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Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration

View ORCID ProfileTerren K. Niethamer, Lillian I. Levin, Michael P. Morley, Apoorva Babu, Su Zhou, View ORCID ProfileEdward E. Morrisey
doi: https://doi.org/10.1101/2022.10.14.512212
Terren K. Niethamer
1Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
2Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104
3Penn-Children’s Hospital of Philadelphia Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104
4Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104
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  • ORCID record for Terren K. Niethamer
Lillian I. Levin
1Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
4Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104
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Michael P. Morley
1Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
3Penn-Children’s Hospital of Philadelphia Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104
4Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104
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Apoorva Babu
1Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
3Penn-Children’s Hospital of Philadelphia Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104
4Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104
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Su Zhou
1Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
4Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104
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Edward E. Morrisey
1Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
2Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104
3Penn-Children’s Hospital of Philadelphia Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104
4Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104
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  • ORCID record for Edward E. Morrisey
  • For correspondence: emorrise@pennmedicine.upenn.edu
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Abstract

Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange with the external environment. Little is known about the transcriptional and signaling factors that drive pulmonary endothelial cell (EC) proliferation and subsequent regeneration of pulmonary capillaries, as well as their response to stress. Here, we show that the transcription factor Atf3 is essential for the regenerative response of the mouse pulmonary endothelium after influenza infection. Atf3 expression defines a subpopulation of capillary ECs enriched in genes involved in endothelial development, differentiation, and migration. During lung alveolar regeneration, this EC population expands and increases expression of genes involved in angiogenesis, blood vessel development, and cellular response to stress. Importantly, endothelial cell-specific loss of Atf3 results in defective alveolar regeneration, in part through increased apoptosis and decreased proliferation in the endothelium. This leads to the general loss of alveolar endothelium and persistent morphological changes to the alveolar niche, including an emphysema-like phenotype with enlarged alveolar airspaces lined with regions that lack vascular investment. Taken together, these data implicate Atf3 as an essential component of the vascular response to acute lung injury that is required for successful lung alveolar regeneration.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 14, 2022.
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Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration
Terren K. Niethamer, Lillian I. Levin, Michael P. Morley, Apoorva Babu, Su Zhou, Edward E. Morrisey
bioRxiv 2022.10.14.512212; doi: https://doi.org/10.1101/2022.10.14.512212
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Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration
Terren K. Niethamer, Lillian I. Levin, Michael P. Morley, Apoorva Babu, Su Zhou, Edward E. Morrisey
bioRxiv 2022.10.14.512212; doi: https://doi.org/10.1101/2022.10.14.512212

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