Required growth facilitators propel axon regeneration across complete spinal cord injury.
Required growth facilitators propel axon regeneration across complete spinal cord injury.
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DOI：
10.1038/s41586-018-0467-6
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发表时间：
2018-09
期刊：
影响因子：
64.8
通讯作者：
Sofroniew MV
中科院分区：
文献类型：
--
作者：
Anderson MA;O'Shea TM;Burda JE;Ao Y;Barlatey SL;Bernstein AM;Kim JH;James ND;Rogers A;Kato B;Wollenberg AL;Kawaguchi R;Coppola G;Wang C;Deming TJ;He Z;Courtine G;Sofroniew MV
成年人在解剖学上完全脊髓损伤（SCI）中，被横断的轴突无法重新生长。不同的分子可以部分促进或减弱轴突在发育过程中或损伤后的生长，但有效逆转这种再生失败仍然难以实现。在这里，我们展示了发育过程中轴突生长所必需的三个因素，但在成人中减弱或缺乏——(i) 神经元内在生长能力、(ii) 生长支持基质和 (iii) 化学吸引，这些因素都是单独需要的，并且组合起来足以刺激成年啮齿类动物在解剖学上完整的 SCI 损伤中强健的轴突再生。在 SCI 之前，我们用骨桥蛋白、胰岛素样生长因子 1 和睫状源神经营养因子重新激活了成熟的降性本体脊髓神经元的生长能力；含有成纤维细胞生长因子 2 和表皮生长因子的诱导生长支持基质；和化学吸引的带有神经胶质源性神经营养因子的本体脊髓轴突，通过生物材料库的空间和时间控制释放来传递，在 SCI 后依次放置。我们在小鼠和大鼠中证明，结合而不是单独提供这三种机制，可以通过星形胶质细胞疤痕边界和非神经组织的病变核心刺激强健的本体脊髓轴突再生，其再生量比对照组强 100 倍以上。受刺激、支持和化学吸引的本体脊髓轴突在病变中心之外重新长出完整的脊柱节段，很好地进入幸存的神经组织，形成显示突触标记的终端状接触，并在病变处传递电生理传导能力的显着恢复。因此，要克服成熟后在解剖学上完整的 SCI 损伤中轴突再生失败的问题，需要联合顺序恢复几种促进轴突生长的发育重要机制。这些发现确定了一种针对完整 SCI 损伤的基于机制的生物修复策略，该策略可能适合与旨在增强重塑回路功能恢复的康复模型一起使用。
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury, –, but efficient reversal of this regrowth failure remains elusive. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults—(i) neuron intrinsic growth capacity,, , , –, (ii) growth-supportive substrate,and (iii) chemoattraction,—are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI,; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor,delivered via spatially and temporally controlled release from biomaterial depots,, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
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DOI：
10.1523/jneurosci.2973-12.2013
发表时间：
2013-03-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Deng LX;Deng P;Ruan Y;Xu ZC;Liu NK;Wen X;Smith GM;Xu XM
通讯作者：
Xu XM
影响因子：
64.5
作者：
AVNUR, Z;GEIGER, B
通讯作者：
GEIGER, B
影响因子：
16.6
作者：
Puttagunta, Radhika;Tedeschi, Andrea;Di Giovanni, Simone
通讯作者：
Di Giovanni, Simone
影响因子：
64.5
作者：
Bei F;Lee HHC;Liu X;Gunner G;Jin H;Ma L;Wang C;Hou L;Hensch TK;Frank E;Sanes JR;Chen C;Fagiolini M;He Z
通讯作者：
He Z
影响因子：
82.9
作者：
Courtine, Gregoire;Song, Bingbing;Sofroniew, Michael V.
通讯作者：
Sofroniew, Michael V.