Fok-Seang J, DiProspero N A, Meiners S, Muir E, Fawcett J W
Physiological Laboratory, University of Cambridge, UK.
Eur J Neurosci. 1998 Jul;10(7):2400-15. doi: 10.1046/j.1460-9568.1998.00251.x.
Repair of demyelination in the CNS requires that oligodendrocyte precursors (OPs) migrate, divide and then myelinate. Repair of axon damage requires axonal regeneration. Limited remyelination and axon regeneration occurs soon after injury, but usually ceases in a few days. In vivo and in vitro experiments have shown that astrocytic environments are not very permissive for migration of OPs or for axonal re-growth. Yet remyelination and axon sprouting early after injury occurs in association with astrocytes, while later astrocytes can exclude remyelination and prevent axon regeneration. A large and changing cast of cytokines are released following CNS injury, so we investigated whether some of these alone or in combination can affect the ability of astrocytes to support migration of OPs and neuritic outgrowth. Interleukin (IL) 1alpha, tumour necrosis factor alpha, transforming growth factor (TGF) beta, basic fibroblast growth factor (bFGF), platelet-derived growth factor and epidermal growth factor alone exerted little or no effect on migration of OPs on astrocytes, whereas interferon (IFN) gamma was inhibitory. The combination of IL-1alpha + bFGF was found to be pro-migratory, and this effect could be neutralized by TGFbeta. We also examined neuritic outgrowth from dorsal root ganglion explants in three-dimensional astrocyte cultures treated with cytokines and found that IL-1alpha + bFGF greatly increased axon outgrowth and that this effect could be blocked by TGFbeta and IFNgamma. All these effects were absent or much smaller when OP migration or axon growth was tested on laminin, so the main effect of the cytokines was via astrocytes. The cytokine effects did not correlate with expression on astrocytes of laminin, fibronectin, tenascin, chondroitin sulphate proteoglycan, N-cadherin, polysialyated NCAM (PSA-NCAM), tissue plasminogen activator (tPA) or urokinase (uPA).
中枢神经系统（CNS）脱髓鞘的修复需要少突胶质前体细胞（OPs）迁移、分裂，然后进行髓鞘形成。轴突损伤的修复需要轴突再生。损伤后不久会发生有限的髓鞘再生和轴突再生，但通常在几天内就会停止。体内和体外实验表明，星形胶质细胞环境对OPs的迁移或轴突再生长并不十分有利。然而，损伤后早期的髓鞘再生和轴突发芽与星形胶质细胞有关，而后期星形胶质细胞会阻止髓鞘再生并防止轴突再生。中枢神经系统损伤后会释放大量且不断变化的细胞因子，因此我们研究了其中一些细胞因子单独或联合使用是否会影响星形胶质细胞支持OPs迁移和神经突生长的能力。白细胞介素（IL）-1α、肿瘤坏死因子α、转化生长因子（TGF）β、碱性成纤维细胞生长因子（bFGF）、血小板衍生生长因子和表皮生长因子单独对星形胶质细胞上OPs的迁移几乎没有影响，而干扰素（IFN）γ具有抑制作用。发现IL-1α + bFGF的组合具有促迁移作用，且这种作用可被TGFβ中和。我们还检测了用细胞因子处理的三维星形胶质细胞培养物中背根神经节外植体的神经突生长情况，发现IL-1α + bFGF能显著增加轴突生长，且这种作用可被TGFβ和IFNγ阻断。当在层粘连蛋白上测试OP迁移或轴突生长时，所有这些作用都不存在或小得多，因此细胞因子的主要作用是通过星形胶质细胞介导的。细胞因子的作用与星形胶质细胞上的层粘连蛋白、纤连蛋白、腱生蛋白、硫酸软骨素蛋白聚糖、N-钙黏蛋白、多唾液酸神经细胞黏附分子（PSA-NCAM）、组织纤溶酶原激活物（tPA）或尿激酶（uPA）的表达无关。
