Novel zebrafish model to investigate the regenerative capacities of oligodendrocytes following demyelination
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Date
16/06/2022Author
Neely, Sarah Anna
Metadata
Abstract
Myelination is critical for rapid action potential propagation along axons within the nervous system, and plays a number of additional important roles including providing metabolic support to axons, thereby facilitating lifelong neuronal health. Consequently, damage to or loss of myelin is associated with impaired nervous system function and axonal degeneration in demyelinating diseases, including Multiple Sclerosis (MS). In response to demyelination, oligodendrocytes can remyelinate axons and repair damaged myelin. However, the extent to which this process occurs endogenously in humans is limited and often fails in progressive disease. In comparison, animal models of remyelination typically have more robust regenerative responses, raising the question of why remyelination fails in humans, and how it can be promoted for the treatment of demyelinating disease.
One such strategy, which has driven the successful discovery of a number of novel therapeutics for the treatment of MS, is to encourage remyelination by promoting the production of new oligodendrocytes generated following demyelination. However, the outcomes of clinical trials which promote oligodendrocyte generation have had varied success, indicating that additional understanding of the process of remyelination is required.
Interestingly, recent research now suggests that oligodendrocytes that survive demyelination can also contribute to remyelination, although the extent to which surviving oligodendrocytes contribute to remyelination compared to newly generated oligodendrocytes remains unclear. I sought to characterise the responses of different oligodendrocytes following demyelination, and compare their regenerative capacities in a novel zebrafish model, where I could follow de- and re-myelination of single oligodendrocytes over time in vivo.
I first characterised the level of myelin sheath and oligodendrocyte loss in a novel zebrafish demyelination model (Tg(mbp:TRPV1-tagRFPt)) in which the addition of capsaicin to the tank water of the zebrafish could be used to induce demyelination. Using transgenic lines to fluorescently label oligodendrocytes and myelin sheaths, and confocal microscopy to image live zebrafish, I followed the process of de- and re-myelination. I hypothesised that a rapid capsaicin treatment would result in severe demyelination and oligodendrocyte loss. However, I found that despite the extensive demyelination, there was a much less severe loss of oligodendrocytes. Given that many oligodendrocytes were extensively demyelinated but survived demyelination, this provided a powerful platform to compare the regenerative potential of oligodendrocytes that survived demyelination, and those which were newly generated following demyelination.
I next assessed the behaviour of single oligodendrocytes following demyelination. By comparing the number of myelin sheaths produced by single surviving and newly generated oligodendrocytes, I found that surviving oligodendrocytes had a much more limited capacity for remyelination. Moreover, surviving oligodendrocytes often mistargeted the myelin they did make to neuronal cell bodies. Additionally, I found that trying to promote remyelination using a Rho-Kinase inhibitor treatment increased sheath production by newly formed oligodendrocytes during development, but only further increased myelin mistargeting by surviving oligodendrocytes following demyelination.
Collectively, this research contributes to the growing body of literature that suggests that oligodendrocytes can survive demyelination and contribute to remyelination. Furthermore, it also raises important questions regarding the potential implications of driving increased remyelination by surviving oligodendrocytes.