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

doi:10.1101/2023.08.30.555522

A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease

bioRxiv [Preprint]. 2023 Sep 4:2023.08.30.555522. doi: 10.1101/2023.08.30.555522.

Authors

Kyungtae Lim^{1

2}, Eimear N Rutherford³, Dawei Sun^{1

2

4}, Dick J H Van den Boomen^{5

6}, James R Edgar⁷, Jae Hak Bang⁸, Lydia E Matesic⁹, Joo-Hyeon Lee^{2

8}, Paul J Lehner⁵, Stefan J Marciniak^{3

10}, Emma L Rawlins^{1

2}, Jennifer A Dickens^{3

10}

Affiliations

¹ Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
² Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
³ Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK.
⁴ Current address: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
⁵ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
⁶ Harvard Medical School, Department of Cell Biology, Harvard University, LHRRB building, 45 Shattuck Street, Boston MA 02115, USA.
⁷ Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
⁸ Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
⁹ Department of Biological Sciences, University of South Carolina, 715 Sumter St., Columbia, SC 29208, USA.
¹⁰ Royal Papworth Hospital, Papworth Road, Trumpington, CB2 0AY.

Abstract

Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant^1-3. 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^4,5. Disease modelling and dissection of mechanisms remains challenging due to complexities in deriving and maintaining AT2 cells ex vivo. 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.

Keywords: E3 ligase; ITCH; pulmonary fibrosis; stem cell; surfactant protein C.

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Abstract

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