Investigating versican as a primary inhibitor of remyelination in models of multiple sclerosis
Date
2022-01
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Abstract
The demyelination that characterizes multiple sclerosis (MS) lesions can be repaired to a degree in some individuals, though in many patients, this repair is inadequate. Remyelination has the potential to restore function in the central nervous system (CNS). In order to promote remyelination in MS lesions, the inhibition of oligodendrocyte precursor cell (OPC) recruitment and differentiation must be overcome. Targeting the deposited extracellular matrix (ECM) factors in the lesion to create a more permissive environment for OPCs is a promising therapeutic strategy. Versican, and likely its V1 isoform, has been identified as a prominent inhibitory chondroitin sulfate proteoglycan (CSPG) that is upregulated in the MS lesion. In this thesis, I sought to determine the outcome of the interaction between newly available purified V1 and OPCs in culture. I observed a robust inhibitory effect of V1 as a substrate and as a soluble treatment on OPCs in vitro. Using the lysolecithin (LPC) murine model of demyelination and remyelination, where versican upregulation in CNS lesions appears to be in macrophages/microglia from previous studies, I conditionally deleted versican from CCR2+ monocytes to evaluate the outcome on OPC presence in the lesion. The conditional versican knockout was dependent on the administration of tamoxifen and resulted in reduced V1 in the lesion compared to controls. With less V1 in the lesion, there was an increase in oligodendrocyte lineage cells during the documented period of remyelination in the LPC lesion. These results are promising in proposing a target for future therapeutic strategies to improve remyelination in MS lesions.
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Keywords
Multiple sclerosis, remyelination, lysolecithin, oligodendrocyte, demyelination, versican
Citation
Jelinek, E. (2022). Investigating versican as a primary inhibitor of remyelination in models of multiple sclerosis (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.