Local lung hypoxia determines epithelial fate decisions during alveolar regeneration.
Ying XiThomas KimAlexis N BrumwellIan H DriverYing WeiVictor TanJulia R JacksonJianming XuDong-Kee LeeJeffrey E GottsMichael A MatthayJohn M ShannonHarold A ChapmanAndrew E VaughanPublished in: Nature cell biology (2017)
After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), 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, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/β-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair.
Keyphrases
- endothelial cells
- single cell
- cell proliferation
- lung function
- rna seq
- stem cells
- high throughput
- cystic fibrosis
- chronic obstructive pulmonary disease
- transcription factor
- induced apoptosis
- quality improvement
- signaling pathway
- air pollution
- induced pluripotent stem cells
- epithelial mesenchymal transition
- amino acid
- heat shock
- contrast enhanced
- low grade
- mesenchymal stem cells
- ionic liquid