Low sulfated heparins target multiple proteins for central nervous system repair

McCanney, G. A., Mcgrath, M. A., Otto, T. D. , Burchmore, R. , Yates, E. A., Bavington, C. D., Willison, H. J. , Turnbull, J. E. and Barnett, S. C. (2019) Low sulfated heparins target multiple proteins for central nervous system repair. Glia, 67(4), pp. 668-687. (doi:10.1002/glia.23562) (PMID:30585359)

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Abstract

The lack of endogenous repair following spinal cord injury (SCI) accounts for the frequent permanent deficits for which effective treatments are absent. Previously, we demonstrated that low sulfated modified heparin mimetics (LS‐mHeps) attenuate astrocytosis, suggesting they may represent a novel therapeutic approach. mHeps are glycomolecules with structural similarities to resident heparan sulfates (HS), which modulate cell signaling by both sequestering ligands, and acting as cofactors in the formation of ligand–receptor complexes. To explore whether mHeps can affect the myelination and neurite outgrowth necessary for repair after SCI, we created lesioned or demyelinated neural cell co‐cultures and exposed them with a panel of mHeps with varying degrees and positions of their sulfate moieties. LS‐mHep7 enhanced neurite outgrowth and myelination, whereas highly sulfated mHeps (HS‐mHeps) had attenuating effects. LS‐mHeps had no effects on myelination or neurite extension in developing, uninjured myelinating cultures, suggesting they might exert their proregenerating effects by modulating or sequestering inhibitory factors secreted after injury. To investigate this, we examined conditioned media from cultures using chemokine arrays and conducted an unbiased proteomics approach by applying TMT‐LC/MS to mHep7 affinity purified conditioned media from these cultures. Multiple protein factors reported to play a role in damage or repair mechanisms were identified, including amyloid betaA4. Amyloid beta peptide (1–42) was validated as an important candidate by treating myelination cultures and shown to inhibit myelination. Thus, we propose that LS‐mHeps exert multiple beneficial effects on mechanisms supporting enhanced repair, and represent novel candidates as therapeutics for CNS damage.

Item Type:Articles
Additional Information:Funding information Chief Scientist Office, Grant/Award Number: ETM/439; Medical Research Scotland, Grant/Award Numbers: PhD‐769‐2014, PhD‐769‐2014; Wellcome Trust, Grant/Award Number: 202789/Z/16/Z; CSO, Grant/Award Number: ETM/439
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burchmore, Dr Richard and McCanney, George and Willison, Professor Hugh and Barnett, Professor Susan and Mcgrath, Mr Michael and Otto, Dr Thomas
Authors: McCanney, G. A., Mcgrath, M. A., Otto, T. D., Burchmore, R., Yates, E. A., Bavington, C. D., Willison, H. J., Turnbull, J. E., and Barnett, S. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Glia
Publisher:Wiley
ISSN:0894-1491
ISSN (Online):1098-1136
Published Online:26 December 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Glia 67(4):668-687
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
690771Oligosaccharides as new therapeutic for CNS repairSusan BarnettChief Scientist office (CSO)ETM/439III -IMMUNOLOGY
707761Development of glycomolecules as novel therapeutics for the treatment of multiple sclerosisHugh WillisonMedical Research Scotland (MEDRESSC)PhD-769-2014III -IMMUNOLOGY
722551Pathophysiological factors in the diagnosis and treatment of the Guillain-Barre syndromesHugh WillisonWellcome Trust (WELLCOTR)202789/Z/16/ZIII -IMMUNOLOGY