Efficient generation and transcriptomic profiling of human iPSC-derived pulmonary neuroendocrine cells

Expansion 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, genes therby recapitulating known functions of primary PNECs. Single-cell RNA sequencing (scRNA-seq) of these iPNEC revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases. Examination of 2 iPSC replicates for their differentiation to iPNEC.

肺神经内分泌细胞（pulmonary neuroendocrine cells, PNECs）的扩增是多种人类肺部疾病的病理特征。由于人类PNECs占肺总细胞数比例极低（<1%）且缺乏成熟的分离方案，相关研究始终存在较大阻碍。本研究通过诱导多能干细胞（induced pluripotent stem cells, iPSCs）诱导生成了诱导型肺神经内分泌细胞（induced PNECs, iPNECs），该细胞可表达PNEC的核心标志物，从而重现了原代PNECs的已知功能。对上述iPNECs进行单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）分析后发现，其基因表达谱具有PNEC相关特征，且该特征在iPNECs与人类胎儿PNECs之间高度吻合。综上，本模型有望提供无限量的人类iPNECs来源，用于探究多种肺部疾病相关的PNEC病理生理学机制。本研究还对2份iPSC重复样本的iPNEC分化过程进行了检测。