Youth and Environmental Enrichment Generate Serum Exosomes Containing miR-219 that Promote CNS Myelination

Glia (Impact Factor: 6.03). 02/2014; 62(2):284-99. DOI: 10.1002/glia.22606
Source: PubMed


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 cells-both 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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    • "Astrocytes in cell culture release leukemia inhibitory factor (LIF) in response to ATP released from axons firing action potentials , which promotes myelination by mature oligodendrocytes (Ishibashi et al., 2006). Recent evidence for other mechanisms of activity-dependent myelination is emerging, for example, via exosome signaling (Frü hbeis et al., 2013; Pusic and Kraig, 2014) and blood oxygen tension (Yuen et al., 2014). "
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    • "Second, SD was induced by a uniform injection of current [i.e., 10 pulses, 10 Hz (100 μs/pulse)] at 1000 μA (i.e., 1000 nC) as previously described (Grinberg et al., 2012). We have established the typical threshold of current delivery needed to evoke slice culture SD in prior experiments (Grinberg et al., 2012; Pusic et al., 2014a). For example, threshold was determined by progressively doubling the amount of applied current [10 pulses, 10 Hz (100 μs/pulse)] beginning with that needed to trigger a half-maximal field potential response from a single stimulus. "
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    Full-text · Article · Dec 2014 · Experimental Neurology
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    • "Cultures that lacked evidence of stratum pyramidale neuronal death were considered viable, and thus suitable for subsequent experimental use. We used hippocampal slice cultures maintained in vitro for 21 to 35 days to model SD in vivo, since culture in this window of time closely parallel the in vivo counterpart (for review see Kunkler et al., 2005 and Pusic et al., 2014). Specifically, the neurovascular unit (Kovacs et al., 2011), multisynaptic electrical activity (Kunkler and Kraig, 1998), pyramidal neuron vitality (Hulse et al., 2008), responsive astrocytes and microglia (Grinberg et al., 2011; Ransohoff and Perry, 2009) and cytokine signaling (Kunkler et al., 2004) resemble that seen in vivo. "
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