摘要：SummaryExpansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their isolation. We used induced pluripotent stem cells (iPSCs) to generate induced PNECs (iPNECs), which express core PNEC markers, including ROBO receptors, and secrete major neuropeptides, recapitulating known functions of primary PNECs. Furthermore, we demonstrate that differentiation efficiency is increased in the presence of an air-liquid interface and inhibition of Notch signaling. Single-cell RNA sequencing (scRNA-seq) revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. In addition, pseudotime analysis of scRNA-seq results suggests a basal cell origin of human iPNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases.Graphical AbstractDisplay OmittedHighlights•PNECs can be efficiently generated from induced pluripotent stem cells (iPSCs)•Induced PNECs express key PNEC markers and express and secrete all major neuropeptides•Induced PNECs resemble the transcriptomic profile of human primary fetal PNECs•Basal cells are able to differentiate into PNECsCell Biology; Stem Cells Research; Transcriptomics
