Mi Sha, Miller Robert H, Tang Wei, Lee Xinhua, Hu Bing, Wu Wutain, Zhang Yiping, Shields Christopher B, Zhang Yongjie, Miklasz Steven, Shea Diana, Mason Jeff, Franklin Robin J M, Ji Benxiu, Shao Zhaohui, Chédotal Alain, Bernard Frederic, Roulois Aude, Xu Janfeng, Jung Vincent, Pepinsky Blake
Biogen Idec, Cambridge, MA 02142, USA.
Ann Neurol. 2009 Mar;65(3):304-15. doi: 10.1002/ana.21581.
Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti-LINGO-1 reagents to promote myelination in vitro and remyelination in the rodent adult central nervous system in vivo.
The effects of LINGO-1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and remyelination, we morphologically and functionally assessed the effects of LINGO-1 antagonists on OPC differentiation and myelin repair.
The data indicate that in vitro treatment with antagonists of LINGO-1 promote OPC differentiation and myelination, whereas in vivo remyelination is accelerated in lysophosphatidylcholine- or cuprizone-induced demyelination. This remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons.
Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination.
在诸如多发性硬化症等疾病中修复脱髓鞘轴突需要激活现有或新募集的少突胶质前体细胞（OPC）中的髓鞘形成程序。修复过程中OPC分化的控制以及髓鞘形成的起始尚不清楚。在本研究中，我们测试了抗LINGO-1试剂在体外促进髓鞘形成以及在啮齿动物成体中枢神经系统体内促进髓鞘再生的能力。
使用共培养和脑片培养制剂相结合的方法，检测LINGO-1拮抗剂对OPC分化和髓鞘形成促进作用的影响。使用三种不同的脱髓鞘和髓鞘再生动物模型，我们从形态学和功能上评估了LINGO-1拮抗剂对OPC分化和髓鞘修复的影响。
数据表明，体外使用LINGO-1拮抗剂处理可促进OPC分化和髓鞘形成，而在溶血磷脂酰胆碱或铜螯合剂诱导的脱髓鞘模型中，体内髓鞘再生加速。这种髓鞘再生与OPC分化增强以及脱髓鞘轴突传导速度的功能恢复相关。
我们的研究表明，拮抗LINGO-1可促进OPC分化和髓鞘再生，并提示LINGO-1作为OPC分化的抑制剂，阻碍中枢神经系统的髓鞘再生。
