Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord.
Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord.
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DOI：
10.1523/jneurosci.3641-09.2009
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发表时间：
2009-11-25
期刊：
影响因子：
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通讯作者：
Houlé JD
中科院分区：
文献类型：
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作者：
Tom VJ;Sandrow-Feinberg HR;Miller K;Santi L;Connors T;Lemay MA;Houlé JD
由于目前尚无脊髓损伤的治疗方法，因此大多数患者都患有长期损伤。因此，旨在促进慢性损伤脊髓功能恢复的策略具有很高的治疗价值。为了成功再生，长期受伤的轴突必须克服其较差的内在生长潜力以及病变部位周围建立的神经胶质疤痕的抑制环境。如果用软骨素酶 ABC (ChABC) 处理远端移植物-宿主界面以裂解疤痕基质中的抑制性硫酸软骨素蛋白多糖，则急性损伤的轴突会再生为生长许可的周围神经移植物 (PNG)，重新进入宿主组织以介导功能恢复。为了确定类似的策略是否对慢性损伤有效，我们将周围神经移植到高度相关的慢性颈挫伤部位，结合 ChABC 治疗神经胶质疤痕和神经胶质细胞源性神经营养因子 (GDNF) 刺激长期损伤的轴突。我们在两种移植范例中测试了这种组合：(1) 移植周围神经以跨越慢性损伤部位，或 (2) 将慢性挫伤部位与第二个更远端损伤部位桥接的 PNG。与 GDNF-PBS 治疗不同，GDNF-ChABC 治疗促进轴突离开 PNG 进入宿主组织，并促进一些功能恢复。周围神经桥轴突的电刺激诱导宿主神经元中的 c-Fos 表达，表明再生纤维的突触接触。因此，我们的数据首次证明，将 ChABC 施用到远端移植物界面可以使慢性损伤的神经元实现功能性轴突再生。
Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high therapeutic value. For successful regeneration, long-injured axons must overcome their poor intrinsic growth potential as well as the inhibitory environment of the glial scar established around the lesion site. Acutely injured axons that regenerate into growth-permissive peripheral nerve grafts (PNGs) reenter host tissue to mediate functional recovery if the distal graft– host interface is treated with chondroitinase ABC (ChABC) to cleave inhibitory chondroitin sulfate proteoglycans in the scar matrix. To determine whether a similar strategy is effective for a chronic injury, we combined grafting of a peripheral nerve into a highly relevant, chronic, cervical contusion site with ChABC treatment of the glial scar and glial cell line-derived neurotrophic factor (GDNF) stimulation of long-injured axons. We tested this combination in two grafting paradigms: (1) a peripheral nerve that was grafted to span a chronic injury site or (2) a PNG that bridged a chronic contusion site with a second, more distal injury site. Unlike GDNF–PBS treatment, GDNF–ChABC treatment facilitated axons to exit the PNG into host tissue and promoted some functional recovery. Electrical stimulation of axons in the peripheral nerve bridge induced c-Fos expression in host neurons, indicative of synaptic contact by regenerating fibers. Thus, our data demonstrate, for the first time, that administering ChABC to a distal graft interface allows for functional axonal regeneration by chronically injured neurons.