Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination.
Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination.
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DOI：
10.1177/1759091416668430
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发表时间：
2016-10
期刊：
影响因子：
4.7
通讯作者：
Hafizi S
中科院分区：
文献类型：
--
作者：
Goudarzi S;Rivera A;Butt AM;Hafizi S
多发性硬化症（MS）治疗的一个关键目标是促进中枢神经系统（CNS）中少突胶质细胞的再生和髓鞘再生。本研究提供的证据表明，维生素K依赖性蛋白生长停滞特异性6（Gas 6）促进这种修复在体外培养的小鼠视神经和小脑。我们首先确定了Gas 6和TAM（Tyro 3、Axl、Mer）受体在小鼠CNS中的表达，所有三种TAM受体在出生后发育中表达增加，在成人中达到最大水平。用Gas 6处理培养的小鼠视神经导致少突胶质细胞数量以及髓鞘碱性蛋白（MBP）表达的显著增加。Gas 6刺激还导致视神经中STAT 3的激活以及参与MS发展的多个基因的下调，包括基质金属蛋白酶-9（MMP 9），其可能降低血脑屏障的完整性并且在MS病变中被发现上调。Gas 6的细胞保护作用在体外小鼠小脑切片培养物中进行了检查，其中使用来苏糖醇诱导脱髓鞘。共处理小脑切片与Gas 6显着衰减脱髓鞘所确定的MBP免疫染色，Gas 6激活酪氨酸受体通过其磷酸化。总之，这些结果表明，Gas 6/TAM信号转导刺激少突胶质细胞的产生，并通过Tyro 3受体增加成年CNS中的髓鞘产生，包括脱髓鞘损伤后的修复。此外，Gas 6对STAT 3信号传导和基质MMP 9下调的影响表明Gas 6潜在的神经胶质细胞修复和免疫调节作用，表明Gas 6-TAM信号传导可能是MS和其他神经病理学的潜在治疗靶点。
A key aim of therapy for multiple sclerosis (MS) is to promote the regeneration of oligodendrocytes and remyelination in the central nervous system (CNS). The present study provides evidence that the vitamin K-dependent protein growth arrest specific 6 (Gas6) promotes such repair in in vitro cultures of mouse optic nerve and cerebellum. We first determined expression of Gas6 and TAM (Tyro3, Axl, Mer) receptors in the mouse CNS, with all three TAM receptors increasing in expression through postnatal development, reaching maximal levels in the adult. Treatment of cultured mouse optic nerves with Gas6 resulted in significant increases in oligodendrocyte numbers as well as expression of myelin basic protein (MBP). Gas6 stimulation also resulted in activation of STAT3 in optic nerves as well as downregulation of multiple genes involved in MS development, including matrix metalloproteinase-9 (MMP9), which may decrease the integrity of the blood–brain barrier and is found upregulated in MS lesions. The cytoprotective effects of Gas6 were examined in in vitro mouse cerebellar slice cultures, where lysolecithin was used to induce demyelination. Cotreatment of cerebellar slices with Gas6 significantly attenuated demyelination as determined by MBP immunostaining, and Gas6 activated Tyro3 receptor through its phosphorylation. In conclusion, these results demonstrate that Gas6/TAM signaling stimulates the generation of oligodendrocytes and increased myelin production via Tyro3 receptor in the adult CNS, including repair after demyelinating injury. Furthermore, the effects of Gas6 on STAT3 signaling and matrix MMP9 downregulation indicate potential glial cell repair and immunoregulatory roles for Gas6, indicating that Gas6-TAM signaling could be a potential therapeutic target in MS and other neuropathologies.
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影响因子：
3.9
作者：
Butt, AM;Pugh, M;James, G
通讯作者：
James, G
影响因子：
8
作者：
Chen, J;Carey, K;Godowski, PJ
通讯作者：
Godowski, PJ
影响因子：
14.8
作者：
De Simoni, Anna;Yu, Lily My
通讯作者：
Yu, Lily My
影响因子：
1.8
作者：
Beckerman, Samuel R.;Jimenez, Joaquin E.;Lemmon, Vance P.
通讯作者：
Lemmon, Vance P.
依赖AXL的信号传导：临床更新。
DOI：
10.1042/cs20110411
发表时间：
2012-04
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Korshunov VA
通讯作者：
Korshunov VA