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Hypoxia promotes airway differentiation in the human lung epithelium

GSE273089 Homo sapiens Expression profiling by high throughput sequencing 4 samples Submitted 2025/07/31 Platform GPL29480
Summary
Human embryos develop under physiological hypoxia, but how hypoxia directly affects human organogenesis remains unknown. We have investigated the effects of hypoxia on human lung epithelia using organoids. First trimester lung epithelial progenitors remain undifferentiated under normoxia, but initiate spontaneous differentiation towards multiple airway cell types, and inhibit alveolar differentiation under hypoxia. Genetic and chemical manipulation experiments showed that these effects were dependent on HIF (Hypoxia-Inducible Factor) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. We identified the cell fate-determining transcription factors KLF4/KLF5 and ASCL1 as direct targets of the HIF pathway, promoting progenitor differentiation to basal and neuroendocrine cells respectively. Chronic hypoxia also induces transdifferentiation of human alveolar type 2 cells into airway cells via the HIF pathway, suggesting that the developmental response to hypoxia is conserved into adulthood and potentially contributes to chronic lung disease.
Published in
Hypoxia promotes airway differentiation in the human lung epithelium
Dong Z, Wit N, Agarwal A et al. · Cell stem cell 2025 · PMID 41075787 · doi:10.1016/j.stem.2025.09.007
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Also filed as BioProject PRJNA1140142 and SRA study SRP522182. Searching any of these in the dataset finder brings you back here.

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