A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.
Kyungtae Lim, Eimear N Rutherford, Dawei Sun, Dick J H Van den Boomen, James R Edgar, Jae Hak Bang, Lydia E Matesic, Joo-Hyeon Lee, Paul J Lehner, Stefan J Marciniak, Emma L Rawlins, Jennifer A Dickens
Author Information
Kyungtae Lim: Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Eimear N Rutherford: Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK.
Dawei Sun: Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Dick J H Van den Boomen: Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
James R Edgar: Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
Jae Hak Bang: Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
Lydia E Matesic: Department of Biological Sciences, University of South Carolina, 715 Sumter St., Columbia, SC 29208, USA.
Joo-Hyeon Lee: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
Paul J Lehner: Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
Stefan J Marciniak: Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK.
Emma L Rawlins: Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Jennifer A Dickens: Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK.
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 mislocalisation of surfactant protein C (SFTPC) variants. Disease modelling and dissection of mechanisms remains challenging due to complexities in deriving and maintaining AT2 cells Here, we describe the development of expandable adult AT2-like organoids derived from human fetal lung 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, demonstrating that their depletion phenocopies the pathological SFTPC redistribution seen for the SFTPC-I73T variant. In summary, we demonstrate the development of a novel alveolar organoid model and use it to identify effectors of SFTPC maturation necessary for AT2 health.
