Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury

Abstract

Pulmonary endothelial cells (ECs) are an essential component of the gas exchange machinery of the lung alveolus. Despite this, the extent and function of lung EC heterogeneity remains incompletely understood. Using single-cell analytics, we identify multiple EC populations in the mouse lung, including macrovascular endothelium (maEC), microvascular endothelium (miECs), and a new population we have termed Car4-high ECs. Car4-high ECs express a unique gene signature, and ligand-receptor analysis indicates they are primed to receive reparative signals from alveolar type I cells. After acute lung injury, they are preferentially localized in regenerating regions of the alveolus. Influenza infection reveals the emergence of a population of highly proliferative ECs that likely arise from multiple miEC populations and contribute to alveolar revascularization after injury. These studies map EC heterogeneity in the adult lung and characterize the response of novel EC subpopulations required for tissue regeneration after acute lung injury.

Data availability

Single-cell RNA sequencing datasets have been deposited in GEO under accession code GSE128944.

The following data sets were generated

Article and author information

Author details

  1. Terren K Niethamer

    Department of Medicine, Department of Cell and Developmental Biology, Penn Center for Pulmonary Biology, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  2. Collin T Stabler

    Department of Medicine, Department of Cell and Developmental Biology, Penn Center for Pulmonary Biology, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  3. John P Leach

    Department of Medicine, Department of Cell and Developmental Biology, Penn Center for Pulmonary Biology, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  4. Jarod A Zepp

    Department of Medicine, Department of Cell and Developmental Biology, Penn Center for Pulmonary Biology, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  5. Michael P Morley

    Department of Medicine, Penn Center for Pulmonary Biology, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  6. Apoorva Babu

    Department of Medicine, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  7. Su Zhou

    Department of Medicine, Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  8. Edward E Morrisey

    Department of Medicine, Department of Cell and Developmental Biology, Penn-CHOP Lung Biology Institute, Penn Cardiovascular Institute, Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    emorrise@pennmedicine.upenn.edu
    Competing interests
    Edward E Morrisey, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5785-1939

Funding

National Institutes of Health (R01-HL087825)

  • Edward E Morrisey

National Institutes of Health (U01-HL134745-01)

  • Edward E Morrisey

National Institutes of Health (R01-HL132999)

  • Edward E Morrisey

National Institutes of Health (R01-HL132349)

  • Edward E Morrisey

National Institutes of Health (T32-HL7586-34)

  • Terren K Niethamer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Gordana Vunjak-Novakovic, Columbia University, United States

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and use of Laboratory Animals and under the oversight of the Institutional Animal Care and Use Committee (IACUC) of the University of Pennsylvania. All mouse experiments were approved by IACUC under protocol #806345.

Version history

  1. Received: October 26, 2019
  2. Accepted: February 22, 2020
  3. Accepted Manuscript published: February 24, 2020 (version 1)
  4. Version of Record published: April 22, 2020 (version 2)

Copyright

© 2020, Niethamer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Terren K Niethamer
  2. Collin T Stabler
  3. John P Leach
  4. Jarod A Zepp
  5. Michael P Morley
  6. Apoorva Babu
  7. Su Zhou
  8. Edward E Morrisey
(2020)
Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury
eLife 9:e53072.
https://doi.org/10.7554/eLife.53072

Share this article

https://doi.org/10.7554/eLife.53072

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