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

Scientific Reports, 2020 · DOI: 10.1038/s41598-020-67526-0 · Published: July 15, 2020

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Following spinal cord injury, scar tissue forms which inhibits axon regeneration. This study uses a modified enzyme, mChABC, to digest the inhibitory components of the scar. The researchers found that mChABC, secreted from Schwann cells, promotes the migration and adhesion of these cells, facilitating their integration with astrocytes at the injury site. This enzyme enables neurite outgrowth, effectively bridging the gap between the peripheral and central nervous systems, offering a potential therapeutic approach for spinal cord injury.

Study Duration

Not specified

Participants

Adult female Sprague Dawley rats

Evidence Level

Not specified

Key Findings

1
mChABC robustly secreted from transduced Schwann cells leads to large-scale CSPG digestion, facilitating migration and adhesion on inhibitory substrates.
2
Secretion of mChABC aids the intermingling of cells at the Schwann cell-astrocyte boundary, enabling neurite growth over the graft/host interface.
3
mChABC gene therapy is equally or more effective than a one-time application of commercially available ChABC in producing these effects.

Research Summary

This study demonstrates that Schwann cells transduced with lentiviral vectors encoding ChABC can constitutively secrete high quantities of active mChABC, leading to CS-GAG removal and altered cell behavior. The mechanisms of mChABC on cellular activity explain the behavioral and regenerative effects of the enzyme in biochemical and in vivo studies. The effects produced from our modified mChABC enzyme are equivalent to, or greater than, the commercially available bChABC.

Practical Implications

Therapeutic Potential

mChABC gene therapy shows promise as a treatment for spinal cord injury by promoting glial integration and axonal regeneration.

Superior Efficacy

The modified mChABC enzyme is as effective as, or more effective than, commercially available bChABC, making it a valuable alternative.

Understanding CSPG Inhibition

The study provides insights into the mechanisms by which CSPGs inhibit cellular migration and growth, particularly through integrin-dependent pathways.

Study Limitations

1
A full biochemical analysis of mChABC activity, as compared to the commercially available bChABC, is still required.
2
Additional processes that could be affected by use of the enzyme, for example, effects on all ECM components, signalling pathways, ligands, receptor binding and autophagy2,64,70. These need to be addressed to determine all the mechanisms through which mChABC may mediate effects at the CNS/PNS boundary.
3
construct should be optimised, perhaps by placing it in an increasingly stable vector such as an adeno-associated virus86, or assessing the risk of insertional mutagenesis in host cells87.

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