Altering Inhibitory Extracellular Matrix Promotes Remyelination

Remyelination is the generation of new myelin sheaths after injury, and is accomplished by oligodendrocyte precursor cells (OPCs) that proliferate, migrate, and differentiate into myelin-forming oligodendrocytes. A number of lesion-associated factors have been identified that interfere with the remyelination response. Chondroitin sulfate proteoglycans (CSPGs) are a family of extracellular matrix molecules that provide structural rigidity to tissues and act as signalling molecules to neurons and glia in the developing nervous system. After injury, CSPGs become highly upregulated by astrocytes as part of the glial scar and restrict axonal regeneration. The role of injury-induced CSPG deposition on OPCs and remyelination is far less understood. In this thesis, I characterized a potent inhibitory phenotype of murine OPC adhesion and process outgrowth cultured on CSPGs in vitro. I explored the various mechanisms underlying this inhibitory response, including candidate receptors, downstream signalling molecules, and structural ligands on CSPGs through selective enzymatic degradation. I screened 245 orally available, Health Canada approved medicines for their ability to overcome OPC process outgrowth in the presence of CSPGs, and found a persistent inhibitory phenotype for all drugs tested. Lastly, I assessed the utility of a novel CSPG synthesis inhibitor, fluorosamine, and found that it reduced CSPG synthesis by astrocytes, resulting in a more permissive environment for OPC growth in vitro. Following experimental demyelination with lysolecithin in vivo, fluorosamine treatment reduced the deposition of CSPGs and enhanced OPC maturation and remyelination. Altering the inhibitory microenvironment after injury may be beneficial for promoting repair in a number of neurological diseases.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Neuroscience

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2015

Author dc:creator

• Keough, Michael

Advisor dc:contributor.advisor

• Yong, V. Wee

• Neuroscience

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/24777

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/2327