A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease DOI Creative Commons
Kyungtae Lim,

Eimear N Rutherford,

Livia Delpiano

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: 44(3), P. 639 - 664

Published: Jan. 15, 2025

Alveolar type 2 (AT2) cells maintain lung health by acting as stem and producing pulmonary surfactant. AT2 dysfunction underlies many diseases, including interstitial disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung modeling dissection underlying mechanisms remain challenging due to complexities deriving maintaining human ex vivo. Here, we describe development mature, expandable organoids derived fetal lungs are phenotypically stable, can differentiate into AT1-like cells, genetically manipulable. We use these test key effectors SFTPC maturation identified a forward genetic screen E3 ligase ITCH, demonstrating that their depletion phenocopies pathological redistribution seen for SFTPC-I73T variant. In summary, demonstrate novel alveolar organoid model it identify necessary health.

Language: Английский

A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease DOI Creative Commons
Kyungtae Lim,

Eimear N Rutherford,

Livia Delpiano

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: 44(3), P. 639 - 664

Published: Jan. 15, 2025

Alveolar type 2 (AT2) cells maintain lung health by acting as stem and producing pulmonary surfactant. AT2 dysfunction underlies many diseases, including interstitial disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung modeling dissection underlying mechanisms remain challenging due to complexities deriving maintaining human ex vivo. Here, we describe development mature, expandable organoids derived fetal lungs are phenotypically stable, can differentiate into AT1-like cells, genetically manipulable. We use these test key effectors SFTPC maturation identified a forward genetic screen E3 ligase ITCH, demonstrating that their depletion phenocopies pathological redistribution seen for SFTPC-I73T variant. In summary, demonstrate novel alveolar organoid model it identify necessary health.

Language: Английский

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