Local lung hypoxia determines epithelial fate decisions during alveolar regeneration.
Ying Xi, Thomas Kim, Alexis N Brumwell, Ian H Driver, Ying Wei, Victor Tan, Julia R Jackson, Jianming Xu, Dong-Kee Lee, Jeffrey E Gotts, Michael A Matthay, John M Shannon, Harold A Chapman, Andrew E Vaughan
Author Information
- Ying Xi: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
- Thomas Kim: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
- Alexis N Brumwell: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
- Ian H Driver: Department of Anatomy, UCSF, San Francisco, California 94143, USA.
- Ying Wei: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
- Victor Tan: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
- Julia R Jackson: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
- Jianming Xu: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
- Dong-Kee Lee: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
- Jeffrey E Gotts: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
- Michael A Matthay: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
- John M Shannon: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
- Harold A Chapman: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA. ORCID
- Andrew E Vaughan: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
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 Krt5 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 Krt5 basal-like state. Activated murine Krt5 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 Sox2 LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair.
Animals
Cell Lineage
Cell Movement
Cell Proliferation
Cell Transdifferentiation
Cells, Cultured
Disease Models, Animal
Epithelial Cells
Female
Gene Expression Profiling
Genotype
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit
Influenza A Virus, H1N1 Subtype
Influenza, Human
Keratin-5
Male
Mice, Transgenic
Orthomyxoviridae Infections
Oxygen
Phenotype
Phosphoproteins
Pulmonary Alveoli
Receptors, Notch
Regeneration
SOXB1 Transcription Factors
Single-Cell Analysis
Time Factors
Trans-Activators
Transcription Factors
Tumor Suppressor Proteins
Wnt Signaling Pathway
HIF1A protein, human
Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit
KRT5 protein, human
Keratin-5
Phosphoproteins
Receptors, Notch
SOX2 protein, human
SOXB1 Transcription Factors
Sox2 protein, mouse
TP63 protein, human
Trans-Activators
Transcription Factors
Trp63 protein, mouse
Tumor Suppressor Proteins
Oxygen
