Date of Award

2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Mao-Draayer, Yang

Abstract

Multiple sclerosis (MS) is a leading cause of neurological disability in young adults. Although current treatments can reduce symptomology and relapse rate, they are unable to prevent the chronic neurodegeneration that occurs at later stages. MS pathology is mediated by complex interactions between invading immune cells, neurons, glia, and endogenous stores of neural progenitor cells (NPCs). Factors critical to NPC/immune cell communication as well as the survival, differentiation, and proliferation of NPCs are not well defined. Elucidation of these factors will allow for the advancement of NPC transplantation therapies as well as the identification of novel pharmacological targets. Fas – a member of the tumor necrosis superfamily of death receptors – has diverse, cell-specific functions and is a major modulator of autoregulation within the immune system. Although Fas is expressed by NPCs, its exact role in this cell type was previously unknown. To contribute to this body of knowledge, the experiments in this dissertation examined the role of the Fas receptor (Fas) and Fas ligand (FasL) in NPC survival, differentiation, and T-cell cross-talk in vitro and in vivo in experimental autoimmune encephalomyelitis (EAE; a well-established animal model of MS). Activation of Fas via FasL increased NPC survival by decreasing apoptosis (as opposed to increasing proliferation) in vitro. This decreased apoptosis correlates with upregulation of the inhibitor of apoptosis protein (IAP) Birc3. Further investigation into the importance of Fas in NPCs was accomplished by comparing wild-type and Fas-deficient (lpr) NPCs. Lpr NPCs exhibited decreased apoptosis, decreased proliferation, and increased differentiation to oligoprogenitor and neuronal lineages. These studies suggest the Fas system plays multifaceted roles in NPCs and that its exact functions are dependent on both functional Fas expression and presence or absence of FasL. To determine the role of Fas/FasL in neuroimmune cross-talk, co-cultures of wild-type or lpr NPCs with different T-cell subtypes (Th1, Th2, and Th17 cells) were performed. Th1 cells were the only subtype capable of inducing NPC apoptosis. Th1-mediated death was dose-dependent and was not mediated via Fas. On the other hand, NPCs were able to induce significant apoptosis in pro-inflammatory Th1 and Th17 cells without affecting anti-inflammatory Th2 cells. NPC-induced Th17 cell death was mediated via Fas. These data suggest NPCs can specifically target pro-inflammatory T-cells and can promote neuroprotection by inducing death of these proencephalogenic cells. Finally, intravenous injection of wild-type or lpr NPCs into EAE mice reduced clinical symptoms and CNS immune infiltrate to the same extent. Few NPCs enter the CNS, where they remain undifferentiated. This suggests the main mechanism through which NPCs produce beneficial results in EAE is via peripheral immunoregulation, which is not dependent on Fas expression. Overall, this dissertation elucidates the Fas system as an important modulator of NPC cell-fate and immunoregulatory capacity.

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