| First Author | Xi Y | Year | 2017 |
| Journal | Nat Cell Biol | Volume | 19 |
| Issue | 8 | Pages | 904-914 |
| PubMed ID | 28737769 | Mgi Jnum | J:249529 |
| Mgi Id | MGI:5921347 | Doi | 10.1038/ncb3580 |
| Citation | Xi Y, et al. (2017) Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol 19(8):904-914 |
| abstractText | After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent DeltaNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1alpha), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1alpha-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1alpha deletion or enhanced Wnt/beta-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair. |
