Journal of Molecular Neuroscience

, Volume 64, Issue 4, pp 601–610 | Cite as

Schwann-Cell Autophagy, Functional Recovery, and Scar Reduction After Peripheral Nerve Repair

  • Po-Yen Ko
  • Cheng-Chang Yang
  • Yao-Lung Kuo
  • Fong-Chin Su
  • Tai-I Hsu
  • Yuan-Kun Tu
  • I-Ming Jou


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.


Autophagy 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.

Authors’ Contributions

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.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.


  1. Abe N, Borson SH, Cavalli V et al (2010) Mammalian target of rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. J Biol Chem 285(36):28034–28043CrossRefPubMedPubMedCentralGoogle Scholar
  2. Adanali G, Verdi M, Tuncel A, Erdogan B, Kargi E (2003) Effects of hyaluronic acid-carboxymethylcellulose membrane on extraneural adhesion formation and peripheral nerve regeneration. J Reconstr Microsurg 19:29–36CrossRefPubMedGoogle Scholar
  3. Bain JR, Mackinnon SE, Hunter RT (1989) Functional evaluation of complete sciatic peroneal, and posterior tibial nerve lesions in the rat. Plast Reconstr Surg 83:129–138CrossRefPubMedGoogle Scholar
  4. Bora FJ (1967) Peripheral nerve repair in cats. The fascicular stitch. J Bone Joint Surg [Am] 49:659–666CrossRefGoogle Scholar
  5. Bucko CD, Joynt RL, Grabb WC (1981) Peripheral nerve regeneration in primates during D-penicillamine-induced lathyrism. Plast Reconstr Surg 67:23–30CrossRefPubMedGoogle Scholar
  6. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and tau: effects on cognitive impairments. J Biol Chem 285:13107–13120CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chong ZZ, Shang YC, Wang S, Maiese K (2012) Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. Prog Neurobiol 99:128–148CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chu CT (2006) Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 65:423–432CrossRefPubMedPubMedCentralGoogle Scholar
  9. Devor M (2001) Neuropathic pain: what do we do with all these theories? Acta Anaesthesiol Scand 45:1121–1127CrossRefPubMedGoogle Scholar
  10. Devor M, Seltzer Z (1999) Pathophysiology of damaged nerves in relation to chronic pain. In: Wall PD, Melzack R (eds) Textbook of pain. Churchill Livingstone, London, pp 129–164Google Scholar
  11. Eather TF, Pollock M, Myers DB (1986) Proximal and distal changes in collagen content of peripheral nerve that follow transection and crush lesions. Exp Neurol 92:299–310CrossRefPubMedGoogle Scholar
  12. Gomez-Sanchez JA, Carty L, Iruarrizaga-Lejarreta M, Palomo-Irigoyen M, Varela-Rey M, Griffith M, Hantke J, Macias-Camara N, Azkargorta M, Aurrekoetxea I, de Juan VG, Jefferies HBJ, Aspichueta P, Elortza F, Aransay AM, Martínez-Chantar ML, Baas F, Mato JM, Mirsky R, Woodhoo A, Jessen KR (2015) Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves. J Cell Biol 210(1):153–168CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gorgulu A, Uzal C, Doganay L, Imer M, Eliuz K, Cobanoglu S (2003) The effect of low-dose external beam radiation on extraneural scarring after peripheral nerve surgery in rats. Neurosurgery 53:1389–1395CrossRefPubMedGoogle Scholar
  14. Graham W, Patakey P, Calabretta A, Munger B, Buda M (1973) Enhancement of peripheral nerve regeneration with triamcinolone after neurorrhaphy. Surg Forum 24:457–461PubMedGoogle Scholar
  15. Hsiao-Yu L, Tsung-Hsun H, Jia-Jin JC et al (2012) Quantitative video-based gait pattern analysis for hemiparkinsonian rats. Med Biol Eng Comput 50:937–946CrossRefGoogle Scholar
  16. Jen-I L, Meng-Yi C, Ming-Long Y et al (2012) Video-based gait analysis for functional evaluation of healing Achilles tendon in rats. Ann Biomed Eng 40(12):2532–2540CrossRefGoogle Scholar
  17. Kim SG, Buel GR, Blenis J (2013) Nutrient regulation of the mTOR complex 1 signaling pathway. Mol Cells 35:463–473CrossRefPubMedPubMedCentralGoogle Scholar
  18. Lane JM, Bora FW Jr, Pleasure D (1978) Neuroma scar formation in rats following peripheral nerve transection. J Bone Joint Surg Am 60:197–203CrossRefPubMedGoogle Scholar
  19. Larsen KE, Sulzer D (2002) Autophagy in neurons: a review. Histol Histopathol 17:897–908PubMedGoogle Scholar
  20. Lundborg G, Danielsen N (1991) Injury, degeneration and regeneration. In: Gelberman RH (ed) Operative nerve repair and reconstruction, vol 1. JB Lippincott, Philadelphia, pp 109–131Google Scholar
