Patient-derived airway organoids from BAL fluid model injury and therapy responses in neonatal bronchopulmonary dysplasia [Dexamethasone]

Lung tissue from fetal and neonatal lung samples is tough to obtain, and capturing cells from a living patient with evolving or established disease is very challenging. We hypothesized that airway organoids derived from BAL samples from intubated preterm neonates with established BPD will recapitulate the epithelial heterogeneity seen in human airways and can be used for studying injury and therapy responses in vitro. BPD patient BAL-derived airway organoids exhibited cellular heterogeneity consistent with that observed in the human airway. BAL sample-derived airway organoids from patients with established BPD contain basal cell progenitors and a spectrum of differentiated epithelial subtypes, including secretory, ciliated, PNECs, and hillock cells. Hyperoxia exposure and treatment with dexamethasone caused significant cellular transcriptional changes and highlighted biological pathways, both known and novel. Sex as a biological variable modulates the response of the BAL-derived airway organoid to hyperoxia exposure and treatment with dexamethasone. We also validated our findings in an independent dataset from human BPD lung samples. BAL-derived human lung organoids represent a cutting-edge model that bridges a critical gap in BPD research. They combine the advantages of being patient-specific and capturing developmental lung biology, with the experimental flexibility of an in vitro system.