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

Elife. 2020 Feb 24:9:e53072. doi: 10.7554/eLife.53072.


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.

Keywords: acute lung injury; lung regeneration; mouse; pulmonary endothelial cells; regenerative medicine; stem cells; vascular biology.

Plain language summary

Animal lungs are filled with tiny air sacks called alveoli, where the gas exchanges that keep organisms alive can take place. Small blood vessels known as capillaries come in close contact with the alveoli, allowing oxygen to be extracted from the air into the blood, and carbon dioxide to be released from the blood into the air. The cells that line the inside of these capillaries (known as pulmonary endothelial cells) are important actors in these exchanges. After having been damaged, for example by viruses like influenza, the lungs need to regenerate and create new capillaries. Yet, it was still unclear how pulmonary endothelial cells participate in the healing process, and if capillaries contain several populations of endothelial cells that play different roles. To investigate this question, Niethamer et al. used an approach called single-cell analytics to examine individual endothelial cells in the alveoli of mice infected with influenza. This revealed that different subtypes of endothelial cells exist in capillaries, and that some may be able to perform slightly different jobs during lung recovery. Niethamer et al. found that all subtypes could quickly multiply after injury to create more endothelial cells and re-establish gas exchanges. However, one newly identified group (called Car4-high ECs) was particularly primed to receive orders from damaged alveoli. These cells were also often found at the sites where the alveoli were most injured. Lung injuries are a major cause of death worldwide. Understanding how pulmonary endothelial cells work when the organ is both healthy and injured should help to find ways to boost repair, and to create therapies that could target these cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Lung Injury / pathology*
  • Animals
  • Endothelium / cytology*
  • Endothelium / pathology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / pathology
  • Female
  • Flow Cytometry
  • Lung / cytology*
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic
  • Orthomyxoviridae Infections / pathology
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / pathology
  • Single-Cell Analysis

Associated data

  • GEO/GSE128944