Cortical injury, such as that following stroke, is one of the leading causes of long-term disabilities world-wide. While some neuroprotective agents given within hours of stroke can reduce damage, there are currently no neurorestorative therapeutics that can enhance long-term recovery. To address this, we tested Mesenchymal Stem Cell (MSC) derived Extracellular Vesicles (EVs) as a treatment for cortical injury in rhesus monkeys (Macaca mulatta). Monkeys treated with EVs 24 hours after injury and again at 14 days after injury recovered more completely and more rapidly than monkeys given a vehicle control. However, the cellular changes associated with enhanced recovery remained unknown. In this dissertation, it was hypothesized that EVs modulated cells within the brain to enhance recovery after cortical injury. To explore this hypothesis, three specific aims were tested. Aim 1: To determine the effects of EVs on microglial reactivity. Since EVs in this study were derived from MSCs, it was hypothesized that they would have an immunomodulatory effect. Using immunohistochemistry, image analyses, and 3-D reconstruction, we showed that microglia shifted from reactive, damaging phenotypes towards homeostatic, surveilling functions in EV-treated monkeys. These effects correlated with reduced time to recovery, suggesting that reduced microglial reactivity enhanced recovery. Aim 2: To assess the effects of EVs on myelination. Because MSCs have regenerative effects, it was hypothesized that these MSC-derived EVs would improve neurorestoration. Using immunohistochemistry, qRT-PCR, Spectral Confocal Reflectance microscopy, and ELISA, we assessed myelination after cortical injury with and without EV treatment. EVs limited oligodendrocyte damage and increased densities of mature oligodendrocytes to enhance myelin maintenance. These effects correlated with improved recovery, suggesting the importance of myelination in recovery after cortical injury. Aim 3: To assess the neuroprotective role of EVs on infarct volumes. While it was hypothesized that EVs would reduce the densities of inflammatory cells (astrocytes, macrophages/microglia, T-cells), hemosiderin accumulation, and infarct volume, we found that EVs did not alter these endpoints. Collectively, our results suggest that EVs modulated microglia and oligodendrocytes to promote neurorestoration. Overall, these findings demonstrate the therapeutic potential of EVs for neurorestoration after cortical injury.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/42060 |
| Date | 17 February 2021 |
| Creators | Go, Veronica |
| Contributors | Moore, Tara L., Rosene, Douglas L. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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