biostudies-literatureLim KCancer Research UKChan Zuckerberg Initiative (CZI)HHS | NIH | National Institute of General Medical Sciencescambridgeuniversity | Cambridge Institute for Medical Research, University of CambridgeKorea University (KU)NIHR | NIHR Cambridge Biomedical Research Centre (NIHR Cambridge BRC)National Research Foundation of KoreaChan Zuckerberg InitiativeKorea UniversityNational Research Foundation of Korea (NRF)UKRI | Engineering and Physical Sciences Research Council (EPSRC)Asthma and Lung UKMedical Research CouncilUKRI | Engineering and Physical Sciences Research CouncilSuh Kyungbae FoundationNIHR | NIHR Cambridge Biomedical Research CentreUKRI | Medical Research CouncilWellcome TrustNIGMS NIH HHSHHS | NIH | National Institute of General Medical Sciences (NIGMS)639-664https://www.ebi.ac.uk/biostudies/studies/S-EPMC11790967biostudies-literatureUnknown44(3)Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant. AT2 dysfunction underlies many lung diseases, including interstitial lung disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung disease modeling and dissection of the underlying mechanisms remain challenging due to complexities in deriving and maintaining human AT2 cells ex vivo. Here, we describe the development of mature, expandable AT2 organoids derived from human fetal lungs which are phenotypically stable, can differentiate into AT1-like cells, and are genetically manipulable. We use these organoids to test key effectors of SFTPC maturation identified in a forward genetic screen including the E3 ligase ITCH, The EMBO journalA novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.PMC11790967CZIF2022-007488P20GM103499MR/P009581/1210688/Z/18/ZMR/R009120/1MR/V028669/1216370/Z/19/Z225221/Z/22/ZBRC-1215-20014109146/Z/15/ZSUHF-20010033MR/Y011813/1221857/Z/20/ZP20 GM103499203144/Z/16/ZRS-2024-00342036MR/V011561/1MR/S005552/1RS-2023-00221182EP/R03558X/1C6946/A24843Edgar JRMatesic LEDickens JALehner PJLin WPredeus ARawlins ELHe PMarciniak SJVan den Boomen DJHRutherford ENDelpiano LSun DBang JHLim KMarioni JCTeichmann SALee JHfalseA novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant. AT2 dysfunction underlies many lung diseases, including interstitial lung disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung disease modeling and dissection of the underlying mechanisms remain challenging due to complexities in deriving and maintaining human AT2 cells ex vivo. Here, we describe the development of mature, expandable AT2 organoids derived from human fetal lungs which are phenotypically stable, can differentiate into AT1-like cells, and are genetically manipulable. We use these organoids to test key effectors of SFTPC maturation identified in a forward genetic screen including the E3 ligase ITCH, 2025-01-01T00:00:00Z2025 Feb2026-06-01T10:38:24.732Z2025-04-04T00:56:07.104ZS-EPMC117909673981500710.1038/s44318-024-00328-6