Zhang Yuan, Li Xing, Ciric Bogoljub, Ma Cun-Gen, Gran Bruno, Rostami Abdolmohamad, Zhang Guang-Xian
Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China.
Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Mol Ther. 2017 Feb 1;25(2):401-415. doi: 10.1016/j.ymthe.2016.12.008. Epub 2016 Dec 28.
Inflammatory demyelination and axonal damage of the CNS are hallmarks of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Fingolimod (FTY720), the first FDA-approved oral medication for MS, suppresses acute disease but is less effective at the chronic stage, and whether it has a direct effect on neuroregeneration in MS and EAE remains unclear. Here we show that FTY720, at nanomolar concentrations, effectively protected survival of neural stem cells (NSCs) and enhanced their development into mature oligodendrocytes (OLGs) in vitro, primarily through the S1P3 and S1P5 receptors. In vivo, treatment with either FTY720 or NSCs alone had no effect on the secondary progressive stage of remitting-relapsing EAE, but a combination therapy with FTY720 and NSCs promoted significant recovery, including ameliorated clinical signs and CNS inflammatory demyelination, enhanced MBP synthesis and remyelination, inhibited axonal degeneration, and reduced astrogliosis. Moreover, FTY720 significantly improved incorporation and survival of transplanted NSCs in the CNS and drove their differentiation into more OLGs but fewer astrocytes, thus promoting remyelination and CNS repair processes in situ. Our data demonstrate a novel effect of FTY720 on NSC differentiation and remyelination, broadening its possible application to NSC-based therapy in the secondary progressive stage of MS.
中枢神经系统的炎性脱髓鞘和轴突损伤是多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）的标志。芬戈莫德（FTY720）是美国食品药品监督管理局（FDA）批准的首个用于治疗MS的口服药物，它能抑制急性期疾病，但在慢性期效果较差，并且其对MS和EAE中神经再生是否有直接作用仍不清楚。在此我们表明，纳摩尔浓度的FTY720主要通过S1P3和S1P5受体，在体外有效保护神经干细胞（NSC）的存活并促进其发育为成熟的少突胶质细胞（OLG）。在体内，单独使用FTY720或NSC治疗对复发缓解型EAE的继发进展期没有影响，但FTY720与NSC的联合治疗促进了显著恢复，包括改善临床症状和中枢神经系统炎性脱髓鞘、增强髓鞘碱性蛋白（MBP）合成和髓鞘再生、抑制轴突退变以及减少星形胶质细胞增生。此外，FTY720显著改善了移植的NSC在中枢神经系统中的整合和存活，并促使它们分化为更多的OLG但更少的星形胶质细胞，从而促进原位髓鞘再生和中枢神经系统修复过程。我们的数据证明了FTY720对NSC分化和髓鞘再生的新作用，拓宽了其在MS继发进展期基于NSC治疗中的可能应用。
