In Vitro Disease Modeling of Hermansky-Pudlak Syndrome Type 2 Using Human Induced Pluripotent Stem Cell-Derived Alveolar Organoids

Summary 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.