The extent of extra-axonal tissue damage determines the levels of CSPG upregulation and the success of experimental axon regeneration in the CNS.
The extent of extra-axonal tissue damage determines the levels of CSPG upregulation and the success of experimental axon regeneration in the CNS.
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DOI：
10.1038/s41598-018-28209-z
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发表时间：
2018-06-29
影响因子：
4.6
通讯作者：
Trakhtenberg EF
中科院分区：
文献类型：
--
作者：
Kim J;Sajid MS;Trakhtenberg EF
成熟的中枢神经系统（CNS）投射神经元在长距离再生轴突的失败极大地限制了各种CNS损伤和疾病后丧失的功能的恢复。尽管已经发现了许多刺激一定程度的轴突再生的操作，其克服了CNS损伤后的抑制性环境，但是再生的程度仍然非常有限，强调了对改进的疗法的需要。再生轴突需要能够支持其生长的神经组织环境，并且损伤后严重的轴突外组织损伤和重塑可能破坏这种环境。在这里，我们使用小鼠视神经的创伤性损伤作为模型系统来研究轴突外组织损伤的程度如何影响实验性轴突再生。轴突再生刺激的shRNA介导的敲低（KD）的Pten基因的表达在视网膜神经节细胞，轴突外组织损伤的程度通过改变视神经挤压的持续时间。尽管使用1秒或5秒挤压没有轴突幸免，但我们发现Pten KD刺激的轴突再生在5秒内与1秒挤压相比显著减少。更严重的轴索外组织损伤并不引起组织萎缩，但导致轴突生长抑制硫酸软骨素蛋白聚糖（CSPG）的神经胶质瘢痕中的上调显着更高，也扩大了神经胶质瘢痕的大小，与不太严重的损伤组织相比。因此，靶向轴突生长的神经元内在机制的轴突再生方法的成功取决于适当的轴突外组织环境的保存，其可能需要通过组织重塑方法同时修复。
The failure of mature central nervous system (CNS) projection neurons to regenerate axons over long distances drastically limits the recovery of functions lost after various CNS injuries and diseases. Although a number of manipulations that stimulate some degree of axon regeneration that overcomes the inhibitory environment after CNS injury have been discovered, the extent of regeneration remains very limited, emphasizing the need for improved therapies. Regenerating axons need nerve tissue environment capable of supporting their growth, and severe extra-axonal tissue damage and remodeling after injury may disrupt such environment. Here, we used traumatic injury to the mouse optic nerve as a model system to investigate how the extent of extra-axonal tissue damage affects experimental axon regeneration. Axon regeneration was stimulated by the shRNA-mediated knockdown (KD) of Pten gene expression in the retinal ganglion cells, and the extent of extra-axonal tissue damage was varied by changing the duration of optic nerve crush. Although no axons were spared using either 1 or 5 seconds crush, we found that Pten KD-stimulated axon regeneration was significantly reduced in 5 seconds compared with 1 second crush. The more severe extra-axonal tissue damage did not cause tissue atrophy, but led to significantly higher upregulation of axon growth-inhibiting chondroitin sulfate proteoglycan (CSPG) in the glial scar and also enlarged glial scar size, compared with less severely damaged tissue. Thus, the success of axon-regenerating approaches that target neuronal intrinsic mechanisms of axon growth is dependent on the preservation of appropriate extra-axonal tissue environment, which may need to be co-concurrently repaired by tissue remodeling methods.
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影响因子：
25
作者：
Lim JH;Stafford BK;Nguyen PL;Lien BV;Wang C;Zukor K;He Z;Huberman AD
通讯作者：
Huberman AD
影响因子：
13.7
作者：
Feuer WJ;Schiffman JC;Davis JL;Porciatti V;Gonzalez P;Koilkonda RD;Yuan H;Lalwani A;Lam BL;Guy J
通讯作者：
Guy J
影响因子：
6.1
作者：
Benowitz LI;Carmichael ST
通讯作者：
Carmichael ST
DOI：
10.1073/pnas.1616811114
发表时间：
2017-01-10
影响因子：
11.1
作者：
Li, Yiqing;Andereggen, Lukas;Benowitz, Larry
通讯作者：
Benowitz, Larry
影响因子：
5.3
作者：
Fischer, D;He, ZG;Benowitz, LI
通讯作者：
Benowitz, LI