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Nat Commun. 2016 Jan 8;7:10160. doi: 10.1038/ncomms10160.

A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity.

Author information

1
Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
2
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
3
Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.
4
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
5
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
6
Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, 9700 AB Groningen, The Netherlands.
7
Cardiovascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
8
Department of Medicine, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
9
St. Michaels's Hospital, Toronto, Ontario M5B 1W8, Canada.

Abstract

Previous studies have shown that biological noise may drive dynamic phenotypic mosaicism in isogenic unicellular organisms. However, there is no evidence for a similar mechanism operating in metazoans. Here we show that the endothelial-restricted gene, von Willebrand factor (VWF), is expressed in a mosaic pattern in the capillaries of many vascular beds and in the aorta. In capillaries, the mosaicism is dynamically regulated, with VWF switching between ON and OFF states during the lifetime of the animal. Clonal analysis of cultured endothelial cells reveals that dynamic mosaic heterogeneity is controlled by a low-barrier, noise-sensitive bistable switch that involves random transitions in the DNA methylation status of the VWF promoter. Finally, the hearts of VWF-null mice demonstrate an abnormal endothelial phenotype as well as cardiac dysfunction. Together, these findings suggest a novel stochastic phenotype switching strategy for adaptive homoeostasis in the adult vasculature.

PMID:
26744078
PMCID:
PMC5154372
DOI:
10.1038/ncomms10160
[Indexed for MEDLINE]
Free PMC Article

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