Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination.
Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination.
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DOI：
10.1002/glia.22606
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发表时间：
2014-02
期刊：
影响因子：
6.2
通讯作者：
Kraig, Richard P.
中科院分区：
文献类型：
--
作者：
Pusic, Aya D.;Kraig, Richard P.
尽管通常被认为是一种白质疾病，但灰质脱髓鞘越来越被认为是多发性硬化症 (MS) 发病机制的重要组成部分，特别是在继发性进展性疾病阶段。灰质损伤的程度与多发性硬化症患者的记忆力下降和认知功能障碍密切相关。衰老同样伴随着髓鞘质丧失导致的认知能力下降，而与年龄相关的髓鞘质再生失败会显着促进多发性硬化症的进展。然而，最近的证据表明，将老年动物置于年轻的全身环境中，可以促进少突胶质细胞前体细胞 (OPC) 分化并改善髓鞘再生。在当前的研究中，我们重点关注这种刺激髓鞘再生的潜力，并表明它涉及血清外泌体，增加 OPC 及其分化为成熟的髓鞘生成细胞的能力——无论是在控制条件下还是在急性脱髓鞘后。衰老动物的环境富集（EE）产生了模仿这种髓鞘形成作用的外泌体。此外，通过来自环境丰富的动物的外泌体刺激 OPC 分化不太可能耗尽祖细胞，因为 EE 本身会促进神经干细胞的增殖。我们发现，年轻的和 EE 血清来源的外泌体都富含 miR-219，这对于通过减少分化抑制性调节因子的表达来产生髓鞘少突胶质细胞是必要且充分的。因此，将外泌体应用于切片培养物后，这些 miR-219 靶 mRNA 的蛋白质转录水平降低。最后，向衰老大鼠鼻腔施用外泌体也增强了髓鞘形成。因此，年轻或环境丰富的动物的外周循环细胞产生的外泌体可能是髓鞘再生的有用疗法。
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.
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影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
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作者：
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158.5
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作者：
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通讯作者：
Trapp, Bruce D.
影响因子：
4.6
作者：
Fredman, Gabrielle;Li, Yongsheng;Dalli, Jesmond;Chiang, Nan;Serhan, Charles N.
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