Heparan sulphate glycosaminoglycan chains contribute to the tethering of coronal factors and are important for extracellular vesicle‐mediated fibroblast activation

Veiga, Sara, Shephard, Alex P., Milward, Kate ORCID: https://orcid.org/0000-0003-3019-4443, Cocks, Alex, Royo, Félix, Falcon‐Perez, Juan M., Clayton, Aled ORCID: https://orcid.org/0000-0002-3087-9226 and Webber, Jason P. ORCID: https://orcid.org/0000-0003-4772-3014 2026. Heparan sulphate glycosaminoglycan chains contribute to the tethering of coronal factors and are important for extracellular vesicle‐mediated fibroblast activation. Journal of Extracellular Biology 5 (5) , e70146. 10.1002/jex2.70146

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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 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	2768-2811
Date of First Compliant Deposit:	13 May 2026
Date of Acceptance:	17 April 2026
Last Modified:	13 May 2026 10:15
URI:	https://orca.cardiff.ac.uk/id/eprint/186975

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