A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease
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ABSTRACT: During human lung development the distal tip epithelial cells act as multipotent progenitors. From ~15 pcw (post conception weeks) the human tip epithelium retains progenitor marker expression, but also upregulates markers of the AT2 lineage. Immature AT2 cells appear in the tissue from 17 pcw. We have recently shown that 16-22 pcw epithelial tip cells can be expanded as organoids and differentiated to AT2 cells. However, the differentiated AT2 cells were not proliferative, limiting their use for functional studies and genetic manipulation. We have now developed a highly robust, efficient, and scalable culture condition (AT2 medium) that induces the differentiation of 16-22 pcw fetal lung tip cells into mature AT2 cells which grow as expandable 3D organoids. In this study, we characterise the fetal-derived AT2 cells, showing that they are stable over long-term passaging, efficiently process and secrete surfactant, and can differentiate into AT1 cells in vitro and in mouse lung transplantation assays. Forward genetic screen identifies candidate effectors of SFTPC trafficking which we validate using CRISPR interference (CRISPRi) in the AT2 organoids. We show that the trafficking of SFTPC requires ubiquitination by HECT domain E3 ligases, particularly Itch, and that their depletion phenocopies the pathological redistribution seen for the SFTPCI73T variant.
ORGANISM(S): Homo sapiens
PROVIDER: GSE237359 | GEO | 2023/08/31
REPOSITORIES: GEO
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