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The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles

Marcela Rosas, David A. Slatter, Samya G. Obaji, Jason Webber Orcid Logo, Jorge Alvarez-Jarreta Orcid Logo, Christopher P. Thomas, Maceler Aldrovandi, Victoria J. Tyrrell, Peter V. Jenkins, Valerie B. O’Donnell, Peter W. Collins Orcid Logo

PLOS ONE, Volume: 15, Issue: 10, Start page: e0240189

Swansea University Author: Jason Webber Orcid Logo

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Abstract

Tissue factor (TF) is critical for the activation of blood coagulation. TF function is regulated by the amount of externalised phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the surface of the cell in which it is expressed. We investigated the role PS and PE in fibroblast TF function....

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Published in: PLOS ONE
ISSN: 1932-6203
Published: Public Library of Science (PLoS) 2020
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URI: https://cronfa.swan.ac.uk/Record/cronfa61407
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Fibroblasts expressed 6&#x2013;9 x 104 TF molecules/cell but had low specific activity for FXa generation. We confirmed that this was associated with minimal externalized PS and PE and characterised for the first time the molecular species of PS/PE demonstrating that these differed from those found in platelets. Mechanical damage of fibroblasts, used to simulate vascular injury, increased externalized PS/PE and led to a 7-fold increase in FXa generation that was inhibited by annexin V and an anti-TF antibody. Platelet-derived extracellular vesicles (EVs), that did not express TF, supported minimal FVIIa-dependent FXa generation but substantially increased fibroblast TF activity. This enhancement in fibroblast TF activity could also be achieved using synthetic liposomes comprising 10% PS without TF. In conclusion, despite high levels of surface TF expression, healthy fibroblasts express low levels of external-facing PS and PE limiting their ability to generate FXa. 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spelling 2022-10-28T16:53:46.0547088 v2 61407 2022-10-03 The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles 25d1a26f9b8bb556bd9412080e40351d 0000-0003-4772-3014 Jason Webber Jason Webber true false 2022-10-03 BMS Tissue factor (TF) is critical for the activation of blood coagulation. TF function is regulated by the amount of externalised phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the surface of the cell in which it is expressed. We investigated the role PS and PE in fibroblast TF function. Fibroblasts expressed 6–9 x 104 TF molecules/cell but had low specific activity for FXa generation. We confirmed that this was associated with minimal externalized PS and PE and characterised for the first time the molecular species of PS/PE demonstrating that these differed from those found in platelets. Mechanical damage of fibroblasts, used to simulate vascular injury, increased externalized PS/PE and led to a 7-fold increase in FXa generation that was inhibited by annexin V and an anti-TF antibody. Platelet-derived extracellular vesicles (EVs), that did not express TF, supported minimal FVIIa-dependent FXa generation but substantially increased fibroblast TF activity. This enhancement in fibroblast TF activity could also be achieved using synthetic liposomes comprising 10% PS without TF. In conclusion, despite high levels of surface TF expression, healthy fibroblasts express low levels of external-facing PS and PE limiting their ability to generate FXa. Addition of platelet-derived TF-negative EVs or artificial liposomes enhanced fibroblast TF activity in a PS dependent manner. These findings contribute information about the mechanisms that control TF function in the fibroblast membrane. Journal Article PLOS ONE 15 10 e0240189 Public Library of Science (PLoS) 1932-6203 8 10 2020 2020-10-08 10.1371/journal.pone.0240189 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee Funding is acknowledged from: The British Heart Foundation (PG/14/29/30783) to PWC. Wellcome Trust (094143/Z/10/Z) to VOD European Research Council (LipidArrays) to VOD. CPT and VJT were funded by Medical Research Council grant (MR/M011445/1). 2022-10-28T16:53:46.0547088 2022-10-03T14:48:22.2998758 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Marcela Rosas 1 David A. Slatter 2 Samya G. Obaji 3 Jason Webber 0000-0003-4772-3014 4 Jorge Alvarez-Jarreta 0000-0002-0946-0957 5 Christopher P. Thomas 6 Maceler Aldrovandi 7 Victoria J. Tyrrell 8 Peter V. Jenkins 9 Valerie B. O’Donnell 10 Peter W. Collins 0000-0002-6410-1324 11 61407__25609__08e5d39fdb454330942798c9f6ef516b.pdf 61407_VoR.pdf 2022-10-28T16:52:47.2714666 Output 1781828 application/pdf Version of Record true © 2020 Rosas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License true eng http://creativecommons.org/licenses/by/4.0/
title The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
spellingShingle The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
Jason Webber
title_short The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
title_full The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
title_fullStr The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
title_full_unstemmed The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
title_sort The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
author_id_str_mv 25d1a26f9b8bb556bd9412080e40351d
author_id_fullname_str_mv 25d1a26f9b8bb556bd9412080e40351d_***_Jason Webber
author Jason Webber
author2 Marcela Rosas
David A. Slatter
Samya G. Obaji
Jason Webber
Jorge Alvarez-Jarreta
Christopher P. Thomas
Maceler Aldrovandi
Victoria J. Tyrrell
Peter V. Jenkins
Valerie B. O’Donnell
Peter W. Collins
format Journal article
container_title PLOS ONE
container_volume 15
container_issue 10
container_start_page e0240189
publishDate 2020
institution Swansea University
issn 1932-6203
doi_str_mv 10.1371/journal.pone.0240189
publisher Public Library of Science (PLoS)
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Tissue factor (TF) is critical for the activation of blood coagulation. TF function is regulated by the amount of externalised phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the surface of the cell in which it is expressed. We investigated the role PS and PE in fibroblast TF function. Fibroblasts expressed 6–9 x 104 TF molecules/cell but had low specific activity for FXa generation. We confirmed that this was associated with minimal externalized PS and PE and characterised for the first time the molecular species of PS/PE demonstrating that these differed from those found in platelets. Mechanical damage of fibroblasts, used to simulate vascular injury, increased externalized PS/PE and led to a 7-fold increase in FXa generation that was inhibited by annexin V and an anti-TF antibody. Platelet-derived extracellular vesicles (EVs), that did not express TF, supported minimal FVIIa-dependent FXa generation but substantially increased fibroblast TF activity. This enhancement in fibroblast TF activity could also be achieved using synthetic liposomes comprising 10% PS without TF. In conclusion, despite high levels of surface TF expression, healthy fibroblasts express low levels of external-facing PS and PE limiting their ability to generate FXa. Addition of platelet-derived TF-negative EVs or artificial liposomes enhanced fibroblast TF activity in a PS dependent manner. These findings contribute information about the mechanisms that control TF function in the fibroblast membrane.
published_date 2020-10-08T04:20:14Z
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