CXCL12/SDF-1 facilitates optic nerve regeneration
CXCL12/SDF-1 facilitates optic nerve regeneration
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CXCL12/SDF-1促进视神经再生
DOI：
10.1016/j.nbd.2013.04.001
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发表时间：
2013-07-01
影响因子：
6.1
通讯作者：
Fischer, Dietmar
中科院分区：
文献类型：
--
作者：
Heskamp, Annemarie;Leibinger, Marco;Fischer, Dietmar
成熟的视网膜神经节细胞(RGC)通常不会再生受损的轴突，但在轴突切断后不久就会发生凋亡。此外，成熟神经元再生轴突的内在能力不足，位于中枢神经系统髓鞘中的抑制分子以及损伤部位形成的胶质瘢痕强烈限制了轴突的再生。然而，视网膜节细胞在炎性刺激(IS)下可以转化为再生状态，使这些神经元能够长出轴突进入受损的视神经。然而，IS刺激再生的结果仍然受到抑制的细胞外环境的限制。在这里，我们报道了趋化因子CXCL12/SDF-1在培养中适度刺激成熟的视网膜神经节细胞在层粘连蛋白上的轴突生长，并且与CNTF相比，对髓鞘具有强大的抑制作用。CXCL12与视网膜节细胞共同作用有利于CNTF刺激视网膜节细胞在髓鞘上的突起生长。成熟的视网膜节细胞表达CXCR4，即同源的CXCL12受体。CXCL12促进轴突生长和抑制轴突生长的作用可被特异性CXCR4拮抗剂和抑制PI3K/AKT/mTOR-途径所阻断，但不能阻断JAK/STAT3-途径。在体内，玻璃体内注射CXCL12可维持视神经损伤后视网膜节细胞mTOR活性，并适度刺激视神经轴突再生，但不影响视网膜节细胞的存活。重要的是，玻璃体内应用CXCL12也显著增加了体内触发的轴突再生。这些数据表明，CXCL12对髓鞘的抑制作用可能是促进视神经再生的一个有用的特征，特别是与其他轴突生长刺激治疗相结合时。(C)2013 Elsevier Inc.保留所有权利。
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. (c) 2013 Elsevier Inc. All rights reserved.