Liu Sihan, Ren Chuanlu, Qu Xuebin, Wu Xiuxiang, Dong Fuxing, Chand Yadav Kaushal, Fan Hongbin, Yao Ruiqin, Geng Deqin
Research Center for Neurobiology, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221000, China.
Department of Neurology, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, 221009, China.
Eur J Neurosci. 2017 Jan;45(2):249-259. doi: 10.1111/ejn.13485.
Remyelination is limited in patients with multiple sclerosis (MS) due to the difficulties in recruiting proliferating oligodendrocyte precursors (OPCs), the inhibition of OPC differentiation and/or maturation, and/or failure in the generation of the myelin sheath. In vitro studies have revealed that miR-219 is necessary for OPC differentiation and monocarboxylate transporter 1 (MCT1) plays a vital role in oligodendrocyte maturation and myelin synthesis. Herein, we hypothesized that miR-219 might promote oligodendrocyte differentiation and attenuate demyelination in a cuprizone (CPZ)-induced demyelinated model by regulating the expression of MCT1. We found that CPZ-treated mice exhibited significantly increased anxiety in the open field test. However, miR-219 reduced anxiety as shown by an increase in the total distance, the central distance and the mean amount of time spent in the central area. miR-219 decreased the quantity of OPCs and increased the number of oligodendrocytes and the level of myelin basic protein (MBP) and cyclic nucleotide 3' phosphodiesterase (CNP) protein. Ultrastructural studies further confirmed that the extent of demyelination was attenuated by miR-219 overexpression. Meanwhile, miR-219 also greatly enhanced MCT1 expression via suppression of oligodendrocyte differentiation inhibitors, Sox6 and Hes5, treatment with the MCT1 inhibitor α-cyano-4-hydroxycinnamate (4-CIN) reduced the number of oligodendrocytes and the protein levels of MBP and CNP. Taken together, these results suggest a novel mode of action of miR-219 via MCT1 in vivo and may provide a new potential remyelination therapeutic target.
由于招募增殖性少突胶质前体细胞（OPC）存在困难、OPC分化和/或成熟受到抑制以及/或者髓鞘生成失败，多发性硬化症（MS）患者的髓鞘再生受到限制。体外研究表明，miR-219是OPC分化所必需的，而单羧酸转运蛋白1（MCT1）在少突胶质细胞成熟和髓鞘合成中起着至关重要的作用。在此，我们假设miR-219可能通过调节MCT1的表达来促进少突胶质细胞分化，并减轻 cuprizone（CPZ）诱导的脱髓鞘模型中的脱髓鞘现象。我们发现，CPZ处理的小鼠在旷场试验中表现出明显增加的焦虑。然而，miR-219降低了焦虑，表现为总距离、中心距离和在中心区域花费的平均时间增加。miR-219减少了OPC的数量，增加了少突胶质细胞的数量以及髓鞘碱性蛋白（MBP）和环核苷酸3'磷酸二酯酶（CNP）蛋白的水平。超微结构研究进一步证实，miR-219过表达减轻了脱髓鞘程度。同时，miR-219还通过抑制少突胶质细胞分化抑制剂Sox6和Hes5大大增强了MCT1的表达，用MCT1抑制剂α-氰基-4-羟基肉桂酸酯（4-CIN）处理减少了少突胶质细胞的数量以及MBP和CNP的蛋白水平。综上所述，这些结果表明miR-219在体内通过MCT1发挥新的作用模式，可能提供一个新的潜在髓鞘再生治疗靶点。
