Hypoxia promotes airway differentiation in the human lung epithelium

Human lungs experience dynamic oxygen tension during development. Here, we show that hypoxia directly regulates human lung epithelial cell identity using tissue-derived organoids. Fetal multipotent lung epithelial progenitors remain undifferentiated in a self-renewing culture condition under normoxia but spontaneously differentiate toward multiple airway cell types and inhibit alveolar differentiation under hypoxia. Using chemical and genetic tools, we demonstrate that hypoxia-induced airway differentiation depends on hypoxia-inducible factor (HIF) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. KLF4 and KLF5 are direct HIF targets that promote basal and secretory cell fates. These findings reveal roles for hypoxia and HIF activity in the developing human lung epithelium and have implications for aberrant cell fate changes in pathological lungs.

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DOI:10.1016/j.stem.2025.09.007

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Hypoxia promotes airway differentiation in the human lung epithelium

GEO:GSE273089

Hypoxia promotes airway differentiation in the human lung epithelium [DamID-seq]

GEO:GSE272859

Hypoxia promotes airway differentiation in the human lung epithelium [Bulk RNA-seq]

GEO:GSE272860

Hypoxia promotes airway differentiation in the human lung epithelium [scRNAseq_hypoxia_AT2]

GEO:GSE296547

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