Hypoxia promotes airway differentiation in the human lung epithelium
Bibliographic record
Abstract
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. Moreover, hypoxia is sufficient to convert alveolar type 2 cells derived from both human fetal and adult lungs to airway cells, including aberrant basal-like cells that exist in human fibrotic lungs. 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. • Hypoxia promotes airway, but inhibits alveolar, cell fates of human lung progenitors • HIF1α and HIF2α have distinct targets and functions in lung epithelial development • KLF4 and KLF5 drive basal and secretory cell differentiation downstream of HIFs • Hypoxia induces aberrant airway differentiation of mature human AT2 cells Dong and colleagues uncover low oxygen-directed differentiation of human lung progenitors to airway rather than alveolar fate and show how the process is controlled by hypoxia-inducible factors. Hypoxia also converts differentiated alveolar cells into airway-like cells. Hypoxia is therefore both a developmental cue and a pathological factor in human lungs.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".