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; Livia Delpiano; Peng He; Weimin Lin; Dawei Sun; Dick J H Van den Boomen; James R Edgar; Jae Hak Bang; Alexander Predeus; Sarah A Teichmann; John C Marioni; Lydia E Matesic; Joo-Hyeon Lee; Paul J Lehner; Stefan J Marciniak; Emma L Rawlins; Jennifer A Dickens

doi:10.1038/s44318-024-00328-6

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

EMBO J. 2025 Jan 15. doi: 10.1038/s44318-024-00328-6. Online ahead of print.

Authors

Kyungtae Lim^#^{1

2

3}, Eimear N Rutherford^#⁴, Livia Delpiano^{1

2}, Peng He^{5

6}, Weimin Lin¹, Dawei Sun^{1

2

7}, Dick J H Van den Boomen^{8

9}, James R Edgar¹⁰, Jae Hak Bang¹¹, Alexander Predeus⁵, Sarah A Teichmann^{5

12}, John C Marioni^{5

6

13

14}, Lydia E Matesic¹⁵, Joo-Hyeon Lee^{2

11}, Paul J Lehner⁸, Stefan J Marciniak^{4

16}, Emma L Rawlins^{17

18}, Jennifer A Dickens^{19

20}

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 Department of Life Sciences, Korea University, 145 Anam-Ro, Seoungbuk-Gu, Seoul, 02841, South Korea.
⁴ Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK.
⁵ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
⁶ European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK.
⁷ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.
⁸ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, CB2 0AW, UK.
⁹ Harvard Medical School, Department of Cell Biology, Harvard University, LHRRB building, 45 Shattuck Street, Boston, MA, 02115, USA.
¹⁰ Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
¹¹ Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, UK.
¹² Theory of Condensed Matter Group, Department of Physics, Cavendish Laboratory, University of Cambridge, Cambridge, UK.
¹³ Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK.
¹⁴ Genentech, South San Francisco, CA, USA.
¹⁵ Department of Biological Sciences, University of South Carolina,, 715 Sumter St., Columbia, SC, 29208, USA.
¹⁶ Royal Papworth Hospital, Papworth Road, Trumpington, CB2 0AY, UK.
¹⁷ Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK. [email protected].
¹⁸ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3DY, UK. [email protected].
¹⁹ Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK. [email protected].
²⁰ Royal Papworth Hospital, Papworth Road, Trumpington, CB2 0AY, UK. [email protected].

^# Contributed equally.

PMID: 39815007
DOI: 10.1038/s44318-024-00328-6

Abstract

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, 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.

Abstract

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