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

Alex L Wilkinson, Samuel Hulme, James I Kennedy, Emily R Mann, Paul Horn, Emma L Shepherd, Kelvin Yin, Marco Y W Zaki, Gareth Hardisty, Wei-Yu Lu, Pia Rantakari, David H Adams, Marko Salmi, Matthew Hoare, Daniel A Patten, Shishir Shetty

Research output: Contribution to journalArticlepeer-review


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. [Abstract copyright: © 2023 The Author(s).]
Original languageEnglish
Article number107966
Pages (from-to)107966
Issue number10
Early online date19 Sept 2023
Publication statusPublished - 20 Oct 2023

Bibliographical note

© 2023 The Authors. This is an open access article under the CC BY license (

Funding: ALW was funded by a Wellcome Trust Ph.D studentship in Mechanisms of Inflammatory Disease and a follow-on fund awarded by the University of Birmingham. DAP and SS are funded by a Medical Research Council Project Grant (MR/R010013/1) and a Cancer Research UK Advanced Clinician Scientist Fellowship (C53575/A29959) awarded to SS. JIK is funded by an Engineering and Physical Sciences Research Council LifETIME CDT Ph.D studentship. MYWZ and SS are funded by the Newton Prize 2020 as a part of the UK’s Official Development Assistance “ODA” and the Newton fund. MH is supported by a CRUK Advanced Clinician Scientist Fellowship (C52489/A19924); CRUK-OHSU Project Award (C52489/A29681); and CRUK Accelerator Award to the HUNTER consortium (C18873/A26813) funded through a partnership between Cancer Research United Kingdom, Fondazione AIRC, and Fundación Científica de la Asociación Española Contra el Cáncer. This paper represents independent research supported by the NIHR Birmingham Biomedical Research Center at the University Hospitals Birmingham NHS Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.


  • Omics
  • Molecular biology
  • Transcriptomics
  • Cell biology
  • Microenvironment


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