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Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries

Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries
Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries
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.
2045-2322
Warren, Philippa
981cc20d-cc8e-493c-ab60-144d5ba8b0bf
Andrews, Melissa
ae987a2f-878e-4ae3-a7a3-a7170712096c
Smith, Marc
cb45ae5c-9291-4e0d-a2eb-30452a196be1
Bartus, Katalin
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Bradbury, Elizabeth
2e0a99fe-e53c-4576-9f89-316a4bee2ee0
Verhaagen, Joost
eedb3793-6169-4803-b886-b3e038e8d05f
Fawcett, James
87e8df06-202e-4d08-bd2f-c5a135b81d71
Kwok, Jessica
68f956ff-7cce-4368-b671-56e58aa928fc
Warren, Philippa
981cc20d-cc8e-493c-ab60-144d5ba8b0bf
Andrews, Melissa
ae987a2f-878e-4ae3-a7a3-a7170712096c
Smith, Marc
cb45ae5c-9291-4e0d-a2eb-30452a196be1
Bartus, Katalin
8313c9c1-d94f-48c7-99d9-7bd662f2fded
Bradbury, Elizabeth
2e0a99fe-e53c-4576-9f89-316a4bee2ee0
Verhaagen, Joost
eedb3793-6169-4803-b886-b3e038e8d05f
Fawcett, James
87e8df06-202e-4d08-bd2f-c5a135b81d71
Kwok, Jessica
68f956ff-7cce-4368-b671-56e58aa928fc

Warren, Philippa, Andrews, Melissa, Smith, Marc, Bartus, Katalin, Bradbury, Elizabeth, Verhaagen, Joost, Fawcett, James and Kwok, Jessica (2020) Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries. Scientific Reports, 10 (1), [11262]. (doi:10.1038/s41598-020-67526-0).

Record type: Article

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.

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270768_1_merged_1589968028_submitted manuscript - Accepted Manuscript
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Accepted/In Press date: 26 May 2020
e-pub ahead of print date: 9 July 2020

Identifiers

Local EPrints ID: 441376
URI: http://eprints.soton.ac.uk/id/eprint/441376
ISSN: 2045-2322
PURE UUID: 916cf704-bd86-42e3-9d7a-68869b8cff35
ORCID for Melissa Andrews: ORCID iD orcid.org/0000-0001-5960-5619

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Date deposited: 11 Jun 2020 16:30
Last modified: 10 Jan 2022 03:09

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Contributors

Author: Philippa Warren
Author: Melissa Andrews ORCID iD
Author: Marc Smith
Author: Katalin Bartus
Author: Elizabeth Bradbury
Author: Joost Verhaagen
Author: James Fawcett
Author: Jessica Kwok

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