Transplants of fibroblasts expressing BDNF and NT-3 promote recovery of bladder and hindlimb function following spinal contusion injury in rats
Transplants of fibroblasts expressing BDNF and NT-3 promote recovery of bladder and hindlimb function following spinal contusion injury in rats
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DOI：
10.1016/j.expneurol.2005.02.022
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Murray, M
中科院分区：
文献类型：
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作者：
Mitsui, T;Fischer, I;Murray, M
我们研究了成纤维细胞，基因修饰表达BDNF和NT-3（Fb-BDNF/NT 3），并移植到胸脊髓损伤部位，是否会提高膀胱功能的恢复，以及这种治疗是否会与重组腰骶脊髓回路牵连膀胱功能。大鼠在T8/9时接受改良的中度挫伤，9天后，将Fb-BDNF/NT 3或未修饰的成纤维细胞（OP对照）递送到脊髓中。与OP对照组相比，Fb-BDNF/NT 3大鼠更早地恢复了无反射膀胱，排尿压力降低，逼尿肌反射亢进发作次数减少。Fb-BDNF/NT 3组的后肢功能也有改善，尽管在更具挑战性的底物（网格）上的运动和对热刺激的缩尾潜伏期显示出持续的缺陷，几乎没有恢复，并且组间没有差异。L 6-S1脊髓的免疫细胞化学显示L 6-S1脊髓的传入和下行投射密度发生变化。小背根轴突的密度增加，在OP对照组的背角的浅层，但不是在Fb-BDNF/NT-3，表明发芽的初级传入损伤后，抑制Fb-BDNF/NT-3。与此相反，营养因子分泌移植物刺激发芽和/或保留下行调节途径投射到腰骶脊髓。突触素免疫反应性在背角中未见差异，这表明突触密度相似，但在两个手术组中通过不同系统的发芽实现。Fb-BDNF/NT 3移植到损伤的脊髓中，从而改善膀胱和后肢功能，这与脊髓回路的重组有关。(c)2005年爱思唯尔公司All rights reserved.
We examined whether fibroblasts, genetically modified to express BDNF and NT-3 (Fb-BDNF/NT3) and transplanted into a thoracic spinal injury site, would enhance recovery of bladder function and whether this treatment would be associated with reorganization of lumbosacral spinal circuits implicated in bladder function. Rats received modified-moderate contusion injuries at T8/9, and 9 days later, Fb-BDNF/NT3 or unmodified fibroblasts (OP-controls) were delivered into the cord. Fb-BDNF/NT3 rats recovered froth areflexic bladder earlier, showed decreased micturition pressure and fewer episodes of detrusor hyperreflexia, compared to OP-controls. There were also improvements in hindlimb function in the Fb-BDNF/NT3 group although locomotion on a more challenging substrate (grid) and tail withdrawal latency in response to a thermal stimulus showed persisting deficits, little recovery, and no differences between the groups. Immunocytochemistry at L6-S1 revealed changes in density of afferent and descending projections to L6-S1 cord. The density of small dorsal root axons increased in the superficial layers of the dorsal horn in OP-controls but not in Fb-BDNF/NT3, suggesting sprouting of primary afferents following injury that was inhibited by Fb-BDNF/NT-3. In contrast, the trophic factor secreting transplants stimulated sprouting and/or sparing of descending modulatory pathways projecting to the lumbosacral spinal cord. No differences in synaptophysin immunoreactivity were seen in the dorsal horn which suggested that synaptic density was similar but achieved by sprouting of different systems in the two operated groups. Fb-BDNF/NT3 transplanted into injured spinal cord thus improved both bladder and hindlimb function, and this was associated with reorganization of spinal circuitry. (c) 2005 Elsevier Inc. All rights reserved.