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Production and Functional Characterization of Placental Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles for the Treatment of Multiple Sclerosis in Vitro

Stagnaro, Ryan.   California State University, Sacramento ProQuest Dissertations Publishing,  2021. 28496880.

Abstract (summary)

Multiple sclerosis (MS) is a heterogeneous disease characterized by auto-immune inflammatory responses, accompanying demyelination and neurodegeneration. MS is thought to occur due to immune cell activation and infiltration of the central nervous system (CNS). The inflammatory response induced by MS leads to the destruction of myelin producing oligodendrocytes (ODs) in the CNS resulting in demyelination of nerve axons and subsequent axon loss. As there is no known cure for MS, current treatments focus on slowing disease progression by addressing the inflammatory component of MS; However, the accompanying neurodegenerative component of the disease is difficult to address. For patients facing continuous nerve damage following MS relapses, there are few effective treatment options. To address this issue, cellular based therapeutics have become an attractive option. Specifically, placenta derived mesenchymal stem/stromal cells (PMSCs) have become a lucrative target to treat MS due to their neuroprotective, pro-angiogenic and immunomodulatory properties. Previous studies in our lab have demonstrated that PMSCs and PMSC derived extracellular vesicle (PMSC-EV) treatments have comparable effects in reducing demyelination symptoms in an induced experimental autoimmune encephalomyelitis (EAE) murine model of MS. While this treatment appeared to be effective in treating motor deficits in EAE mice, the mechanism by which PMSC-EVs reverse demyelination is unknown. The primary focus of this project was to further elucidate the mechanism of action of PMSC-EVs on a cell model of MS. The first step in this project was to generate PMSC-EV populations. We explored the optimal culture conditions to isolate PMSCs and PMSC-EVs to achieve both immunomodulatory and neuroprotective properties. We also aimed to perform in vitro studies to further uncover the mechanism by which PMSC-EVs drive oligodendrocyte progenitor cell (OPC) maturation into ODs or preserve existing ODs. Previous data had suggested that there may be differences in the immunosuppressive potential of matched PMSC cell lines. As such, we decided to also determine culture condition effects on neuroprotection. We then aimed to characterize differences in culture condition of PMSC-EV properties and determine if there were any changes in the resulting physical properties of the associated EVs. We also focused on achieving a high EV sample size to look deeper into the PMSC-EVs mechanism of action and determine if the ameliorating effect is through driving OPCs to differentiate into mature ODs or preserving existing ODs. We determined there was not a significant change in culture condition phenotype, cell doubling rates or neuroprotective properties; thus, either culture condition could likely be used. The next steps for this project will be to elucidate the mechanism of action by PMSC-EVs on OPCs. As a part of this ongoing project, we aim to treat isolated OPCs with PMSC-EVs. While the OPCs were isolated, the treatment has yet to be completed due to time constraints. However, the setup for the experiment yielded great insight on how to increase efficiency of the treatment. This project sought to further characterize differences in PMSC-EV productions and the potential mechanism behind the PMSC-EVs reversal of MS symptoms and the repair of damage to the nervous system. These data will provide valuable insight into further identifying the potential mechanisms-of-action of PMSC-EVs for the treatment of MS and provide foundational information on more efficient PMSC-EV production to further improve the efficacy of this potential treatment.

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Production and Functional Characterization of Placental Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles for the Treatment of Multiple Sclerosis in Vitro
Stagnaro, Ryan
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ProQuest Dissertations and Theses
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