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The senescent secretome drives PLVAP expression in cultured human hepatic endothelial cells to promote monocyte transmigration.

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Wilkinson, Alex L 
Hulme, Samuel 
Kennedy, James I 
Mann, Emily R 
Horn, Paul 

Abstract

Liver sinusoidal endothelial cells (LSEC) undergo significant phenotypic change in chronic liver disease (CLD), and yet the factors that drive this process and the impact on their function as a vascular barrier and gatekeeper for immune cell recruitment are poorly understood. Plasmalemma-vesicle-associated protein (PLVAP) has been characterized as a marker of LSEC in CLD; notably we found that PLVAP upregulation strongly correlated with markers of tissue senescence. Furthermore, exposure of human LSEC to the senescence-associated secretory phenotype (SASP) led to a significant upregulation of PLVAP. Flow-based assays demonstrated that SASP-driven leukocyte recruitment was characterized by paracellular transmigration of monocytes while the majority of lymphocytes migrated transcellularly. Knockdown studies confirmed that PLVAP selectively supported monocyte transmigration mediated through PLVAP's impact on LSEC permeability by regulating phospho-VE-cadherin expression and endothelial gap formation. PLVAP may therefore represent an endothelial target that selectively shapes the senescence-mediated immune microenvironment in liver disease.

Description

Keywords

Cell biology, Microenvironment, Molecular biology, Omics, Transcriptomics

Journal Title

iScience

Conference Name

Journal ISSN

2589-0042
2589-0042

Volume Title

Publisher

Elsevier BV
Sponsorship
Cancer Research UK (via Newcastle University) (BH183441)
Cancer Research UK (DRCPFA-Jun22\100001)
Medical Research Council (MR/R010013/1)
Cancer Research UK (19924)
MRC (MR/X00970X/1)