Neurodegeneration and dysfunction cause mobility impairment and/or paralysis in millions of adults, worldwide. Motor deficit and recovery in adults depend upon the plasticity of the neuromuscular junction (NMJ), a tripartite, biochemical synapse that transduces electrical impulses from the brain into voluntary contraction of skeletal muscle. Nonmyelinating Schwann cells (nmSCs) of the NMJ have been increasingly recognized as active synaptic partners with motor neurons and muscle and have become recent therapeutic targets for regeneration. nmSC synaptic transmission, plasticity, and growth are strongly modulated by brain-derived neurotrophic factor (BDNF), whose regenerative abilities have been explored through emerging biomaterials and tissue-engineered systems, as well as via clinical trials. Experimental models engineered to investigate integrated NMJ response(s) to local gradients of BDNF will both advance our understanding of key modulators of synaptic activity, postinjury, and aid in the development of NMJ-targeted, regenerative therapies to restore mobility. The current study examined the ability of nmSCs to respond to microfluidically controlled BDNF signaling upon different haptotactic substrates of motor neurons (MNs) and laminin adhesion coating. Tests seeding nmSCs sequentially with MNs illustrated that sequential seeding reported a fivefold increase in levels of tropomyosin receptor kinase B expression in response to BDNF signaling and a nearly fivefold increase in migration distance along BDNF gradients. By contrast, concurrent seeding of MNs and nmSCs upon laminin adhesion coating illustrated a difference in migration distance of less than one third-fold over control. Our findings are among the first to examine migratory responses of nmSCs for regenerative strategies and highlight the potential to restabilize NMJ synaptic activity by affecting nmSC behaviors through therapeutic BDNF and seeding with MNs.

中文翻译：

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神经元底物改变非髓鞘雪旺细胞对受控的脑源性神经营养因子梯度的迁移反应。

神经变性和功能障碍导致全球成千上万的成年人行动不便和/或瘫痪。成人的运动障碍和恢复取决于神经肌肉接头（NMJ）的可塑性，它是一种三方生化突触，可将大脑的电脉冲转换为骨骼肌的自愿收缩。NMJ的非髓鞘雪旺细胞（nmSCs）已被越来越多地视为运动神经元和肌肉的活跃突触伴侣，并已成为再生的最新治疗靶点。nmSC的突触传递，可塑性和生长受到脑源性神经营养因子（BDNF）的强烈调节，该因子的再生能力已通过新兴的生物材料和组织工程系统以及临床试验得到了探索。设计用于研究NMJ对BDNF局部梯度的综合NMJ反应的实验模型，既可以增进我们对突触活性，损伤后关键调节因子的了解，也可以帮助开发针对NMJ的再生疗法以恢复活动能力。当前的研究检查了nmSCs对运动神经元（MNs）和层粘连蛋白粘附涂层的不同触觉底物对微流体控制的BDNF信号作出反应的能力。用MN依次播种nmSC的试验表明，连续播种报告响应BDNF信号的原肌球蛋白受体激酶B表达水平增加了5倍，沿着BDNF梯度的迁移距离增加了近5倍。相比之下，在层粘连蛋白粘附涂层上同时播种MN和nmSC的现象表明，迁移距离的差异比对照少了三分之一。我们的发现是第一个检查nmSCs的再生策略迁移反应，并强调了通过治疗性BDNF和MNs播种影响nmSC行为来稳定NMJ突触活性的潜力。