One million estimated cases of spinal cord injury (SCI) have been reported in the United States and repairing an injury has constituted a difficult clinical challenge. The complex, dynamic, inhibitory microenvironment postinjury, which is characterized by proinflammatory signaling from invading leukocytes and lack of sufficient factors that promote axonal survival and elongation, limits regeneration. Herein, we investigated the delivery of polycistronic vectors, which have the potential to coexpress factors that target distinct barriers to regeneration, from a multiple channel poly(lactide-co-glycolide) (PLG) bridge to enhance spinal cord regeneration. In this study, we investigated polycistronic delivery of IL-10 that targets proinflammatory signaling, and NT-3 that targets axonal survival and elongation. A significant increase was observed in the density of regenerative macrophages for IL-10+NT-3 condition relative to conditions without IL-10. Furthermore, combined delivery of IL-10+NT-3 produced a significant increase of axonal density and notably myelinated axons compared with all other conditions. A significant increase in functional recovery was observed for IL-10+NT-3 delivery at 12 weeks postinjury that was positively correlated to oligodendrocyte myelinated axon density, suggesting oligodendrocyte-mediated myelination as an important target to improve functional recovery. These results further support the use of multiple channel PLG bridges as a growth supportive substrate and platform to deliver bioactive agents to modulate the SCI microenvironment and promote regeneration and functional recovery.

中文翻译：

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IL-10和NT-3的多顺反子传递在小鼠脊髓损伤模型中促进少突胶质细胞的髓鞘形成和功能恢复。

在美国，估计有100万例脊髓损伤（SCI）病例，而修复损伤已成为一项艰巨的临床挑战。复杂的，动态的，抑制性的微环境损伤后，其特征是入侵白细胞的促炎信号传导以及缺乏促进轴突存活和伸长的足够因素，限制了再生。在这里，我们研究了多顺反子载体的传递，它有可能从多通道聚（丙交酯-co）共表达靶向不同再生障碍的因子。-乙交酯（PLG）桥以增强脊髓再生。在这项研究中，我们调查了靶向促炎性信号传导的IL-10和靶向轴突存活和伸长的NT-3的多顺反子传递。相对于没有IL-10的条件，观察到IL-10 + NT-3条件的再生巨噬细胞密度显着增加。此外，与所有其他条件相比，IL-10 + NT-3的联合递送显着增加了轴突密度，尤其是髓鞘轴突。损伤后第12周，IL-10 + NT-3传递的功能恢复显着增加，与少突胶质细胞的髓鞘轴突密度呈正相关，提示少突胶质细胞介导的髓鞘形成是改善功能恢复的重要靶标。