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

Lim, K.; Rutherford, E. N.; Sun, D.; Van den Boomen, D. J.; Edgar, J. R.; Bang, J.; Matesic, L. E.; Lee, J.-H.; Lehner, P. J.; Marciniak, S. J.; Rawlins, E. L.; Dickens, J. A.

doi:10.1101/2023.08.30.555522

bioRxiv · 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

Lim, K.·Rutherford, E. N.·Sun, D.·Van den Boomen, D. J.·Edgar, J. R.·Bang, J.·Matesic, L. E.·Lee, J.-H.·Lehner, P. J.·Marciniak, S. J.·Rawlins, E. L.·Dickens, J. A.

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Abstract

Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant1-3. AT2 dysfunction underlies many lung diseases including interstitial lung disease (ILD), in which some inherited forms result from mislocalisation of surfactant protein C (SFTPC) variants4,5. 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.

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Lim, K., Rutherford, E. N., Sun, D., Van den Boomen, D. J., Edgar, J. R., Bang, J., Matesic, L. E., Lee, J.-H., Lehner, P. J., Marciniak, S. J., Rawlins, E. L., Dickens, J. A.. 2023-08-30. A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease. https://doi.org/10.1101/2023.08.30.555522

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