Assistant Professor Korea University Korea University, Seoul-t'ukpyolsi, Republic of Korea
Abstract: Alveolar type 2 cells play a vital role in lung homeostasis as stem cells and producing pulmonary surfactant. Disorders in AT2 cell physiology affects development of various lung diseases, including interstitial lung diseases in human. Particularly, certain inherited forms are linked to the mislocalization of surfactant protein C (SFTPC) variants. Modelling SFTPC mutations and investigating underlying pathogenic mechanisms has been challenging due to difficulties in deriving and expanding human AT2 cells in vitro. In this study, we show the development of mature, expandable AT2 organoids from human fetal lungs. These organoids are phenotypically stable, capable of differentiating into AT1-like cells, and amenable to genetic modification. Using this organoid model, we tested key regulators of SFTPC maturation identified in a forward genetic screen, including the E3 ligase ITCH. Overall, this study introduces a novel human alveolar organoid model, which we used to identify essential factors in SFTPC maturation required for AT2 cell function.
Funding Source: K.L. is supported by a Korea University grant and by the National Research Foundation of Korea (NRF) grant funded by Korea government (MSIT) (RS-2024-00342036 and RS-2023-00221182)
