precision medicine approaches in respiratory disorders.