Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Stem Cell Reports. 2019 Mar 5;12(3):431-440. doi: 10.1016/j.stemcr.2019.01.014. Epub 2019 Feb 14.
It has been challenging to generate in vitro models of alveolar lung diseases, as the stable culture of alveolar type 2 (AT2) cells has been difficult. Methods of generating and expanding AT2 cells derived from induced pluripotent stem cells (iPSCs) have been established and are expected to be applicable to disease modeling. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by dysfunction of lysosome-related organelles, such as lamellar bodies (LBs), in AT2 cells. From an HPS type 2 (HPS2) patient, we established disease-specific iPSCs (HPS2-iPSCs) and their gene-corrected counterparts. By live cell imaging, the LB dynamics were visualized and altered distribution, enlargement, and impaired secretion of LBs were demonstrated in HPS2-iPSC-derived AT2 cells. These findings provide insight into the AT2 dysfunction in HPS patients and support the potential use of human iPSC-derived AT2 cells for future research on alveolar lung diseases.
体外肺泡疾病模型的构建一直具有挑战性，因为稳定培养肺泡Ⅱ型（AT2）细胞较为困难。已经建立了从诱导多能干细胞（iPSC）生成和扩增 AT2 细胞的方法，预计可适用于疾病建模。Hermansky-Pudlak 综合征（HPS）是一种常染色体隐性疾病，其特征是 AT2 细胞中溶酶体相关细胞器（如板层小体（LB））功能障碍。我们从 HPS 型 2（HPS2）患者中建立了疾病特异性 iPSC（HPS2-iPSC）及其基因校正的对应物。通过活细胞成像，可视化了 LB 动力学，并证明 HPS2-iPSC 衍生的 AT2 细胞中 LB 的分布改变、增大和分泌受损。这些发现为 HPS 患者的 AT2 功能障碍提供了深入了解，并支持使用人 iPSC 衍生的 AT2 细胞进行未来肺泡肺疾病的研究。
