Schwann-Cell Autophagy, Functional Recovery, and Scar Reduction After Peripheral Nerve Repair
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The functional outcome after peripheral nerve repair is often unpredictable for many reasons, e.g., the severity of neuronal death and scarring. Axonal degeneration significantly affects outcomes. Post-injury axonal degeneration in peripheral nerves is accompanied by myelin degradation initiated by Schwann cells (SCs), which activate autophagy, a ubiquitous cytoprotective process essential for degrading and recycling cellular constituents. Scar formation occurs concomitantly with nerve insult and axonal degeneration. The association between SC autophagy and the mechanisms of nerve scar formation is still unknown. A rat model of peripheral nerve lesions induced by sciatic nerve transection injuries was used to examine the function of autophagy in fibrosis reduction during the early phase of nerve repair. Rats were treated with rapamycin (autophagy inducer) or 3-methyladenine (autophagy inhibitor). One week after the nerve damage, fibrosis was potently inhibited in rapamycin-treated rats and, based on gait analysis, yielded a better functional outcome. Immunohistochemistry showed that the autophagic activity of SCs and the accumulation of neurofilaments were upregulated in rapamycin-treated rats. A deficiency of SC autophagic activity might be an early event in nerve scar formation, and modulating autophagy might be a powerful pharmacological approach for improving functional outcomes.
KeywordsAutophagy Nerve injury Rapamycin Neurosurgery Scarring
We are grateful to Kuen-Jer Tsai, PhD, Ms. I-Wen Shene, Ms. Shu Hsien Shih, and Ms. Ying-Chiu Lin for their excellent assistance. None of the authors has a commercial interest relevant to the manuscript.
Po-Yen Ko and Cheng-Chang Yang contributed equally to this work. Po-Yen Ko and Cheng-Chang Yang carried out the study design, acquiring and analyzing the data, and drafting of the articles; Yao-Lung Kuo, Tai-I Hsu participated in the critical revision of the article for important intellectual content, and technical or logical support; Fong-Chin Su, Yuan-Kun Tu, and I-Ming Jou participated in the final approval of the article provision of the study, obtaining of funding, provision of study materials, and critical revision of the article for important intellectual content. All authors have read and approved the final submitted manuscript.
This study was supported by grant NSC106-2314-B-006-004 from the National Science Council, Taiwan, grant EDAHP 106004 from the E-Da Hospital, Taiwan.
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Conflicts of Interest
The authors declare that they have no conflict of interest.
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