Microtopographical cues promote peripheral nerve regeneration via transient mTORC2 activation

Thomson, S. E., Charalambous, C., Smith, C.-A. , Tsimbouri, P. M. , Déjardin, T., Kingham, P. J., Hart, A. M. and Riehle, M. O. (2017) Microtopographical cues promote peripheral nerve regeneration via transient mTORC2 activation. Acta Biomaterialia, 60, pp. 220-231. (doi: 10.1016/j.actbio.2017.07.031) (PMID:28754648) (PMCID:PMC5593812)

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Abstract

Despite microsurgical repair, recovery of function following peripheral nerve injury is slow and often incomplete. Outcomes could be improved by an increased understanding of the molecular biology of regeneration and by translation of experimental bioengineering strategies. Topographical cues have been shown to be powerful regulators of the rate and directionality of neurite regeneration, and in this study we investigated the downstream molecular effects of linear micropatterned structures in an organotypic explant model. Linear topographical cues enhanced neurite outgrowth and our results demonstrated that the mTOR pathway is important in regulating these responses. mTOR gene expression peaked between 48 and 72 h, coincident with the onset of rapid neurite outgrowth and glial migration, and correlated with neurite length at 48 h. mTOR protein was located to glia and in a punctate distribution along neurites. mTOR levels peaked at 72 h and were significantly increased by patterned topography (p < 0.05). Furthermore, the topographical cues could override pharmacological inhibition. Downstream phosphorylation assays and inhibition of mTORC1 using rapamycin highlighted mTORC2 as an important mediator, and more specific therapeutic target. Quantitative immunohistochemistry confirmed the presence of the mTORC2 component rictor at the regenerating front where it co-localised with F-actin and vinculin. Collectively, these results provide a deeper understanding of the mechanism of action of topography on neural regeneration, and support the incorporation of topographical patterning in combination with pharmacological mTORC2 potentiation within biomaterial constructs used to repair peripheral nerves.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Thomson, Miss Suzanne and Kingham, Dr Paul and Tsimbouri, Dr Monica and Riehle, Dr Mathis and Hart, Mr Andrew and Smith, Mrs Carol-Anne
Authors: Thomson, S. E., Charalambous, C., Smith, C.-A., Tsimbouri, P. M., Déjardin, T., Kingham, P. J., Hart, A. M., and Riehle, M. O.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Acta Biomaterialia
Publisher:Elsevier
ISSN:1742-7061
ISSN (Online):1878-7568
Published Online:25 July 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Acta Biomaterialia 60: 220-231
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
645301Translational development of a novel 3-D nerve conduit - addressing the neurobiology of peripheral nerve injuries to improve outcomes following surgical repair.Mathis RiehleMedical Research Council (MRC)MR/L017741/1RI MOLECULAR CELL & SYSTEMS BIOLOGY