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

doi:10.1016/j.isci.2023.107966

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 journal › Article › peer-review

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. [Abstract copyright: © 2023 The Author(s).]

Original language	English
Article number	107966
Pages (from-to)	107966
Journal	iScience
Volume	26
Issue number	10
Early online date	19 Sept 2023
DOIs	https://doi.org/10.1016/j.isci.2023.107966
Publication status	Published - 20 Oct 2023

Bibliographical note

© 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

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.

Keywords

Omics
Molecular biology
Transcriptomics
Cell biology
Microenvironment

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10.1016/j.isci.2023.107966Licence: CC BY 4.0

1-s2.0-S2589004223020436-main
© 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/
Final published version, 7.1 MBLicence: CC BY 4.0

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Wilkinson, A. L., Hulme, S., Kennedy, J. I., Mann, E. R., Horn, P., Shepherd, E. L., Yin, K., Zaki, M. Y. W., Hardisty, G., Lu, W.-Y., Rantakari, P., Adams, D. H., Salmi, M., Hoare, M., Patten, D. A., & Shetty, S. (2023). The senescent secretome drives PLVAP expression in cultured human hepatic endothelial cells to promote monocyte transmigration. iScience, 26(10), 107966. Article 107966. https://doi.org/10.1016/j.isci.2023.107966

@article{bb6871c95f64479192f698f595cdd1e2,

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

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. [Abstract copyright: {\textcopyright} 2023 The Author(s).]",

keywords = "Omics, Molecular biology, Transcriptomics, Cell biology, Microenvironment",

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

note = "{\textcopyright} 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ 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{\textquoteright}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 Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer. 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.",

year = "2023",

month = oct,

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doi = "10.1016/j.isci.2023.107966",

language = "English",

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Wilkinson, AL, Hulme, S, Kennedy, JI, Mann, ER, Horn, P, Shepherd, EL, Yin, K, Zaki, MYW, Hardisty, G, Lu, W-Y, Rantakari, P, Adams, DH, Salmi, M, Hoare, M, Patten, DA & Shetty, S 2023, 'The senescent secretome drives PLVAP expression in cultured human hepatic endothelial cells to promote monocyte transmigration', iScience, vol. 26, no. 10, 107966, pp. 107966. https://doi.org/10.1016/j.isci.2023.107966

TY - JOUR

T1 - The senescent secretome drives PLVAP expression in cultured human hepatic endothelial cells to promote monocyte transmigration

AU - Wilkinson, Alex L

AU - Hulme, Samuel

AU - Kennedy, James I

AU - Mann, Emily R

AU - Horn, Paul

AU - Shepherd, Emma L

AU - Yin, Kelvin

AU - Zaki, Marco Y W

AU - Hardisty, Gareth

AU - Lu, Wei-Yu

AU - Rantakari, Pia

AU - Adams, David H

AU - Salmi, Marko

AU - Hoare, Matthew

AU - Patten, Daniel A

AU - Shetty, Shishir

N1 - © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ 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.

PY - 2023/10/20

Y1 - 2023/10/20

N2 - 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).]

AB - 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).]

KW - Omics

KW - Molecular biology

KW - Transcriptomics

KW - Cell biology

KW - Microenvironment

UR - https://www.sciencedirect.com/science/article/pii/S2589004223020436

UR - http://www.scopus.com/inward/record.url?scp=85173437766&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2023.107966

DO - 10.1016/j.isci.2023.107966

M3 - Article

C2 - 37810232

SN - 2589-0042

VL - 26

SP - 107966

JO - iScience

JF - iScience

IS - 10

M1 - 107966

ER -

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

Abstract

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Keywords

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