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

Yohei Korogi; Shimpei Gotoh; Satoshi Ikeo; Yuki Yamamoto; Naoyuki Sone; Koji Tamai; Satoshi Konishi; Tadao Nagasaki; Hisako Matsumoto; Isao Ito; Toyofumi F Chen-Yoshikawa; Hiroshi Date; Masatoshi Hagiwara; Isao Asaka; Akitsu Hotta; Michiaki Mishima; Toyohiro Hirai

doi:10.1016/j.stemcr.2019.01.014

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

Stem Cell Reports. 2019 Mar 5;12(3):431-440. doi: 10.1016/j.stemcr.2019.01.014. Epub 2019 Feb 14.

Authors

Yohei Korogi¹, Shimpei Gotoh², Satoshi Ikeo¹, Yuki Yamamoto¹, Naoyuki Sone¹, Koji Tamai¹, Satoshi Konishi¹, Tadao Nagasaki¹, Hisako Matsumoto¹, Isao Ito¹, Toyofumi F Chen-Yoshikawa³, Hiroshi Date³, Masatoshi Hagiwara⁴, Isao Asaka⁵, Akitsu Hotta⁶, Michiaki Mishima¹, Toyohiro Hirai¹

Affiliations

¹ Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
² 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. Electronic address: a0009650@kuhp.kyoto-u.ac.jp.
³ Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
⁴ Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁵ Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
⁶ Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.

Abstract

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.

Keywords: HPS; Hermansky-Pudlak syndrome; MX35; alveolar organoid; alveolar type 2 cell; iPSC; lamellar body; pluripotent stem cell; pulmonary fibrosis; pulmonary surfactant.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alveolar Epithelial Cells / pathology*
Cell Line
Hermanski-Pudlak Syndrome / pathology*
Humans
Induced Pluripotent Stem Cells / pathology*
Lung / pathology
Lung Diseases / pathology
Organelles / pathology
Organoids / pathology*

Supplementary concepts

Hermansky Pudlak syndrome 2