Advertisement

Peripheral Nerve Regeneration and Dedifferentiation

  • Xiaobing Fu
  • Andong Zhao
  • Tian Hu
Chapter

Abstract

Peripheral nerve regeneration is one of the few processes that have been deeply investigated by scientists and researchers for a long time in the field of regenerative medicine. Anesthesia, paralysis, and lack of autonomic control of the affected body areas are results of peripheral nerve lesions. After trauma, axons distal to the injury are disconnected from the degenerate and neuronal body, bringing about the peripheral organs’ denervation. A microenvironment is created by Wallerian degeneration distal to the lesion site supporting axonal regrowth, whereas the neuron body switches in phenotype to boost axonal regeneration. Axonal regeneration’s importance is to substitute the degenerated distal nerve section and attain target organs’ reinnervation and restitution of their roles. In comparison with the central nervous system, the peripheral nerve could be easily obtained and dissected. In addition, several animal models of the peripheral nerve system have provided wonderful experimental materials for generations of scientists. Schwann cell dedifferentiation is the initial phase of peripheral nerve regeneration. And the model of Wallerian degeneration demonstrates one excellent biological process, which the repair and regeneration are orchestrated by certain sorts of cells. This review has summed up current studies on peripheral nerve regeneration, Schwann cell dedifferentiation, and the underlying molecular mechanisms. Among the molecular mechanisms, critical signaling pathways responsible for Schwann cell dedifferentiation and epigenetics were illustrated in detail.

Keywords

Peripheral nervous system Schwann cell Signal pathways Molecular mechanisms Dedifferentiation Regeneration 

