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首页> 外文期刊>Neurobiology of disease >CXCL12/SDF-1 facilitates optic nerve regeneration
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CXCL12/SDF-1 facilitates optic nerve regeneration

机译：CXCL12 / SDF-1促进视神经再生

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Mature retinal ganglion cells (RGCs) do not normally regenerate injured axons, but undergo apoptosis soon after axotomy. Besides the insufficient intrinsic capability of mature neurons to regrow axons inhibitory molecules located in myelin of the central nervous system as well as the glial scar forming at the site of injury strongly limit axon regeneration. Nevertheless, RGCs can be transformed into a regenerative state upon inflammatory stimulation (IS), enabling these neurons to grow axons into the injured optic nerve. The outcome of IS stimulated regeneration is, however, still limited by the inhibitory extracellular environment. Here, we report that the chemokine CXCL12/SDF-1 moderately stimulates neurite growth of mature RGCs on laminin in culture and, in contrast to CNTF, exerts potent disinhibitory effects towards myelin. Consistently, co-treatment of RGCs with CXCL12 facilitated CNTF stimulated neurite growth of RGCs on myelin. Mature RGCs express CXCR4, the cognate CXCL12 receptor. Furthermore, the neurite growth promoting and disinhibitory effects of CXCL12 were abrogated by a specific CXCR4 antagonist and by inhibition of the PI3K/AKT/mTOR-, but not the JAK/STAT3-pathway. In vivo, intravitreal application of CXCL12 sustained mTOR activity in RGCs upon optic nerve injury and moderately stimulated axon regeneration in the optic nerve without affecting the survival of RGCs. Importantly, intravitreal application of CXCL12 also significantly increased IS triggered axon regeneration in vivo. These data suggest that the disinhibitory effect of CXCL12 towards myelin may be a useful feature to facilitate optic nerve regeneration, particularly in combination with other axon growth stimulatory treatments.
机译：成熟的视网膜神经节细胞（RGC）通常不会再生受损的轴突，但在轴切术后不久会发生凋亡。除了成熟的神经元固有的内在能力不足以再生位于中枢神经系统髓鞘的轴突抑制分子外，在损伤部位形成的神经胶质瘢痕也强烈限制了轴突再生。尽管如此，RGC可以在炎症刺激（IS）的作用下转变为再生状态，从而使这些神经元能够将轴突生长到受损的视神经中。然而，IS刺激的再生的结果仍然受到抑制性细胞外环境的限制。在这里，我们报道趋化因子CXCL12 / SDF-1适度刺激了层粘连蛋白在培养物中成熟RGC的神经突生长，并且与CNTF相反，对髓磷脂发挥了有效的抑制作用。一致地，RGC与CXCL12的共同处理促进了CNTF刺激了髓磷脂上RGC的神经突生长。成熟的RGC表达CXCR4，同源的CXCL12受体。此外，CXCL12的神经突生长促进和抑制作用被特定的CXCR4拮抗剂和PI3K / AKT / mTOR-（但不包括JAK / STAT3-途径）抑制所废除。在体内，玻璃体腔内应用CXCL12在视神经损伤后在RGC中维持mTOR活性，并适度刺激视神经轴突再生，而不会影响RGC的存活。重要的是，玻璃体内应用CXCL12还可显着增加IS触发体内的轴突再生。这些数据表明，CXCL12对髓磷脂的抑制作用可能是促进视神经再生的有用功能，特别是与其他轴突生长刺激疗法联合使用时。

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