Targeting RPTP sigma with lentiviral shRNA promotes neurites outgrowth of cortical neurons and improves functional recovery in a rat spinal cord contusion model
Targeting RPTP sigma with lentiviral shRNA promotes neurites outgrowth of cortical neurons and improves functional recovery in a rat spinal cord contusion model
复制标题
在大鼠脊髓挫伤模型中，用慢病毒 shRNA 靶向 RPTP sigma 可促进皮质神经元的神经突生长并改善功能恢复
DOI：
10.1016/j.brainres.2014.08.048
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发表时间：
2014
期刊：
影响因子：
2.9
通讯作者：
Feng Shi-Qing
中科院分区：
文献类型：
--
作者：
Zhou Heng-Xing;Li Xue-Ying;Li Fu-Yuan;Liu Chang;Liang Zhi-Pin;Liu Shen;Zhang Bin;Wang Tian-Yi;Chu Tian-Ci;Lu Lu;Ning Guang-Zhi;Kong Xiao-Hong;Feng Shi-Qing
脊髓损伤（spinal cord injury，SCI）后，硫酸软骨素蛋白多糖（chondroitin sulfate proteoglycans，CSPGs）的表达迅速上调，是胶质瘢痕的主要化学成分和主要排斥因子，在成年哺乳动物脊髓再生能力极其有限的过程中发挥重要作用。尽管已经测试了许多克服抑制的方法，但迄今为止还没有设计出具有临床可行性的成功方法。最近发现受体蛋白酪氨酸磷酸酶σ（RPTPσ）是CSPG介导的抑制作用的功能性受体。鉴于RNA干扰（RNAi）的潜在临床应用，我们研究了沉默RPTPσ vialentivirus介导的RNA干扰是否能促进脊髓损伤后轴突再生和功能恢复。RPTPσ缺失的原代大鼠大脑皮层神经元突起在体外与CSPG接触时，其延伸和穿越能力显著增强。Wistar大鼠脊髓损伤的挫伤模型（纽约大学（NYU）撞击器）用于体内实验。在损伤部位局部注射编码RPTPσ shRNA的慢病毒可促进轴突再生和突触形成，但不影响瘢痕形成。同时，RPTPσ耗竭后，体内功能（运动和感觉）恢复也得到增强。因此，通过RNAi沉默RPTPσ的策略可能被证明是治疗SCI的有益、有效和有价值的方法。
After spinal cord injury (SCI), the rapidly upregulated chondroitin sulfate proteoglycans (CSPGs), the prominent chemical constituents and main repulsive factors of the glial scar, play an important role in the extremely limited ability to regenerate in adult mammals. Although many methods to overcome the inhibition have been tested, no successful method with clinical feasibility has been devised to date. It was recently discovered that receptor protein tyrosine phosphatase sigma (RPTPσ) is a functional receptor for CSPGs-mediated inhibition. In view of the potential clinical application of RNA interference (RNAi), here we investigated whether silencing RPTPσvialentivirus-mediated RNA interference can promote axon regeneration and functional recovery after SCI. Neurites of primary rat cerebral cortical neurons with depleted RPTPσ exhibited a significant enhancement in elongation and crossing ability when they encountered CSPGsin vitro. A contusion model of spinal cord injury in Wistar rats (the New York University (NYU) impactor) was used forin vivoexperiments. Local injection of lentivirus encoding RPTPσ shRNA at the lesion site promoted axon regeneration and synapse formation, but did not affect the scar formation. Meanwhile,in vivofunctional recovery (motor and sensory) was also enhanced after RPTPσ depletion. Therefore, strategies directed at silencing RPTPσ by RNAi may prove to be a beneficial, efficient and valuable approach for the treatment of SCI.