Lentiviral vector-mediated gradients of GDNF in the injured peripheral nerve: effects on nerve coil formation, Schwann cell maturation and myelination.
Lentiviral vector-mediated gradients of GDNF in the injured peripheral nerve: effects on nerve coil formation, Schwann cell maturation and myelination.
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DOI：
10.1371/journal.pone.0071076
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tannemaat MR
中科院分区：
文献类型：
--
作者：
Eggers R;de Winter F;Hoyng SA;Roet KC;Ehlert EM;Malessy MJ;Verhaagen J;Tannemaat MR
尽管周围神经具有再生能力，但仅有一小部分患者在手术重建主要周围神经损伤后恢复正常功能，从而对生活质量造成严重和持久的负面影响。胶质细胞源性神经营养因子(GDNF)对运动神经元有很强的存活和生长促进作用，但局部水平的升高会导致再生轴突的捕获和神经线圈的形成。这种现象被称为“糖果店”效应。在这项研究中，我们在前根撕脱后的坐骨神经中创建了GDNF的梯度。这一方法也使我们能够研究增加GDNF浓度对损伤周围神经中雪旺细胞增殖和形态的影响。我们证明慢病毒载体可以用来在完整和受损的大鼠坐骨神经中创建4厘米长的GDNF梯度。在整个梯度上形成了神经线圈，并且随着神经中GDNF水平的增加，神经线圈的数量和大小增加。在神经线圈中，雪旺细胞密度增加，其形态被破坏，轴突的髓鞘形成严重受损。在远端应用GDNF梯度后，再生和存活的运动神经元总数并没有增加，但发芽增加确实导致坐骨神经远端段运动轴突数的增加。这些结果表明，慢病毒载体介导的GDNF的过表达对雪旺细胞和轴突都产生了多重影响，并且在相对较低浓度的外源GDNF下已经形成了神经线圈。通过使用表达可调控的GDNF的病毒载体来控制GDNF的表达，可能是为了避免运动轴突捕获并防止对雪旺细胞的增殖和髓鞘形成的影响。
Although the peripheral nerve is capable of regeneration, only a small minority of patients regain normal function after surgical reconstruction of a major peripheral nerve lesion, resulting in a severe and lasting negative impact on the quality of life. Glial cell-line derived neurotrophic factor (GDNF) has potent survival- and outgrowth-promoting effects on motoneurons, but locally elevated levels of GDNF cause trapping of regenerating axons and the formation of nerve coils. This phenomenon has been called the “candy store” effect. In this study we created gradients of GDNF in the sciatic nerve after a ventral root avulsion. This approach also allowed us to study the effect of increasing concentrations of GDNF on Schwann cell proliferation and morphology in the injured peripheral nerve. We demonstrate that lentiviral vectors can be used to create a 4 cm long GDNF gradient in the intact and lesioned rat sciatic nerve. Nerve coils were formed throughout the gradient and the number and size of the nerve coils increased with increasing GDNF levels in the nerve. In the nerve coils, Schwann cell density is increased, their morphology is disrupted and myelination of axons is severely impaired. The total number of regenerated and surviving motoneurons is not enhanced after the distal application of a GDNF gradient, but increased sprouting does result in higher number of motor axon in the distal segment of the sciatic nerve. These results show that lentiviral vector mediated overexpression of GDNF exerts multiple effects on both Schwann cells and axons and that nerve coil formation already occurs at relatively low concentrations of exogenous GDNF. Controlled expression of GDNF, by using a viral vector with regulatable GDNF expression, may be required to avoid motor axon trapping and to prevent the effects on Schwann cell proliferation and myelination.
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