  21. Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA (2010) Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci 30:1166–1175CrossRefPubMedPubMedCentralGoogle Scholar
  22. Marinelli S, Pavone F et al (2011) Schwann cell autophagy counteracts the onset and chronification. Pain 155:93–107CrossRefGoogle Scholar
  23. Mathur A, Merrell JC, Russell RC, Zook EG (1983) A scanning electron microscopy evaluation of peripheral nerve regeneration. Scan Electron Microsc 1983(Pt 2):975–981Google Scholar
  24. McCallion RL, Ferguson MW (1996) Fetal wound healing and the development of antiscarring therapies for adult wound healing. In: Clark RA (ed) The molecular and cell biology of wound repair, 2nd edn. Plenum Press, New York, pp 561–599Google Scholar
  25. Nachemson AK, Lundborg G, Myrhage R, Rank F (1985) Nerve regeneration after pharmacological suppression of the scar reaction at the suture site. An experimental study on the effect of estrogen-progesterone, methylprednisolone-acetate and cis-hydroxyproline in rat sciatic nerve. Scand J Plast Reconstr Surg 19:255–260CrossRefPubMedGoogle Scholar
  26. Ozgenel GY (2003) Effects of hyaluronic acid on peripheral nerve scarring and regeneration in rats. Microsurgery 23:575–581CrossRefPubMedGoogle Scholar
  27. Ozgenel GY, Filiz G (2003) Effects of human amniotic fluid on peripheral nerve scarring and regeneration in rats. J Neurosurg 98:371–377CrossRefPubMedGoogle Scholar
  28. Ozgenel GY, Filiz G (2004) Combined application of human amniotic membrane wrapping and hyaluronic acid injection in epineurectomized rat sciatic nerve. J Reconstr Microsurg 20:153–157CrossRefPubMedGoogle Scholar
  29. Peterson J, Russell L, Andrus K, Mackinnon M, Silver J, Kliot M (1996) Reduction of extraneural scarring by ADCON-T/N after surgical intervention. Neurosurgery 38:976–983CrossRefGoogle Scholar
  30. Rangaraju S, Verrier JD, Madorsky I, Nicks J, Dunn WA Jr, Notterpek L (2010) Rapamycin activates autophagy and improves myelination in explant cultures from neuropathic mice. J Neurosci 30:11388–11397CrossRefPubMedPubMedCentralGoogle Scholar
  31. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595CrossRefPubMedGoogle Scholar
  32. Robinson PP, Loescher AR, Smith KG (2000) A prospective, quantitative study on the clinical outcome of lingual nerve repair. Br J Oral Maxillofacial Surg 38:255–263CrossRefGoogle Scholar
  33. Rubinsztein DC, Difiglia M, Heintz N et al (2005) Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1:11–22CrossRefPubMedGoogle Scholar
  34. Rydevik M, Bergstrom F, Mitts C, Danielson N (2002) Locally applied collagenase and regeneration of transected and repaired rat sciatic nerves. Scand J Plast Reconstr Surg Hand Surg 36:193–196CrossRefPubMedGoogle Scholar
  35. Sunderland S (1978) Nerves and nerve injuries, 2nd edn. Churchill Livingstone, London, pp 188–200Google Scholar
  36. Sunderland S (1987) Nerves and nerve injuries. Churchill Livingstone, New York, pp 173–176Google Scholar
  37. Sunderland S, Bradley KC (1959) Endoneurial tube shrinkage in the distal segment of a severed nerve. J Comp Neurol 93:411–420CrossRefGoogle Scholar
  38. Wehling P, Pak M, Cleveland S, Nieper R (1992) The influence of bacterial collagenase on regeneration of severed rat sciatic nerves. Acta Neurochir 119:121–127CrossRefPubMedGoogle Scholar
  39. Yates JM, Smith KG, Robinson PP (2000) Ectopic neural activity from myelinated afferent fibres in the lingual nerve of the ferret following three types of injury. Brain Res 874:37–47CrossRefPubMedGoogle Scholar
  40. Yates JM, Smith KG, Robinson PP (2004) The effect of triamcinolone hexacetonide on the spontaneous and mechanically-induced ectopic discharge following lingual nerve injury in the ferret. Pain 111:261–269CrossRefPubMedGoogle Scholar
  41. Zou T, Ling C, Xiao Y, Tao X, Ma D, Chen ZL, Strickland S, Song H (2006) Exogenous tissue plasminogen activator enhances peripheral nerve regeneration and functional recovery after injury in mice. J Neuropath Exp Neurol 65:78–86CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringNational Cheng Kung UniversityTainanTaiwan
  2. 2.Department of OrthopedicsNational Cheng Kung University HospitalTainanTaiwan
  3. 3.Institute of Basic Medical Sciences, College of MedicineNational Cheng Kung UniversityTainanTaiwan
  4. 4.Department of Plastic SurgeonNational Cheng Kung University HospitalTainanTaiwan
  5. 5.Department of OrthopedicsE-Da HospitalKaohsiungTaiwan

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