Theranostics 2020; 10(4):1649-1677. doi:10.7150/thno.40919

Research Paper

Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration

Rui Li1,2,3, Duohui Li1, Chengbiao Wu2, Libing Ye1, Yanqing Wu4, Yuan Yuan1, Shengnan Yang1, Ling Xie1, Yuqin Mao1, Ting Jiang1, Yiyang Li1, Jian Wang1, Hongyu Zhang1, Xiaokun Li1, Jian Xiao1✉

1. Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
2. Research Center, Affiliated Xiangshang Hospital, Wenzhou Medical University, Ningbo, Zhejiang, 315700, China
3. PCFM Lab, School of Chemistry, Sun Yat-sen University, Guangzhou, Guangdong 510127, China
4. The Institute of Life Sciences, Wenzhou University, Wenzhou 325035, China

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Citation:
Li R, Li D, Wu C, Ye L, Wu Y, Yuan Y, Yang S, Xie L, Mao Y, Jiang T, Li Y, Wang J, Zhang H, Li X, Xiao J. Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration. Theranostics 2020; 10(4):1649-1677. doi:10.7150/thno.40919. Available from http://www.thno.org/v10p1649.htm

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Abstract

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.

Keywords: Myelin debris clearance, Autophagic flux, Nerve growth factor (NGF), Schwann cells, Nerve regeneration