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Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.

Andrew E Vaughan1, Alexis N Brumwell1, Ying Xi1

  • 1Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, California 94143, USA.

Nature
|December 24, 2014

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View abstract on PubMed

Summary

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  • Biomedical And Clinical Sciences
  • Oncology And Carcinogenesis
  • Predictive And Prognostic Markers
  • Lineage-negative Progenitors Mobilize To Regenerate Lung Epithelium After Major Injury.
    • This summary is machine-generated.

    Researchers discovered rare lung stem cells (LNEPs) that regenerate damaged lung tissue. These cells require Notch signaling for repair, and dysregulation can lead to fibrosis, offering new insights into lung regeneration and disease.

    Area of Science:

    • Pulmonary Medicine
    • Stem Cell Biology
    • Regenerative Medicine

    Background:

    • Lung tissue repair models traditionally focus on differentiated cells.
    • The role of specialized stem/progenitor cells in lung regeneration remains less understood.
    • Previous research has not characterized lineage-negative epithelial stem/progenitor (LNEP) cells in the distal lung.

    Purpose of the Study:

    • To identify and characterize a novel population of lung stem cells responsible for tissue regeneration.
    • To elucidate the molecular mechanisms governing LNEP activation and differentiation after injury.
    • To investigate the role of Notch signaling in LNEP-mediated lung repair and its implications in fibrosis.

    Main Methods:

    • Single-cell sequencing to identify LNEP surface markers.
    • Influenza and bleomycin injury models in mice.
    • Orthotopic transplantation of isolated LNEPs.
    • Lineage tracing studies.
    • Pharmacological manipulation of Notch signaling.

    Main Results:

    • A rare population of lineage-negative epithelial stem/progenitor (LNEP) cells was identified in the normal distal lung.
    • Activated LNEPs express ΔNp63 and cytokeratin 5, proliferate, migrate, and differentiate into mature lung epithelium following injury.
    • Lineage tracing showed limited contribution from mature cells, while LNEP transplantation confirmed their regenerative capacity and multipotency.
    • Notch signaling is essential for LNEP activation; its blockade promotes alveolar cell fate, while persistent signaling causes 'micro-honeycombing' indicative of failed regeneration.
    • Human fibrotic lungs exhibit honeycomb cysts and evidence of hyperactive Notch signaling, mirroring findings in mouse models.

    Conclusions:

    • Distinct stem/progenitor cell pools are activated for lung tissue repair, dependent on injury severity.
    • LNEPs are critical for regenerating injured lung epithelium, with Notch signaling dynamics dictating repair outcomes.
    • Aberrant Notch signaling in LNEPs may contribute to the pathogenesis of pulmonary fibrosis.

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