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

doi:10.1038/ncb3580

Local lung hypoxia determines epithelial fate decisions during alveolar regeneration

Nat Cell Biol. 2017 Aug;19(8):904-914. doi: 10.1038/ncb3580. Epub 2017 Jul 24.

Authors

Affiliations

¹ Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California 94143, USA.
² Department of Anatomy, UCSF, San Francisco, California 94143, USA.
³ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
⁴ Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
⁵ Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

PMID: 28737769
PMCID: PMC5600325
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^pos 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^pos basal-like state. Activated murine Krt5^pos 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^pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair.

MeSH terms

Animals
Cell Lineage*
Cell Movement
Cell Proliferation*
Cell Transdifferentiation*
Cells, Cultured
Disease Models, Animal
Epithelial Cells / metabolism*
Epithelial Cells / pathology
Epithelial Cells / virology
Female
Gene Expression Profiling
Genotype
Humans
Hypoxia / genetics
Hypoxia / metabolism*
Hypoxia / pathology
Hypoxia / virology
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Influenza A Virus, H1N1 Subtype / pathogenicity
Influenza, Human / genetics
Influenza, Human / metabolism*
Influenza, Human / pathology
Influenza, Human / virology
Keratin-5 / genetics
Keratin-5 / metabolism
Male
Mice, Transgenic
Orthomyxoviridae Infections / genetics
Orthomyxoviridae Infections / metabolism*
Orthomyxoviridae Infections / pathology
Orthomyxoviridae Infections / virology
Oxygen / metabolism*
Phenotype
Phosphoproteins / genetics
Phosphoproteins / metabolism
Pulmonary Alveoli / metabolism*
Pulmonary Alveoli / pathology
Pulmonary Alveoli / virology
Receptors, Notch / metabolism
Regeneration*
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Single-Cell Analysis
Time Factors
Trans-Activators / genetics
Trans-Activators / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism
Wnt Signaling Pathway

Substances

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

Abstract

MeSH terms

Substances

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