Warren, PM, Andrews, MR, Smith, M et al. (5 more authors) (2020) Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries. Scientific Reports, 10. 11262. ISSN 2045-2322
Abstract
Schwann cell grafts support axonal growth following spinal cord injury, but a boundary forms between the implanted cells and host astrocytes. Axons are reluctant to exit the graft tissue in large part due to the surrounding inhibitory environment containing chondroitin sulphate proteoglycans (CSPGs). We use a lentiviral chondroitinase ABC, capable of being secreted from mammalian cells (mChABC), to examine the repercussions of CSPG digestion upon Schwann cell behaviour in vitro. We show that mChABC transduced Schwann cells robustly secrete substantial quantities of the enzyme causing large-scale CSPG digestion, facilitating the migration and adhesion of Schwann cells on inhibitory aggrecan and astrocytic substrates. Importantly, we show that secretion of the engineered enzyme can aid the intermingling of cells at the Schwann cell-astrocyte boundary, enabling growth of neurites over the putative graft/host interface. These data were echoed in vivo. This study demonstrates the profound effect of the enzyme on cellular motility, growth and migration. This provides a cellular mechanism for mChABC induced functional and behavioural recovery shown in in vivo studies. Importantly, we provide in vitro evidence that mChABC gene therapy is equally or more effective at producing these effects as a one-time application of commercially available ChABC.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number Wings For Life Spinal Cord Research Foundation WFL-UK-008/15 Proj 118 MRC (Medical Research Council) RG84584 Wings For Life Spinal Cord Research Foundation WFL-UK-008/15 International Spinal Research Trust NRB119 - Kwok MRC (Medical Research Council) MR/S011110/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 29 May 2020 13:11 |
Last Modified: | 31 Jul 2020 14:59 |
Status: | Published |
Publisher: | Nature Research |
Identification Number: | 10.1038/s41598-020-67526-0 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:161342 |