Neuregulin facilitates nerve regeneration by speeding Schwann cell migration via ErbB2/3-dependent FAK pathway.
Neuregulin facilitates nerve regeneration by speeding Schwann cell migration via ErbB2/3-dependent FAK pathway.
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DOI：
10.1371/journal.pone.0053444
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liao WC
中科院分区：
文献类型：
--
作者：
Chang HM;Shyu MK;Tseng GF;Liu CH;Chang HS;Lan CT;Hsu WM;Liao WC
雪旺细胞（Sc）的充分迁移对于周围神经损伤（PNI）后再生过程中的轴突引导至关重要。考虑到neuregulin-erbB-FAK信号通路是发育过程中参与调控Sc迁移的重要通路，本研究旨在通过体外和体内方法研究neuregulin在成年PNI后是否发挥其有益作用，并进一步确定参与神经再生的下游通路的潜在变化。用神经调节蛋白处理培养的RSC 96细胞进行erbB 2/3免疫荧光和FAK免疫印迹。通过细胞粘附、扩散和迁移试验评估神经调节蛋白对Sc的潜在影响。为了评价神经调节蛋白在神经再生中的作用，采用慢性端侧神经吻合术（ESN）建立了PNI的体内模型。体外研究表明，经neuregulin作用后，erbB 2/3不仅表达于细胞膜，而且分布于细胞质和细胞核。erbB 2/3的激活与FAK磷酸化呈正相关。Neuregulin还使Sc粘附、铺展和迁移分别增加127.2± 5.0%、336.8± 3.0%和80.0± 5.7%。在体内研究中，neuregulin显著加快Sc迁移的速度，并增加损伤神经远端残端Sc的表达。逆行标记和复合肌肉动作电位记录（CMAP）也表明，neuregulin成功地促进神经再生，引起明显更大的CMAP和促进目标肌肉的快速神经支配。由于神经调节蛋白通过加速Sc经由erbB 2/3-FAK途径的迁移而成功地改善了轴-神经胶质相互作用，因此神经调节蛋白的治疗性使用可作为促进PNI后神经再生进展的有前景的策略。
Adequate migration of Schwann cells (Sc) is crucial for axon-guidance in the regenerative process after peripheral nerve injury (PNI). Considering neuregulin-erbB-FAK signaling is an essential pathway participating in the regulation of Sc migration during development, the present study is aimed to examine whether neuregulin would exert its beneficial effects on adult following PNI and further determine the potential changes of downstream pathway engaged in neuro-regeneration by both in vitro and in vivo approaches. Cultured RSC96 cells treated with neuregulin were processed for erbB2/3 immunofluorescence and FAK immunoblotings. The potential effects of neuregulin on Sc were assessed by cell adherence, spreading, and migration assays. In order to evaluate the functional significance of neuregulin on neuro-regeneration, the in vivo model of PNI was performed by chronic end-to-side neurorrhaphy (ESN). In vitro studies indicated that after neuregulin incubation, erbB2/3 were not only expressed in cell membranes, but also distributed throughout the cytoplasm and nucleus of RSC96 cells. Activation of erbB2/3 was positively correlated with FAK phosphorylation. Neuregulin also increases Sc adherence, spreading, and migration by 127.2±5.0%, 336.8±3.0%, and 80.0±5.7%, respectively. As for in vivo study, neuregulin significantly accelerates the speed of Sc migration and increases Sc expression in the distal stump of injured nerves. Retrograde labeling and compound muscle action potential recordings (CMAP) also showed that neuregulin successfully facilitates nerve regeneration by eliciting noticeably larger CMAP and promoting quick re-innervation of target muscles. As neuregulin successfully improves axo-glial interaction by speeding Sc migration via the erbB2/3-FAK pathway, therapeutic use of neuregulin may thus serve as a promising strategy to facilitate the progress of nerve regeneration after PNI.
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通讯作者：
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