After Nerve Injury, Lineage Tracing Shows That Myelin and Remak Schwann Cells Elongate Extensively and Branch to Form Repair Schwann Cells, Which Shorten Radically on Remyelination

Abstract

There is consensus that, distal to peripheral nerve injury, myelin and Remak cells reorganize to form cellular columns, Bungner's bands, which are indispensable for regeneration. However, knowledge of the structure of these regeneration tracks has not advanced for decades and the structure of the cells that form them, denervated or repair Schwann cells, remains obscure. Furthermore, the origin of these cells from myelin and Remak cells and their ability to give rise to myelin cells after regeneration has not been demonstrated directly, although these conversions are believed to be central to nerve repair. Using genetic lineage-tracing and scanning-block face electron microscopy, we show that injury of sciatic nerves from mice of either sex triggers extensive and unexpected Schwann cell elongation and branching to form long, parallel processes. Repair cells are 2- to 3-fold longer than myelin and Remak cells and 7- to 10-fold longer than immature Schwann cells. Remarkably, when repair cells transit back to myelinating cells, they shorten ∼7-fold to generate the typically short internodes of regenerated nerves. The present experiments define novel morphological transitions in injured nerves and show that repair Schwann cells have a cell-type-specific structure that differentiates them from other cells in the Schwann cell lineage. They also provide the first direct evidence using genetic lineage tracing for two basic assumptions in Schwann cell biology: that myelin and Remak cells generate the elongated cells that build Bungner bands in injured nerves and that such cells can transform to myelin cells after regeneration. SIGNIFICANCE STATEMENT After injury to peripheral nerves, the myelin and Remak Schwann cells distal to the injury site reorganize and modify their properties to form cells that support the survival of injured neurons, promote axon growth, remove myelin-associated growth inhibitors, and guide regenerating axons to their targets. We show that the generation of these repair-supportive Schwann cells involves an extensive cellular elongation and branching, often to form long, parallel processes. This generates a distinctive repair cell morphology that is favorable for the formation of the regeneration tracks that are essential for nerve repair. Remyelination, conversely, involves a striking cell shortening to form the typical short myelin cells of regenerated nerves. We also provide evidence for direct lineage relationships between: (1) repair cells and myelin and Remak cells of uninjured nerves and (2) remyelinating cells in regenerated nerves.

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References 41

1. 1.
   c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration · 2012

   No notice
2. 2.

   Atanasoski S, Shumas S, Dickson C, Scherer SS, Suter U (2001 ) Differential cyclin D1 requirements of proliferating Schwann cells during development and after injury. Mol Cell Neurosci 18:581–592.

   Not in our library10.1006/mcne.2001.1055

3. 3.

   Atanasoski S, Boentert M, De Ventura L, Pohl H, Baranek C, Beier K, Young P, Barbacid M, Suter U (2008 ) Postnatal Schwann cell proliferation but not myelination is strictly and uniquely dependent on cyclin-dependent kinase 4 (cdk4). Mol Cell Neurosci 37:519–527.

   Not in our library10.1016/j.mcn.2007.11.005

4. 4.

   Benito C, Davis CM, Gomez-Sanchez JA, Turmaine M, Meijer D, Poli V, Mirsky R, Jessen KR (2017 ) STAT3 controls the long-term survival and phenotype of repair Schwann cells during nerve regeneration. J Neurosci 37:4255–4269.

   Not in our library10.1523/jneurosci.3481-16.2017

5. 5.
   Molecular Mechanisms Involved in Schwann Cell Plasticity · 2017

   No notice
6. 6.

   Boyd JG, Gordon T (2003 ) Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury. Mol Neurobiol 27:277–324.

   Not in our library10.1385/mn:27:3:277

7. 7.

   Brosius Lutz A, Barres BA (2014 ) Contrasting the glial response to axon injury in the central and peripheral nervous systems. Dev Cell 28:7–17.

   Not in our library10.1016/j.devcel.2013.12.002

8. 8.

   Cattin AL, Lloyd AC (2016 ) The multicellular complexity of peripheral nerve regeneration. Curr Opin Neurobiol 39:38–46.

   Not in our library10.1016/j.conb.2016.04.005

9. 9.

