W.M. Keck Center for Collaborative Neuroscience, Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, New Jersey, USA.
Mol Ther. 2010 Oct;18(10):1769-77. doi: 10.1038/mt.2010.133. Epub 2010 Jul 6.
Tenascin-C (TNC), a major component of the extracellular matrix, is strongly upregulated after injuries of the central nervous system (CNS) but its role in tissue repair is not understood. Both regeneration promoting and inhibiting roles of TNC have been proposed considering its abilities to both support and restrict neurite outgrowth in vitro. Here, we show that spontaneous recovery of locomotor functions after spinal cord injury is impaired in adult TNC-deficient (TNC(-/-)) mice in comparison to wild-type (TNC(+/+)) mice. The impaired recovery was associated with attenuated excitability of the plantar Hoffmann reflex (H-reflex), reduced glutamatergic input, reduced sprouting of monaminergic axons in the lumbar spinal cord and enhanced post-traumatic degeneration of corticospinal axons. The degeneration of corticospinal axons in TNC(-/-) mice was normalized to TNC(+/+) levels by application of the alternatively spliced TNC fibronectin type III homologous domain D (fnD). Finally, overexpression of TNC-fnD via adeno-associated virus in wild-type mice improved locomotor recovery, increased monaminergic axons sprouting, and reduced lesion scar volume after spinal cord injury. The functional efficacy of the viral-mediated TNC indicates a potentially useful approach for treatment of spinal cord injury.
Tenascin-C（TNC）是细胞外基质的主要成分，在中枢神经系统（CNS）损伤后强烈上调，但它在组织修复中的作用尚不清楚。考虑到 TNC 具有体外支持和限制神经突生长的能力，因此有人提出 TNC 具有促进再生和抑制再生的作用。在这里，我们发现与野生型（TNC（+/+））小鼠相比，脊髓损伤后成年 TNC 缺陷（TNC（-/-））小鼠运动功能的自发恢复受损。这种恢复受损与足底 Hoffmann 反射（H-反射）兴奋性降低、谷氨酸能输入减少、单胺能轴突在腰椎脊髓中的发芽减少以及皮质脊髓轴突损伤后退化增强有关。通过应用交替剪接的 TNC 纤维连接蛋白 III 同源结构域 D（fnD），TNC（-/-）小鼠的皮质脊髓轴突退化恢复到 TNC（+/+）水平。最后，通过腺相关病毒在野生型小鼠中过表达 TNC-fnD 可改善运动功能恢复，增加单胺能轴突发芽，并减少脊髓损伤后的损伤瘢痕体积。病毒介导的 TNC 的功能效果表明，这是一种治疗脊髓损伤的潜在有用方法。
