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Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation

Sara Veiga, Alex P. Shephard, Kate Milward, Alex Cocks, Félix Royo, Juan M. Falcon‐Perez Orcid Logo, Aled Clayton, Jason Webber Orcid Logo

Journal of Extracellular Biology, Volume: 5, Issue: 5

Swansea University Author: Jason Webber Orcid Logo

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DOI (Published version): 10.1002/jex2.70146

Abstract

Extracellular vesicles (EVs) play a critical role in intercellular communication, yet the contribution of the EV corona and associated surface structures, such as heparan sulphate glycosaminoglycan (HS GAG) chains, to EV function remains poorly understood. In this study, we highlight a hitherto unkn...

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Published in: Journal of Extracellular Biology
ISSN: 2768-2811 2768-2811
Published: Wiley 2026
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URI: https://cronfa.swan.ac.uk/Record/cronfa71783
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In this study, we highlight a hitherto unknown requirement of HS GAG chains for the simultaneous delivery of a myriad assortment of growth factors by EVs. We demonstrate an attenuated function following enzymatic removal of HS GAG chains from the surface of prostate cancer (PCa)-derived EVs, using heparinase III (HepIII). Our results confirm that digestion of HS GAG chains is specific and does not compromise EV integrity regarding size or tetraspanin expression. Enzymatic removal of HS GAG chains did, however, substantially altered the vesicular protein profile, reducing the expression of factors such as midkine, CYR61 and TFPI implicating HS GAG chains as a mode of tethering these factors to the EV surface. Importantly, EV-associated HS GAG chains are required for functional delivery of such factors, resulting in successful activation of cellular signalling pathways for SCF, IGF-1, midkine and VEGF in recipient fibroblasts. 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spelling 2026-05-15T15:16:56.8864881 v2 71783 2026-04-22 Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation 25d1a26f9b8bb556bd9412080e40351d 0000-0003-4772-3014 Jason Webber Jason Webber true false 2026-04-22 MEDS Extracellular vesicles (EVs) play a critical role in intercellular communication, yet the contribution of the EV corona and associated surface structures, such as heparan sulphate glycosaminoglycan (HS GAG) chains, to EV function remains poorly understood. In this study, we highlight a hitherto unknown requirement of HS GAG chains for the simultaneous delivery of a myriad assortment of growth factors by EVs. We demonstrate an attenuated function following enzymatic removal of HS GAG chains from the surface of prostate cancer (PCa)-derived EVs, using heparinase III (HepIII). Our results confirm that digestion of HS GAG chains is specific and does not compromise EV integrity regarding size or tetraspanin expression. Enzymatic removal of HS GAG chains did, however, substantially altered the vesicular protein profile, reducing the expression of factors such as midkine, CYR61 and TFPI implicating HS GAG chains as a mode of tethering these factors to the EV surface. Importantly, EV-associated HS GAG chains are required for functional delivery of such factors, resulting in successful activation of cellular signalling pathways for SCF, IGF-1, midkine and VEGF in recipient fibroblasts. Furthermore, HS GAG chain removal attenuated EV-induced fibroblast production of pro-angiogenic factors VEGF and angiogenin as well as inflammatory factors VCAM-1 and IL-1α alpha/IL-1F1, underscoring the role of vesicular HS GAG chains in mediating functional outcomes. These findings highlight the importance of EV surface HS GAG chains in growth factor delivery and signalling, providing new insights into the EV corona and its relevance in pathological processes relating to modulation of the tissue microenvironment. Journal Article Journal of Extracellular Biology 5 5 Wiley 2768-2811 2768-2811 9 5 2026 2026-05-09 10.1002/jex2.70146 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University SU Library paid the OA fee (TA Institutional Deal) Prostate Cancer UK (Grant Number: CDF13-001); Cancer Research Wales (Grant Number: 2492). 2026-05-15T15:16:56.8864881 2026-04-22T16:14:32.2382774 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Sara Veiga 1 Alex P. Shephard 2 Kate Milward 3 Alex Cocks 4 Félix Royo 5 Juan M. Falcon‐Perez 0000-0003-3133-0670 6 Aled Clayton 7 Jason Webber 0000-0003-4772-3014 8 71783__36756__8a4d4c12c63c4f2f969586fafbcbc441.pdf 71783.VoR.pdf 2026-05-15T15:14:55.2512331 Output 2729595 application/pdf Version of Record true © 2026 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License. true eng http://creativecommons.org/licenses/by/4.0/
title Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation
spellingShingle Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation
Jason Webber
title_short Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation
title_full Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation
title_fullStr Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation
title_full_unstemmed Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation
title_sort Heparan Sulphate Glycosaminoglycan Chains Contribute to the Tethering of Coronal Factors and Are Important for Extracellular Vesicle‐Mediated Fibroblast Activation
author_id_str_mv 25d1a26f9b8bb556bd9412080e40351d
author_id_fullname_str_mv 25d1a26f9b8bb556bd9412080e40351d_***_Jason Webber
author Jason Webber
author2 Sara Veiga
Alex P. Shephard
Kate Milward
Alex Cocks
Félix Royo
Juan M. Falcon‐Perez
Aled Clayton
Jason Webber
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container_title Journal of Extracellular Biology
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container_issue 5
publishDate 2026
institution Swansea University
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2768-2811
doi_str_mv 10.1002/jex2.70146
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
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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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description Extracellular vesicles (EVs) play a critical role in intercellular communication, yet the contribution of the EV corona and associated surface structures, such as heparan sulphate glycosaminoglycan (HS GAG) chains, to EV function remains poorly understood. In this study, we highlight a hitherto unknown requirement of HS GAG chains for the simultaneous delivery of a myriad assortment of growth factors by EVs. We demonstrate an attenuated function following enzymatic removal of HS GAG chains from the surface of prostate cancer (PCa)-derived EVs, using heparinase III (HepIII). Our results confirm that digestion of HS GAG chains is specific and does not compromise EV integrity regarding size or tetraspanin expression. Enzymatic removal of HS GAG chains did, however, substantially altered the vesicular protein profile, reducing the expression of factors such as midkine, CYR61 and TFPI implicating HS GAG chains as a mode of tethering these factors to the EV surface. Importantly, EV-associated HS GAG chains are required for functional delivery of such factors, resulting in successful activation of cellular signalling pathways for SCF, IGF-1, midkine and VEGF in recipient fibroblasts. Furthermore, HS GAG chain removal attenuated EV-induced fibroblast production of pro-angiogenic factors VEGF and angiogenin as well as inflammatory factors VCAM-1 and IL-1α alpha/IL-1F1, underscoring the role of vesicular HS GAG chains in mediating functional outcomes. These findings highlight the importance of EV surface HS GAG chains in growth factor delivery and signalling, providing new insights into the EV corona and its relevance in pathological processes relating to modulation of the tissue microenvironment.
published_date 2026-05-09T06:25:03Z
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