Intercostal nerve implants transduced with an adenoviral vector encoding neurotrophin-3 promote regrowth of injured rat corticospinal tract fibers and improve hindlimb function
Intercostal nerve implants transduced with an adenoviral vector encoding neurotrophin-3 promote regrowth of injured rat corticospinal tract fibers and improve hindlimb function
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DOI：
10.1006/exnr.2000.7413
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发表时间：
2000-07-01
影响因子：
5.3
通讯作者：
Verhaagen, J
中科院分区：
文献类型：
--
作者：
Blits, P;Dijkhuizen, PA;Verhaagen, J
在中枢神经组织损伤后，受损的神经元不能自发地再生其轴突。然而，将周围神经植入CNS中确实导致轴突再生进入这些移植物中，并且是促进CNS再生的最有力的策略之一。在本研究中，植入后的周围神经桥背侧半切与离体基因转移与腺病毒载体编码神经营养因子-3（Ad-NT-3），以检查这是否会刺激再生的脊髓，皮质脊髓束（CST），进入和超越周围神经植入物的长下行道之一。我们选择使用编码NT-3的腺病毒载体，因为CST轴突对这种神经营养因子敏感，而周围神经植入物中的许旺细胞不表达这种神经营养因子。在植入Ad-NT-3转导的肋间神经后16周，大约3 - 4倍的顺行追踪的皮质脊髓束纤维通过病变下方的灰质再生轴突。与对照组动物相比。CST纤维再生发生在病变部位远端超过8 mm处。然而，在转导的外周植入物中没有观察到再生的CST纤维。与用编码LacZ的腺病毒载体治疗的对照动物相比，用Ad-NT-3转导外周神经的动物也表现出后肢功能的改善。因此，外周神经组织桥中NT-3的瞬时过表达显然足以刺激CST纤维的再生长并促进后肢功能的恢复，但不会导致CST纤维再生成这样的移植物。总而言之，将成熟的神经移植方法与病毒载体基因转移相结合，可以促进受损CST纤维通过灰质的再生，并改善后肢功能的恢复。(C)北京大学出版社.
Following injury to central nervous tissues, damaged neurons are unable to regenerate their axons spontaneously. Implantation of peripheral nerves into the CNS, however, does result in axonal regeneration into these transplants and is one of the most powerful strategies to promote CNS regeneration. In the present study implantation of peripheral nerve bridges following dorsal hemisection is combined with ex vivo gene transfer with adenoviral vectors encoding neurotrophin-3 (Ad-NT-3) to examine whether this would stimulate regeneration of one of the long descending tracts of the spinal cord, the corticospinal tract (CST), into and beyond the peripheral nerve implant. We chose to use an adenoviral vector encoding NT-3 because CST axons are sensitive to this neurotrophin and Schwann cells in peripheral nerve implants do not express this neurotrophin. At 16 weeks postimplantation of Ad-NT-3-transduced intercostal nerves, approximately three- to fourfold more of the anterogradely traced corticospinal tract fibers had regrown their axons through gray matter below the lesion. site when compared to control animals. Regrowth of CST fibers occurred over more than 8 mm distal to the lesion site. No regenerating CST fibers were, however, observed into the transduced peripheral implant. Animals with a peripheral nerve transduced with Ad-NT-3 also exhibited improved function of the hindlimbs when compared to control animals treated with an adenoviral vector encoding LacZ. Thus, transient overexpression of NT-3 in peripheral nerve tissue bridges is apparently sufficient to stimulate regrowth of CST fibers and to promote recovery of hindlimb function, but does not result in regeneration of CST fibers into such transplants. Taken together, combining an established neurotransplantation approach with viral vector-gene transfer promotes the regrowth of injured CST fibers through gray matter and improves the recovery of hindlimb function. (C) 2000 Academic Press.