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Cell Stem Cell. 2018 Aug 2;23(2):210-225.e6. doi: 10.1016/j.stem.2018.07.011.

Endothelial Regeneration of Large Vessels Is a Biphasic Process Driven by Local Cells with Distinct Proliferative Capacities.

Author information

1
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2
Department of Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Department of Neuroscience, University of California, Los Angeles, Los Angeles, CA 90095, USA.
4
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5
Molecular, Cellular, and Integrative Physiology Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
7
Division of Pulmonary Biology and Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH 45229, USA.
8
Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH 43210, USA.
9
Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
10
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: arispe@mcdb.ucla.edu.

Abstract

The cellular and mechanistic bases underlying endothelial regeneration of adult large vessels have proven challenging to study. Using a reproducible in vivo aortic endothelial injury model, we characterized cellular dynamics underlying the regenerative process through a combination of multi-color lineage tracing, parabiosis, and single-cell transcriptomics. We found that regeneration is a biphasic process driven by distinct populations arising from differentiated endothelial cells. The majority of cells immediately adjacent to the injury site re-enter the cell cycle during the initial damage response, with a second phase driven by a highly proliferative subpopulation. Endothelial regeneration requires activation of stress response genes including Atf3, and aged aortas compromised in their reparative capacity express less Atf3. Deletion of Atf3 reduced endothelial proliferation and compromised the regeneration. These findings provide important insights into cellular dynamics and mechanisms that drive responses to large vessel injury.

KEYWORDS:

angiogenesis; endothelial progenitor; single-cell sequencing; vascular; vascular repair

PMID:
30075129
PMCID:
PMC6178982
[Available on 2019-08-02]
DOI:
10.1016/j.stem.2018.07.011

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