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Nature cell biology
Aug, 2017;19 (8): 904-914.

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
  1. Ying Xi: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
  2. Thomas Kim: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
  3. Alexis N Brumwell: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
  4. Ian H Driver: Department of Anatomy, UCSF, San Francisco, California 94143, USA.
  5. Ying Wei: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
  6. Victor Tan: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
  7. Julia R Jackson: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
  8. Jianming Xu: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
  9. Dong-Kee Lee: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
  10. Jeffrey E Gotts: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
  11. Michael A Matthay: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
  12. John M Shannon: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
  13. Harold A Chapman: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA. ORCID
  14. Andrew E Vaughan: Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
PMID: 28737769 DOI: 10.1038/ncb3580

Abstract

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.

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Grants

  1. R01 CA193455/NCI NIH HHS
  2. F32 HL117600/NHLBI NIH HHS
  3. R01 HL084376/NHLBI NIH HHS
  4. T32 HL007185/NHLBI NIH HHS
  5. R00 HL131817/NHLBI NIH HHS
  6. R37 HL051856/NHLBI NIH HHS
  7. U01 HL111054/NHLBI NIH HHS
  8. R01 HL128484/NHLBI NIH HHS
  9. T32 GM008339/NIGMS NIH HHS
  10. K99 HL131817/NHLBI NIH HHS
  11. U01 HL134766/NHLBI NIH HHS
  12. R01 CA112403/NCI NIH HHS

MeSH Term

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

Chemicals

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
Journal Article

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