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Required growth facilitators propel axon regeneration across complete spinal cord injury
Nature ( IF 64.8 ) Pub Date : 2018-08-29 , DOI: 10.1038/s41586-018-0467-6
Mark A Anderson 1, 2 , Timothy M O'Shea 1 , Joshua E Burda 1 , Yan Ao 1 , Sabry L Barlatey 2 , Alexander M Bernstein 1 , Jae H Kim 1 , Nicholas D James 2 , Alexandra Rogers 1 , Brian Kato 1 , Alexander L Wollenberg 3 , Riki Kawaguchi 4 , Giovanni Coppola 4 , Chen Wang 5 , Timothy J Deming 3 , Zhigang He 5 , Gregoire Courtine 2 , Michael V Sofroniew 1
Affiliation  

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 injury1–3, but efficient reversal of this regrowth failure remains elusive4. 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 capacity2,5–9, (ii) growth-supportive substrate10,11 and (iii) chemoattraction12,13—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 SCI14,15; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor16,17 delivered via spatially and temporally controlled release from biomaterial depots18,19, 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.Stimulating the intrinsic growth capacity of neurons and providing growth-supportive substrate and chemoattraction can allow axon regrowth across anatomically complete spinal cord injuries in adult rodents.

中文翻译:

所需的生长促进剂在完全脊髓损伤中推动轴突再生

横断的轴突无法在成人的解剖学上完全脊髓损伤 (SCI) 中再生。不同的分子可以在发育过程中或受伤后部分促进或减弱轴突生长 1-3,但这种再生失败的有效逆转仍然难以实现 4。在这里,我们展示了在发育过程中对轴突生长至关重要但在成人中减弱或缺乏的三个因素——(i) 神经元内在生长能力 2,5–9,(ii) 生长支持底物 10,11 和 (iii) 趋化作用 12,13 - 所有这些都是单独需要的,并且结合起来足以刺激成年啮齿动物在解剖学上完整的 SCI 损伤中强大的轴突再生。在 SCI14、15 之前,我们用骨桥蛋白、胰岛素样生长因子 1 和睫状衍生神经营养因子重新激活了成熟的下行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底物;和具有神经胶质源性神经营养因子 16, 17 的化学吸引的原脊髓轴突通过空间和时间控制释放从生物材料仓库 18, 19 传递,顺序放置在 SCI 之后。我们在小鼠和大鼠中表明,结合提供这三种机制,但不是单独提供,通过星形胶质细胞瘢痕边界和非神经组织的损伤核心刺激了强大的原脊柱轴突再生,比对照高 100 多倍。受刺激、支持和化学吸引的脊髓本体轴突在损伤中心之外重新长出完整的脊柱节段,很好地传递到幸免的神经组织中,形成显示突触标记的终端样接触,并传达跨病变的电生理传导能力的显着恢复。因此,克服成熟后解剖学上完整的 SCI 损伤轴突再生的失败需要联合顺序恢复促进轴突生长的几种发育基本机制。这些发现为完整的 SCI 损伤确定了一种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。刺激神经元的内在生长能力并提供生长支持底物和化学吸引可以允许成年啮齿动物在解剖学上完全脊髓损伤后轴突再生。克服成熟后解剖学上完整的 SCI 损伤轴突再生的失败需要联合顺序恢复几种促进轴突生长的发育基本机制。这些发现为完整的 SCI 损伤确定了一种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。刺激神经元的内在生长能力并提供生长支持底物和化学吸引可以允许成年啮齿动物在解剖学上完全脊髓损伤后轴突再生。克服成熟后解剖学上完整的 SCI 损伤轴突再生的失败需要联合顺序恢复几种促进轴突生长的发育基本机制。这些发现为完整的 SCI 损伤确定了一种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。刺激神经元的内在生长能力并提供生长支持底物和化学吸引可以允许成年啮齿动物在解剖学上完全脊髓损伤后轴突再生。
更新日期:2018-08-29
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