The role of Galectin-3 in the subventricular zone response to demyelination

Multiple sclerosis (MS) is a debilitating neurological condition that causes demyelination and axon degeneration. While relapsing forms of the disease have been treatable for many years, progressive forms lack definitive treatment. An hypothesised therapy involves neural stem cells repairing and replacing damaged oligodendrocytes and neurons. The subventricular zone (SVZ) is a known site of adult neurogenesis and is adjacent to the corpus callosum (CC) white matter region. Previous studies have suggested that SVZ stem cells give rise to oligodendrocytes in the demyelinated CC in both MS and its animal models. This thesis examines the hypothesis that the pro-inflammatory molecule Galectin-3 (Gal-3) impacts on the SVZ regenerative response. The thesis firstly shows a juxtaposition of inflammation between the SVZ and CC, with the SVZ becoming less inflamed during cuprizone treatment while the CC becomes more inflamed. This observation occurs with Gal-3+ astrocytes and microglia, CD45+ haematopoietic cells, and PHi3+ proliferating cells. The absence of Gal-3 in knockout transgenic mice does not, however, alter this inflammation. The thesis then shows an increase in knockout mice compared to wild-type mice of myelin basic protein levels in layer six of the motor cortex, as well as suggesting knockout mice have more SVZ cells migrating into the CC. These findings lead to the hypothesis of Gal-3 absence allowing SVZ cells to migrate into the CC and possibly lower cortical layers, and contributing to better remyelination. This mechanism is evaluated further with in vitro studies, which show that Gal-3 enhances neuronal differentiation in SVZ neurosphere cultures. Gal-3 absence does not, however, cause a significant change in the proportion of oligodendrocytes in SVZ neurosphere cultures, or in the number of oligodendrocytes after cuprizone treatment. Overall this thesis provides results that could impact on the best utilisation of SVZ stem cells to treat MS.