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Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination
Enhancing repair of myelin is an important, but still elusive therapeutic goal in many neurological disorders(1). In Multiple Sclerosis (MS), an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyt...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970518/ https://www.ncbi.nlm.nih.gov/pubmed/26416758 http://dx.doi.org/10.1038/nature14957 |
Sumario: | Enhancing repair of myelin is an important, but still elusive therapeutic goal in many neurological disorders(1). In Multiple Sclerosis (MS), an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells (OPCs) and endogenous adult neural stem cells (NSCs) resident within the subventricular zone (SVZ) are known sources of remyelinating cells(2). Here, we characterize the contribution to remyelination of a subset of adult NSCs, identified by their expression of Gli1, a transcriptional effector of the Sonic Hedgehog (Shh) pathway. We show that these cells are recruited from the SVZ to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of NSCs, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signaling was ineffective indicating that Gli1’s role in both augmenting hedgehog signaling and retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis (RR-EAE) and is neuroprotective. Thus, endogenous NSCs can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders. |
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