References

  1. 1.
    Rosberg HE, Carlsson KS, Dahlin LB. Prospective study of patients with injuries to the hand and forearm: costs, function, and general health. Scand J Plast Reconstr Surg Hand Surg. 2005;39(6):360–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Sunderland S. Rate of regeneration in human peripheral nerves; analysis of the interval between injury and onset of recovery. Arch Neurol Psychiatry. 1947;58(3):251–95.CrossRefPubMedGoogle Scholar
  3. 3.
    Fu SY, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation. J Neurosci. 1995;15(5 Pt 2):3886–95.PubMedGoogle Scholar
  4. 4.
    Fu SY, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged axotomy. J Neurosci. 1995;15(5 Pt 2):3876–85.PubMedGoogle Scholar
  5. 5.
    Bunge RP. Expanding roles for the Schwann cell: ensheathment, myelination, trophism and regeneration. Curr Opin Neurobiol. 1993;3(5):805–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Chen YY, et al. Axon and Schwann cell partnership during nerve regrowth. J Neuropathol Exp Neurol. 2005;64(7):613–22.CrossRefPubMedGoogle Scholar
  7. 7.
    Fawcett JW, Keynes RJ. Peripheral nerve regeneration. Annu Rev Neurosci. 1990;13:43–60.CrossRefPubMedGoogle Scholar
  8. 8.
    Chen ZL, Yu WM, Strickland S. Peripheral regeneration. Annu Rev Neurosci. 2007;30:209–33.CrossRefPubMedGoogle Scholar
  9. 9.
    Scheib J, Hoke A. Advances in peripheral nerve regeneration. Nat Rev Neurol. 2013;9(12):668–76.CrossRefPubMedGoogle Scholar
  10. 10.
    Navarro X, Vivo M, Valero-Cabre A. Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol. 2007;82(4):163–201.CrossRefPubMedGoogle Scholar
  11. 11.
    Allodi I, Udina E, Navarro X. Specificity of peripheral nerve regeneration: interactions at the axon level. Prog Neurobiol. 2012;98(1):16–37.CrossRefPubMedGoogle Scholar
  12. 12.
    Arthur-Farraj PJ, et al. c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron. 2012;75(4):633–47.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Glenn TD, Talbot WS. Signals regulating myelination in peripheral nerves and the Schwann cell response to injury. Curr Opin Neurobiol. 2013;23(6):1041–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Parkinson DB, et al. c-Jun is a negative regulator of myelination. J Cell Biol. 2008;181(4):625–37.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Shy ME, et al. Axon-Schwann cell interactions regulate the expression of c-jun in Schwann cells. J Neurosci Res. 1996;43(5):511–25.CrossRefPubMedGoogle Scholar
  16. 16.
    Fontana X, et al. c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling. J Cell Biol. 2012;198(1):127–41.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Newbern J, Birchmeier C. Nrg1/ErbB signaling networks in Schwann cell development and myelination. Semin Cell Dev Biol. 2010;21(9):922–8.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Leimeroth R, et al. Membrane-bound neuregulin1 type III actively promotes Schwann cell differentiation of multipotent progenitor cells. Dev Biol. 2002;246(2):245–58.CrossRefPubMedGoogle Scholar
  19. 19.
    Chen S, et al. Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function. J Neurosci. 2006;26(12):3079–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Michailov GV, et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science. 2004;304(5671):700–3.CrossRefPubMedGoogle Scholar
  21. 21.
    Syed N, et al. Soluble neuregulin-1 has bifunctional, concentration-dependent effects on Schwann cell myelination. J Neurosci. 2010;30(17):6122–31.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Murphy P, et al. The regulation of Krox-20 expression reveals important steps in the control of peripheral glial cell development. Development. 1996;122(9):2847–57.PubMedGoogle Scholar
  23. 23.
    Harrisingh MC, et al. The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. EMBO J. 2004;23(15):3061–71.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Napoli I, et al. A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron. 2012;73(4):729–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Woodhoo A, et al. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci. 2009;12(7):839–U46.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shin YK, et al. The Neuregulin-Rac-MKK7 pathway regulates antagonistic c-jun/Krox20 expression in Schwann cell dedifferentiation. Glia. 2013;61(6):892–904.CrossRefPubMedGoogle Scholar
  27. 27.
    Jung J, et al. Actin polymerization is essential for myelin sheath fragmentation during Wallerian degeneration. J Neurosci. 2011;31(6):2009–15.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yang DP, et al. p38 MAPK activation promotes denervated Schwann cell phenotype and functions as a negative regulator of Schwann cell differentiation and myelination. J Neurosci. 2012;32(21):7158–68.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Myers RR, et al. Inhibition of p38 MAP kinase activity enhances axonal regeneration. Exp Neurol. 2003;184(2):606–14.CrossRefPubMedGoogle Scholar
  30. 30.
    Heinen A, et al. The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination. Proc Natl Acad Sci U S A. 2008;105(25):8748–53.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lee HK, et al. Proteasome inhibition suppresses Schwann cell dedifferentiation in vitro and in vivo. Glia. 2009;57(16):1825–34.CrossRefPubMedGoogle Scholar
  32. 32.
    Liu H, et al. Matrix metalloproteinase inhibition enhances the rate of nerve regeneration in vivo by promoting dedifferentiation and mitosis of supporting schwann cells. J Neuropathol Exp Neurol. 2010;69(4):386–95.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Apra C, et al. Cthrc1 is a negative regulator of myelination in Schwann cells. Glia. 2012;60(3):393–403.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yun B, et al. MicroRNA-deficient Schwann cells display congenital hypomyelination. J Neurosci. 2010;30(22):7722–8.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Viader A, et al. MicroRNAs modulate Schwann cell response to nerve injury by reinforcing transcriptional silencing of dedifferentiation-related genes. J Neurosci. 2011;31(48):17358–69.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Yu B, et al. miR-182 inhibits Schwann cell proliferation and migration by targeting FGF9 and NTM, respectively at an early stage following sciatic nerve injury. Nucleic Acids Res. 2012;40(20):10356–65.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Grijalva I, et al. Expression of neurotrimin in the normal and injured adult human spinal cord. Spinal Cord. 2006;44(5):280–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Lum M, et al. Fibroblast growth factor-9 inhibits astrocyte differentiation of adult mouse neural progenitor cells. J Neurosci Res. 2009;87(10):2201–10.CrossRefPubMedGoogle Scholar
  39. 39.
    Li S, et al. Let-7 microRNAs regenerate peripheral nerve regeneration by targeting nerve growth factor. Mol Ther. 2015;23(3):423–33.CrossRefPubMedGoogle Scholar
  40. 40.
    Yu B, et al. miR-221 and miR-222 promote Schwann cell proliferation and migration by targeting LASS2 after sciatic nerve injury. J Cell Sci. 2012;125(Pt 11):2675–83.CrossRefPubMedGoogle Scholar
  41. 41.
    Timmer M, et al. Axonal regeneration across long gaps in silicone chambers filled with Schwann cells overexpressing high molecular weight FGF-2. Cell Transplant. 2003;12(3):265–77.CrossRefPubMedGoogle Scholar
  42. 42.
    Pettingill LN, Minter RL, Shepherd RK. Schwann cells genetically modified to express neurotrophins promote spiral ganglion neuron survival in vitro. Neuroscience. 2008;152(3):821–8.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Fang Y, et al. A new type of Schwann cell graft transplantation to promote optic nerve regeneration in adult rats. J Tissue Eng Regen Med. 2010;4(8):581–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Hu Y, et al. Lentiviral-mediated transfer of CNTF to schwann cells within reconstructed peripheral nerve grafts enhances adult retinal ganglion cell survival and axonal regeneration. Mol Ther. 2005;11(6):906–15.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2018

Authors and Affiliations

  • Xiaobing Fu
    • 1
  • Andong Zhao
    • 2
  • Tian Hu
    • 3
  1. 1.Key Laboratory of Wound Repair and Regeneration of PLAThe First Hospital Affiliated to the PLA General HospitalBeijingChina
  2. 2.Tianjin Medical UniversityTianjinChina
  3. 3.School of MedicineNankai UniversityTianjinChina

Personalised recommendations