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

Austin I. McDonald, Aditya S. Shirali, Raquel Aragón, Feiyang Ma, Gloria Hernandez, Don A. Vaughn, Julia J. Mack, Tiffany Y. Lim, Hannah Sunshine, Peng Zhao, Vladimir Kalinichenko, Tsonwin Hai, Matteo Pelegrini, Reza Ardehali, M. Luisa Iruela-Arispe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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. Quiescent endothelial cells are able to mount a robust mitotic response even in the presence of pulsatile and high-velocity blood flow. McDonald et al. showed that regeneration of aortic inner lining involves a subset of cells with hidden proliferative capacity that undergo rapid and significant transcriptional changes.

Original languageEnglish (US)
Pages (from-to)210-225.e6
JournalCell stem cell
Volume23
Issue number2
DOIs
StatePublished - Aug 2 2018

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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