Neurotrophin-3 gradients established by lentiviral gene delivery promote short-distance axonal bridging beyond cellular grafts in the injured spinal cord
Neurotrophin-3 gradients established by lentiviral gene delivery promote short-distance axonal bridging beyond cellular grafts in the injured spinal cord
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DOI：
10.1523/jneurosci.0734-06.2006
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发表时间：
2006-09-20
影响因子：
5.3
通讯作者：
Blesch, Armin
中科院分区：
文献类型：
--
作者：
Taylor, Laura;Jones, Leonard;Blesch, Armin
将神经营养因子递送至脊髓损伤（SCI）部位促进轴突生长进入但不超出损伤部位。我们测试了这一假设，即持续的生长因子梯度超出SCI区域将促进显著的轴突桥接进入和超出病变。成年大鼠接受C3损伤以横切上行背柱感觉轴突，并将自体骨髓基质细胞移植到损伤处，为生长到受伤区域提供细胞桥梁。同时，将表达神经营养素-3（NT-3）或绿色荧光蛋白（GFP）（对照）的慢病毒载体注射到病变的头侧宿主脊髓中，以促进轴突延伸超过移植物/病变。四周后，在接受表达NT-3的慢病毒载体的动物中，通过ELISA可检测到病变以外的NT-3梯度，最高平均NT-3水平位于靠近嘴侧载体注射部位。与GFP载体相比，在注射NT-3载体的动物中，显著更多的上升感觉轴突延伸到病变部位的嘴侧组织中，但仅当NT-3载体转导区从注射部位连续延伸到移植物时;从移植物到嘴侧组织的NT-3表达中的任何“间隙”导致轴突桥接失败。尽管轴突桥接超出病变，再生轴突没有继续生长在很长的距离，即使在病变以外的持续生长因子梯度的存在。这些研究结果表明，局部和连续梯度的NT-3可以实现轴突桥接超出胶质瘢痕，但长距离的增长是不可持续的简单的营养刺激。
Neurotrophic factor delivery to sites of spinal cord injury (SCI) promotes axon growth into but not beyond lesion sites. We tested the hypothesis that sustained growth factor gradients beyond regions of SCI will promote significant axonal bridging into and beyond lesions. Adult rats underwent C3 lesions to transect ascending dorsal column sensory axons, and autologous bone marrow stromal cells were grafted into the lesion to provide a cellular bridge for growth into the injured region. Concurrently, lentiviral vectors expressing neurotrophin-3 (NT-3) or green fluorescent protein (GFP) ( controls) were injected into the host cord rostral to the lesion to promote axon extension beyond the graft/lesion. Four weeks later, NT-3 gradients beyond the lesion were detectable by ELISA in animals that received NT-3-expressing lentiviral vectors, with highest average NT-3 levels located near the rostral vector injection site. Significantly more ascending sensory axons extended into tissue rostral to the lesion site in animals injected with NT-3 vectors compared with GFP vectors, but only if the zone of NT-3 vector transduction extended continuously from the injection site to the graft; any "gap" in NT-3 expression from the graft to rostral tissue resulted in axon bridging failure. Despite axon bridging beyond the lesion, regenerating axons did not continue to grow over very long distances, even in the presence of a continuing growth factor gradient beyond the lesion. These findings indicate that a localized and continuous gradient of NT-3 can achieve axonal bridging beyond the glial scar, but growth for longer distances is not sustainable simply with a trophic stimulus.