Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration
Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration
复制标题
神经生长因子激活雪旺细胞中的自噬，增强髓鞘碎片清除并加速神经再生
DOI：
10.7150/thno.40919
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Xiao, Jian
中科院分区：
文献类型：
--
作者：
Li, Rui;Li, Duohui;Xiao, Jian
原理：雪旺细胞（SC）中的自噬对于周围神经损伤（PNI）后髓鞘碎片的降解和清除至关重要。神经生长因子（nerve growth factor，NGF）在周围神经纤维重建和促进轴突再生中起重要作用。然而，目前尚不清楚，如果在促进神经再生的神经生长因子的作用是通过自噬清除髓鞘碎片在SC介导。方法：在大鼠坐骨神经挤压伤模型中，给予游离的NGF溶液加/不加药理学抑制剂。体外培养原代雪旺细胞（Schwann cells，SC）及其细胞系，在含神经生长因子（NGF）的正常培养基中培养，通过添加匀浆髓鞘组分，观察SC对变性髓鞘的吞噬和清除能力。结果如下：在PNI早期给予外源性NGF可激活去分化SC的自噬，加速髓鞘碎片的清除和吞噬，促进轴突和髓鞘的再生。这些神经生长因子的作用被自噬抑制剂有效地阻断。此外，抑制p75 kD神经营养因子受体（p75 NTR）信号或使AMP活化蛋白激酶（AMPK）失活也可抑制NGF的作用。结论：NGF促进早期神经再生的作用与其加速SC内髓鞘碎片的自噬清除密切相关，这一作用可能受p75 NTR/AMPK/mTOR轴的调节。因此，我们的研究提供了强有力的支持，神经生长因子可能作为一个强大的药物治疗周围神经损伤。
Rationale: Autophagy in Schwann cells (SCs) is crucial for myelin debris degradation and clearance following peripheral nerve injury (PNI). Nerve growth factor (NGF) plays an important role in reconstructing peripheral nerve fibers and promoting axonal regeneration. However, it remains unclear if NGF effect in enhancing nerve regeneration is mediated through autophagic clearance of myelin debris in SCs. Methods: In vivo, free NGF solution plus with/without pharmacological inhibitors were administered to a rat sciatic nerve crush injury model. In vitro, the primary Schwann cells (SCs) and its cell line were cultured in normal medium containing NGF, their capable of swallowing or clearing degenerated myelin was evaluated through supplement of homogenized myelin fractions. Results: Administration of exogenous NGF could activate autophagy in dedifferentiated SCs, accelerate myelin debris clearance and phagocytosis, as well as promote axon and myelin regeneration at early stage of PNI. These NGF effects were effectively blocked by autophagy inhibitors. In addition, inhibition of the p75 kD neurotrophin receptor (p75NTR) signal or inactivation of the AMP-activated protein kinase (AMPK) also inhibited the NGF effect as well. Conclusions: NGF effect on promoting early nerve regeneration is closely associated with its accelerating autophagic clearance of myelin debris in SCs, which probably regulated by the p75NTR/AMPK/mTOR axis. Our studies thus provide strong support that NGF may serve as a powerful pharmacological therapy for peripheral nerve injuries.