This article details research on how low oxygen levels, or hypoxia, influence the development and differentiation of human lung epithelial cells, utilizing tissue-derived organoids. The authors found that hypoxia promotes airway differentiation in fetal lung progenitors while inhibiting alveolar cell fate, revealing that low oxygen acts as a developmental cue. Key to this process are the hypoxia-inducible factors (HIFs), particularly HIF1α and HIF2α, which have distinct roles: HIF1α is necessary for airway differentiation, whereas HIF2α specifically promotes basal cell fate but suppresses other airway and alveolar fates. Furthermore, the study indicates that chronic hypoxia can convert differentiated alveolar type 2 (AT2) cells, even those from adult lungs, into aberrant airway-like cells, suggesting a role for hypoxia as a pathological factor in lung diseases like fibrosis.

References:

• Dong Z, Wit N, Agarwal A, et al. Hypoxia promotes airway differentiation in the human lung epithelium[J]. Cell Stem Cell, 2025.