Modeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs

Abstract Background Somatic cells differentiated from patient-specific human induced pluripotent stem cells (iPSCs) could be a useful tool in human cell-based disease research. Hermansky–Pudlak syndrome (HPS) is an autosomal recessive genetic disorder characterized by oculocutaneous albinism and a p...

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Autores principales:	Takahiro Suezawa, Shuhei Kanagaki, Yohei Korogi, Kazuhisa Nakao, Toyohiro Hirai, Koji Murakami, Masatoshi Hagiwara, Shimpei Gotoh
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	HPS1 Patient-specific iPSCs Alveolar epithelial type 2 cells Giant lamellar body Diseases of the respiratory system RC705-779
Acceso en línea:	https://doaj.org/article/4ebaca0035124502b6d85d268d034e87
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spelling	oai:doaj.org-article:4ebaca0035124502b6d85d268d034e872021-11-08T11:03:49ZModeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs10.1186/s12931-021-01877-81465-993Xhttps://doaj.org/article/4ebaca0035124502b6d85d268d034e872021-11-01T00:00:00Zhttps://doi.org/10.1186/s12931-021-01877-8https://doaj.org/toc/1465-993XAbstract Background Somatic cells differentiated from patient-specific human induced pluripotent stem cells (iPSCs) could be a useful tool in human cell-based disease research. Hermansky–Pudlak syndrome (HPS) is an autosomal recessive genetic disorder characterized by oculocutaneous albinism and a platelet dysfunction. HPS patients often suffer from lethal HPS associated interstitial pneumonia (HPSIP). Lung transplantation has been the only treatment for HPSIP. Lysosome-related organelles are impaired in HPS, thereby disrupting alveolar type 2 (AT2) cells with lamellar bodies. HPSIP lungs are characterized by enlarged lamellar bodies. Despite species differences between human and mouse in HPSIP, most studies have been conducted in mice since culturing human AT2 cells is difficult. Methods We generated patient-specific iPSCs from patient-derived fibroblasts with the most common bi-allelic variant, c.1472_1487dup16, in HPS1 for modeling severe phenotypes of HPSIP. We then corrected the variant of patient-specific iPSCs using CRISPR-based microhomology-mediated end joining to obtain isogenic controls. The iPSCs were then differentiated into lung epithelial cells using two different lung organoid models, lung bud organoids (LBOs) and alveolar organoids (AOs), and explored the phenotypes contributing to the pathogenesis of HPSIP using transcriptomic and proteomic analyses. Results The LBOs derived from patient-specific iPSCs successfully recapitulated the abnormalities in morphology and size. Proteomic analysis of AOs involving iPSC-derived AT2 cells and primary lung fibroblasts revealed mitochondrial dysfunction in HPS1 patient-specific alveolar epithelial cells. Further, giant lamellar bodies were recapitulated in patient-specific AT2 cells. Conclusions The HPS1 patient-specific iPSCs and their gene-corrected counterparts generated in this study could be a new research tool for understanding the pathogenesis of HPSIP caused by HPS1 deficiency in humans.Takahiro SuezawaShuhei KanagakiYohei KorogiKazuhisa NakaoToyohiro HiraiKoji MurakamiMasatoshi HagiwaraShimpei GotohBMCarticleHPS1Patient-specific iPSCsAlveolar epithelial type 2 cellsGiant lamellar bodyDiseases of the respiratory systemRC705-779ENRespiratory Research, Vol 22, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HPS1 Patient-specific iPSCs Alveolar epithelial type 2 cells Giant lamellar body Diseases of the respiratory system RC705-779
spellingShingle	HPS1 Patient-specific iPSCs Alveolar epithelial type 2 cells Giant lamellar body Diseases of the respiratory system RC705-779 Takahiro Suezawa Shuhei Kanagaki Yohei Korogi Kazuhisa Nakao Toyohiro Hirai Koji Murakami Masatoshi Hagiwara Shimpei Gotoh Modeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs
description	Abstract Background Somatic cells differentiated from patient-specific human induced pluripotent stem cells (iPSCs) could be a useful tool in human cell-based disease research. Hermansky–Pudlak syndrome (HPS) is an autosomal recessive genetic disorder characterized by oculocutaneous albinism and a platelet dysfunction. HPS patients often suffer from lethal HPS associated interstitial pneumonia (HPSIP). Lung transplantation has been the only treatment for HPSIP. Lysosome-related organelles are impaired in HPS, thereby disrupting alveolar type 2 (AT2) cells with lamellar bodies. HPSIP lungs are characterized by enlarged lamellar bodies. Despite species differences between human and mouse in HPSIP, most studies have been conducted in mice since culturing human AT2 cells is difficult. Methods We generated patient-specific iPSCs from patient-derived fibroblasts with the most common bi-allelic variant, c.1472_1487dup16, in HPS1 for modeling severe phenotypes of HPSIP. We then corrected the variant of patient-specific iPSCs using CRISPR-based microhomology-mediated end joining to obtain isogenic controls. The iPSCs were then differentiated into lung epithelial cells using two different lung organoid models, lung bud organoids (LBOs) and alveolar organoids (AOs), and explored the phenotypes contributing to the pathogenesis of HPSIP using transcriptomic and proteomic analyses. Results The LBOs derived from patient-specific iPSCs successfully recapitulated the abnormalities in morphology and size. Proteomic analysis of AOs involving iPSC-derived AT2 cells and primary lung fibroblasts revealed mitochondrial dysfunction in HPS1 patient-specific alveolar epithelial cells. Further, giant lamellar bodies were recapitulated in patient-specific AT2 cells. Conclusions The HPS1 patient-specific iPSCs and their gene-corrected counterparts generated in this study could be a new research tool for understanding the pathogenesis of HPSIP caused by HPS1 deficiency in humans.
format	article
author	Takahiro Suezawa Shuhei Kanagaki Yohei Korogi Kazuhisa Nakao Toyohiro Hirai Koji Murakami Masatoshi Hagiwara Shimpei Gotoh
author_facet	Takahiro Suezawa Shuhei Kanagaki Yohei Korogi Kazuhisa Nakao Toyohiro Hirai Koji Murakami Masatoshi Hagiwara Shimpei Gotoh
author_sort	Takahiro Suezawa
title	Modeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs
title_short	Modeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs
title_full	Modeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs
title_fullStr	Modeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs
title_full_unstemmed	Modeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs
title_sort	modeling of lung phenotype of hermansky–pudlak syndrome type i using patient-specific ipscs
publisher	BMC
publishDate	2021
url	https://doaj.org/article/4ebaca0035124502b6d85d268d034e87
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Modeling of lung phenotype of Hermansky–Pudlak syndrome type I using patient-specific iPSCs

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