The adult mammalian central nervous system contains a population of immature, undifferentiated, multipotent cells, neural stem cells (NSCs) that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may, in turn, give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells, as well as neural and glial precursors. The capacity of NSCs to repair damage in the adult has been demonstrated in several experimental systems. However, in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), remyelination and neuro-regeneration do not occur to a sufficient extent. We have previously shown that NSCs express a number of immune receptors such as CD80 and CD86 that are upregulated by exposure to IFN-? or TNF-a. We have now preliminary data suggesting that IFN-? affects the intrinsic NSC properties of self-renewal capacity and migratory capacity.
Our aims i n this proposal are:
Aim 1.) To examine the effect of IFN-? and the transcription factor STAT1 on the self-renewal program of NSCs in vivo and on their molecular program in vitro. Our preliminary data suggest that STAT1 is a critical factor for the responses of NSCs to interferon-? and that loss of self- renewal capacity after IFN-? treatment is STAT1 dependent. Using STAT1 KO mice, we will we will determine the effect of STAT1 deficiency on NSCs in vivo in an inflammatory environment. We will then investigate the effects of IFN-? on genes and proteins that are critical for self-renewal.
Aim 2.) To examine the effect of IFN- ? on migration of NSCs in vivo and on the molecular program in vitro. Our preliminary data suggest that migration of NSCs to SDF1 is inhibited by IFN-? in vitro and that this is independent of STAT1. We will use in vivo models to investigate the effects of inflammation on migration of stem cells, and will evaluate the molecular impact of IFN-? on migration related genes.
Aim 3.) To examine the effect of STAT1 on differentiation of NSCs in vivo and on the differentiation molecular program in vitro focusing on neurogenic differentiation. Our hypothesis, supported by preliminary data, is that inflammatory mediators interact with master regulators of stem cell programs and modify these programs. The experimental plan outlined above will allow us to begin unraveling the complexities of these interactions. Public health relevance: IFN-? is an inflammatory cytokine that is up-regulated in the central nervous system in many diseases such as MS, Alzheimer's disease and HIV dementia. Understanding how IFN-? impacts the ability of NSCs to proliferate and repair is critical in understanding the pathogenesis of these neurodegenerative diseases and finding treatments that can reverse damage to the nervous system. ? ? ? ?
