miR-219 attenuates demyelination in cuprizone-induced demyelinated mice by regulating monocarboxylate transporter 1
miR-219 attenuates demyelination in cuprizone-induced demyelinated mice by regulating monocarboxylate transporter 1
复制标题
miR-219通过调节单羧酸转运蛋白1减轻铜宗诱导的脱髓鞘小鼠的脱髓鞘
DOI：
10.1111/ejn.13485
复制
发表时间：
2017-01-01
影响因子：
3.4
通讯作者：
Geng, Deqin
中科院分区：
文献类型：
--
作者：
Liu, Sihan;Ren, Chuanlu;Geng, Deqin
多发性硬化症（MS）患者的再髓鞘形成受到限制，原因是难以招募增殖性少突胶质细胞前体（OPCs）， OPC分化和/或成熟受到抑制，以及/或髓鞘生成失败。体外研究表明，miR-219是OPC分化所必需的，而MCT1在少突胶质细胞成熟和髓磷脂合成中起着至关重要的作用。在本文中，我们假设miR-219可能通过调节MCT1的表达，在铜酮（CPZ）诱导的脱髓鞘模型中促进少突胶质细胞分化并减弱脱髓鞘。我们发现cpz处理的小鼠在空地试验中表现出明显增加的焦虑。然而，miR-219通过增加总距离、中心距离和在中心区域的平均时间来减少焦虑。miR-219降低了OPCs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，过表达miR-219可减轻脱髓鞘的程度。同时，miR-219还通过抑制少突胶质细胞分化抑制剂Sox6和Hes5显著增强MCT1表达，MCT1抑制剂-cyano-4-hydroxycinnamate （4-CIN）处理可减少少突胶质细胞数量和MBP和CNP蛋白水平。综上所述，这些结果提示了miR-219通过MCT1在体内的一种新的作用模式，并可能提供一个新的潜在的髓鞘再生治疗靶点。
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 -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 invivo and may provide a new potential remyelination therapeutic target.