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. During the previous funding period we have examined the effects of inflammation on the multipotentiality of neural stem/progenitor cells in vivo and in vitro. We found that NSCs proliferate, start to differentiate, and migrate out of the subventricular zone during the acute phase of the disease. But as the disease progresses proliferation of the stem cells subsides. Furthermore, we have observed that during chronic EAE, microglia remain activated in the absence of inflammatory infiltrates. This situation is reminiscent of the chronic phase of multiple sclerosis, where neuro-degeneration and loss of brain parenchyma occur in the absence of gadolinium enhancing lesions on MRI. We will examine the hypothesis that chronically activated microglia are responsible, at least in part for the dysfunction in stem cell function. We will address this hypothesis in the following aims.
Aim 1. Differential interaction of acutely versus chronically activated microglia with neural progenitor cells.
Aim 2. How do NSCs modulate microglial activation in the SVZ.
Aim 3. We will examine if reversal of chronic microglia activation will restore normal NSC functionality. These investigations will have an impact on our understanding of the pathogenesis of neuro-degeneration in multiple sclerosis and provide a model that may be used to target treatments for chronic disease.
Despite recent advances in the diagnosis and treatment of multiple sclerosis (MS) we still lack a consensus regarding the etiology, pathogenesis and the mechanisms of disease progression. This proposal will address the hypothesis that the innate immune system (through persistent activation of microglia) may play a role in the chronic dysfunction of neural stem/progenitor cells. The findings will have impact on understanding the pathogenesis of disease progression in MS and may provide a model for testing new therapies for preventing neuro-degeneration.
|Elyaman, Wassim; Khoury, Samia J (2017) Th9 cells in the pathogenesis of EAE and multiple sclerosis. Semin Immunopathol 39:79-87|
|Kurdi, Ahmed T; Bassil, Ribal; Olah, Marta et al. (2016) Tiam1/Rac1 complex controls Il17a transcription and autoimmunity. Nat Commun 7:13048|
|Merzaban, Jasmeen S; Imitola, Jaime; Starossom, Sarah C et al. (2015) Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis. Glycobiology 25:1392-409|
|Starossom, Sarah C; Mascanfroni, Ivan D; Imitola, Jaime et al. (2012) Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity 37:249-63|
|Imitola, Jaime; Cote, Daniel; Rasmussen, Stine et al. (2011) Multimodal coherent anti-Stokes Raman scattering microscopy reveals microglia-associated myelin and axonal dysfunction in multiple sclerosis-like lesions in mice. J Biomed Opt 16:021109|
|Rasmussen, Stine; Imitola, Jaime; Ayuso-Sacido, Angel et al. (2011) Reversible neural stem cell niche dysfunction in a model of multiple sclerosis. Ann Neurol 69:878-91|
|Kivisakk, Pia; Imitola, Jaime; Rasmussen, Stine et al. (2009) Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol 65:457-69|
|Elyaman, Wassim; Bradshaw, Elizabeth M; Uyttenhove, Catherine et al. (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106:12885-90|
|Wang, Yue; Imitola, Jaime; Rasmussen, Stine et al. (2008) Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol 64:417-27|
|Pluchino, Stefano; Muzio, Luca; Imitola, Jaime et al. (2008) Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain 131:2564-78|
Showing the most recent 10 out of 22 publications