   Court FA, Sherman DL, Pratt T, Garry EM, Ribchester RR, Cottrell DF, Fleetwood-Walker SM, Brophy PJ (2004 ) Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves. Nature 431:191–195.

   Not in our library10.1038/nature02841

10. 10.

    Eggers R, Tannemaat MR, Ehlert EM, Verhaagen J (2010 ) A spatio-temporal analysis of motoneuron survival, axonal regeneration and neurotrophic factor expression after lumbar ventral root avulsion and implantation. Exp Neurol 223:207–220.

    Not in our library10.1016/j.expneurol.2009.07.021

11. 11.

    Fricker FR, Antunes-Martins A, Galino J, Paramsothy R, La Russa F, Perkins J, Goldberg R, Brelstaff J, Zhu N, McMahon SB, Orengo C, Garratt AN, Birchmeier C, Bennett DL (2013 ) Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination. Brain 136:2279–2297.

    Not in our library10.1093/brain/awt148

12. 12.

    Glenn TD, Talbot WS (2013 ) Signals regulating myelination in peripheral nerves and the Schwann cell response to injury. Curr Opin Neurobiol 23:1041–1048.

    Not in our library10.1016/j.conb.2013.06.010

13. 13.

    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 HB, 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 210:153–168.

    Not in our library10.1083/jcb.201503019

14. 14.

    Grim M, Halata Z, Franz T (1992 ) Schwann cells are not required for guidance of motor nerves in the hindlimb in Splotch mutant mouse embryos. Anat Embryol (Berl) 186:311–318.

    Not in our library10.1007/bf00185979

15. 15.

    Hantke J, Carty L, Wagstaff LJ, Turmaine M, Wilton DK, Quintes S, Koltzenburg M, Baas F, Mirsky R, Jessen KR (2014 ) c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy. Brain 137:2922–2937.

    Not in our library10.1093/brain/awu257

16. 16.

    Hildebrand C, Kocsis JD, Berglund S, Waxman SG (1985 ) Myelin sheath remodelling in regenerated rat sciatic nerve. Brain Res 358:163–170.

    Not in our library10.1016/0006-8993(85)90960-6

17. 17.

    Hirata K, Kawabuchi M (2002 ) Myelin phagocytosis by macrophages and non-macrophages during Wallerian degeneration. Microsc Res Tech 57:541–547.

    Not in our library10.1002/jemt.10108

18. 18.
    The repair Schwann cell and its function in regenerating nerves · 2016

    No notice
19. 19.

    Jessen KR, Mirsky R, Arthur-Farraj P (2015a ) The role of cell plasticity in tissue repair: adaptive cellular reprogramming. Dev Cell 34:613–620.

    Not in our library10.1016/j.devcel.2015.09.005

20. 20.

    Jessen KR, Mirsky R, Lloyd AC (2015b ) Schwann cells: development and role in nerve repair. Cold Spring Harb Perspect Biol 7:a020487.

    Not in our library10.1101/cshperspect.a020487

21. 21.

    Kim HA, Pomeroy SL, Whoriskey W, Pawlitzky I, Benowitz LI, Sicinski P, Stiles CD, Roberts TM (2000 ) A developmentally regulated switch directs regenerative growth of Schwann cells through cyclin D1. Neuron 26:405–416.

    Not in our library10.1016/s0896-6273(00)81173-3

22. 22.

    Klein D, Groh J, Wettmarshausen J, Martini R (2014 ) Nonuniform molecular features of myelinating Schwann cells in models for CMT1: distinct disease patterns are associated with NCAM and c-Jun upregulation. Glia 62:736–750.

    Not in our library10.1002/glia.22638

23. 23.

    Le LQ, Liu C, Shipman T, Chen Z, Suter U, Parada LF (2011 ) Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. Cancer Res 71:4686–4695.

    Not in our library10.1158/0008-5472.can-10-4577

24. 24.

    Leone DP, Genoud S, Atanasoski S, Grausenburger R, Berger P, Metzger D, Macklin WB, Chambon P, Suter U (2003 ) Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells. Mol Cell Neurosci 22:430–440.

    Not in our library10.1016/s1044-7431(03)00029-0

25. 25.
    Epigenomic reprogramming in peripheral nerve injury · 2016

    Not checked
26. 26.

