The promotion of functional recovery and nerve regeneration after spinal cord injury by lentiviral vectors encoding Lingo-1 shRNA delivered by Pluronic F-127
The promotion of functional recovery and nerve regeneration after spinal cord injury by lentiviral vectors encoding Lingo-1 shRNA delivered by Pluronic F-127
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Pluronic F-127 编码 Lingo-1 shRNA 的慢病毒载体促进脊髓损伤后的功能恢复和神经再生
DOI：
10.1016/j.biomaterials.2012.11.013
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发表时间：
2013-02-01
期刊：
影响因子：
14
通讯作者：
Wan, Yong
中科院分区：
文献类型：
--
作者：
Wu, Hong-Fu;Cen, Jing-Sheng;Wan, Yong
Lingo-1在中枢神经系统（CNS）的少突胶质细胞和神经元上选择性表达，并且作为神经再生的关键负调节剂，这意味着脊髓损伤（SCI）的治疗靶点。在这里，我们描述了一种策略，以敲低Lingo-1表达在体内使用慢病毒载体编码Lingo-1短harpin干扰RNA（shRNA）交付的普朗尼克F-127（PF-127）凝胶，非细胞毒性支架和基因递送载体，在成年大鼠T10脊髓完全横断后。我们发现，PF-127封装Lingo-1 shRNA慢病毒载体的管理有效地下调Lingo-1的表达，并表现出转导效率与单独使用载体在体外少突胶质细胞培养。此外，当Lingo-1 shRNA与PF-127凝胶在较低的病毒浓度下共转染到损伤部位时，在体内观察到类似的沉默效果和更高的转染效率。凝胶和Lingo-1 RNAi的共移植显著促进功能恢复和神经再生，促进神经突起生长和突触形成，保护有髓轴突，并诱导胶质细胞增殖。此外，联合植入还改善了神经元存活并抑制了细胞凋亡，这可能与脊髓损伤后内质网（ER）应激的减弱有关。总之，我们的数据表明，通过凝胶支架递送Lingo-1 shRNA是一种有价值的SCI治疗方法，PF-127将病毒载体递送到脊髓可能为研究和开发SO治疗方法提供策略。(C)2012爱思唯尔有限公司保留所有权利。
Lingo-1 is selectively expressed on both oligodendrocytes and neurons in the central nervous system (CNS) and serves as a key negative regulator of nerve regeneration, implying a therapeutic target for spinal cord injury (SCI). Here we described a strategy to knock-down Lingo-1 expression in vivo using lentiviral vectors encoding Lingo-1 short harpin interfering RNA (shRNA) delivered by Pluronic F-127 (PF-127) gel, a non-cytotoxic scaffold and gene delivery carrier, after the complete transection of the T10 spinal cord in adult rats. We showed administration of PF-127 encapsulating Lingo-1 shRNA lentiviral vectors efficiently down-regulated the expression of Lingo-1, and exhibited transduction efficiency comparable to using vectors alone in oligodendrocyte culture in vitro. Furthermore, similar silencing effects and higher transfection efficiency were observed in vivo when Lingo-1 shRNA was co-delivered to the injured site by PF-127 gel with lower viral concentrations. Cografting of gel and Lingo-1 RNAi significantly promoted functional recovery and nerve regeneration, enhanced neurite outgrowth and synapses formation, preserved myelinated axons, and induced the proliferation of glial cells. In addition, the combined implantation also improved neuronal survival and inhibited cell apoptosis, which may be associated with the attenuation of endoplasmic reticulum (ER) stress after SCI. Together, our data indicated that delivering Lingo-1 shRNA by gel scaffold was a valuable treatment approach to SCI, and PF-127 delivery of viral vectors to the spinal cord may provide strategy to study and develop therapies for SO. (C) 2012 Elsevier Ltd. All rights reserved.