期刊
GLIA
卷 62, 期 2, 页码 284-299出版社
WILEY
DOI: 10.1002/glia.22606
关键词
neuroimmune; hippocampal slice culture; remyelination; multiple sclerosis; aging
资金
- National Institute of Health Common Fund, through the Office of Strategic Coordination/Office of the Director [1 UH 2 TR000918]
- Core facilities funds from the National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR000430]
- Illinois Pilot grant from the National Multiple Sclerosis Society [IL-0009]
- National Institute of Neurological Disorders and Stroke [NS-19108]
- National Institute of Child Health and Human Disorders [5 PO1 HD 09402]
- White Foundation
- National Institute of General Medicine Training Grant [T32-GM07839]
Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression. However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cellsboth under control conditions and after acute demyelination. Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination. GLIA 2014;62:284-299
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