    Martini R (1994 ) Expression and functional roles of neural cell surface molecules and extracellular matrix components during development and regeneration of peripheral nerves. J Neurocytol 23:1–28.

    Not in our library10.1007/bf01189813

27. 27.

    Murinson BB, Archer DR, Li Y, Griffin JW (2005 ) Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents. J Neurosci 25:1179–1187.

    Not in our library10.1523/jneurosci.1372-04.2005

28. 28.

    Parkinson DB, Bhaskaran A, Arthur-Farraj P, Noon LA, Woodhoo A, Lloyd AC, Feltri ML, Wrabetz L, Behrens A, Mirsky R, Jessen KR (2008 ) c-Jun is a negative regulator of myelination. J Cell Biol 181:625–637.

    Not in our library10.1083/jcb.200803013

29. 29.

    Reynolds ML, Woolf CJ (1992 ) Terminal Schwann cells elaborate extensive processes following denervation of the motor endplate. J Neurocytol 21:50–66.

    Not in our library10.1007/bf01206897

30. 30.

    Ribeiro S, Napoli I, White IJ, Parrinello S, Flanagan AM, Suter U, Parada LF, Lloyd AC (2013 ) Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. Cell Rep 5:126–136.

    Not in our library10.1016/j.celrep.2013.08.033

31. 31.

    Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C (1997 ) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389:725–730.

    Not in our library10.1038/39593

32. 32.

    Scheib J, Höke A (2013 ) Advances in peripheral nerve regeneration. Nat Rev Neurol 9:668–676.

    Not in our library10.1038/nrneurol.2013.227

33. 33.

    Son YJ, Thompson WJ (1995 ) Nerve sprouting in muscle is induced and guided by processes extended by Schwann cells. Neuron 14:133–141.

    Not in our library10.1016/0896-6273(95)90247-3

34. 34.

    Sulaiman OA, Gordon T (2009 ) Role of chronic Schwann cell denervation in poor functional recovery after nerve injuries and experimental strategies to combat it. Neurosurgery 65:A105–A114.

    Not in our library10.1227/01.neu.0000358537.30354.63

35. 35.

    Sulaiman W, Gordon T (2013 ) Neurobiology of peripheral nerve injury, regeneration, and functional recovery: from bench top research to bedside application. Ochsner J 13:100–108.

    Not in our library

36. 36.

    Suzuki K, Lovera M, Schmachtenberg O, Couve E (2015 ) Axonal degeneration in dental pulp precedes human primary teeth exfoliation. J Dent Res 94:1446–1453.

    Not in our library10.1177/0022034515593055

37. 37.

    Truett GE, Heeger P, Mynatt RL, Truett AA, Walker JA, Warman ML (2000 ) Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT). Biotechniques 29:52–54.

    Not in our library10.2144/00291bm09

38. 38.

    Webster HD, Martin R, O'Connell MF (1973 ) The relationships between interphase Schwann cells and axons before myelination: a quantitative electron microscopic study. Dev Biol 32:401–416.

    Not in our library10.1016/0012-1606(73)90250-9

39. 39.

    Weinberg HJ, Spencer PS (1978 ) The fate of Schwann cells isolated from axonal contact. J Neurocytol 7:555–569.

    Not in our library10.1007/bf01260889

40. 40.

    Yang DP, Zhang DP, Mak KS, Bonder DE, Pomeroy SL, Kim HA (2008 ) Schwann cell proliferation during Wallerian degeneration is not necessary for regeneration and remyelination of the peripheral nerves: axon-dependent removal of newly generated Schwann cells by apoptosis. Mol Cell Neurosci 38:80–88.

    Not in our library10.1016/j.mcn.2008.01.017

Cited by papers we hold 8

• Mature but not developing Schwann cells promote axon regeneration after peripheral nerve injury · 2022
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• An RNA-sequencing transcriptome of the rodent Schwann cell response to peripheral nerve injury · 2022
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• Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair · 2021
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• Transcriptional profiling of mouse peripheral nerves to the single-cell level to build a sciatic nerve ATlas (SNAT) · 2021
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• Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury · 2021
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• Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury · 2020
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• Schwann Cell Precursors; Multipotent Glial Cells in Embryonic Nerves · 2019
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• The Success and Failure of the Schwann Cell Response to Nerve Injury · 2019
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