Meningeal cells and glia establish a permissive environment for axon regeneration after spinal cord injury in newts

Neural Development - 2011
Katherine Zukor1, David T. Kent2, Shannon J. Odelberg2
1Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT 84132, USA
2Department of Internal Medicine, Division of Cardiology, University of Utah, Salt Lake City, UT 84132, USA

Tóm tắt

Abstract Background Newts have the remarkable ability to regenerate their spinal cords as adults. Their spinal cords regenerate with the regenerating tail after tail amputation, as well as after a gap-inducing spinal cord injury (SCI), such as a complete transection. While most studies on newt spinal cord regeneration have focused on events occurring after tail amputation, less attention has been given to events occurring after an SCI, a context that is more relevant to human SCI. Our goal was to use modern labeling and imaging techniques to observe axons regenerating across a complete transection injury and determine how cells and the extracellular matrix in the injury site might contribute to the regenerative process. Results We identify stages of axon regeneration following a spinal cord transection and find that axon regrowth across the lesion appears to be enabled, in part, because meningeal cells and glia form a permissive environment for axon regeneration. Meningeal and endothelial cells regenerate into the lesion first and are associated with a loose extracellular matrix that allows axon growth cone migration. This matrix, paradoxically, consists of both permissive and inhibitory proteins. Axons grow into the injury site next and are closely associated with meningeal cells and glial processes extending from cell bodies surrounding the central canal. Later, ependymal tubes lined with glia extend into the lesion as well. Finally, the meningeal cells, axons, and glia move as a unit to close the gap in the spinal cord. After crossing the injury site, axons travel through white matter to reach synaptic targets, and though ascending axons regenerate, sensory axons do not appear to be among them. This entire regenerative process occurs even in the presence of an inflammatory response. Conclusions These data reveal, in detail, the cellular and extracellular events that occur during newt spinal cord regeneration after a transection injury and uncover an important role for meningeal and glial cells in facilitating axon regeneration. Given that these cell types interact to form inhibitory barriers in mammals, identifying the mechanisms underlying their permissive behaviors in the newt will provide new insights for improving spinal cord regeneration in mammals.

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Tài liệu tham khảo

Davis BM, Ayers JL, Koran L, Carlson J, Anderson MC, Simpson SB: Time course of salamander spinal cord regeneration and recovery of swimming: HRP retrograde pathway tracing and kinematic analysis. Exp Neurol. 1990, 108: 198-213. 10.1016/0014-4886(90)90124-B.

Silver J, Miller JH: Regeneration beyond the glial scar. Nat Rev Neurosci. 2004, 5: 146-156. 10.1038/nrn1326.

Singer M, Nordlander RH, Egar M: Axonal guidance during embryogenesis and regeneration in the spinal cord of the newt: the blueprint hypothesis of neuronal pathway patterning. J Comp Neurol. 1979, 185: 1-21. 10.1002/cne.901850102.

Piatt J: Regeneration of the spinal cord in the salamander. J Exp Zool. 1955, 129: 177-207. 10.1002/jez.1401290109.

Butler EG, Ward MB: Reconstitution of the spinal cord after ablation in adult Triturus. Dev Biol. 1967, 15: 464-486. 10.1016/0012-1606(67)90038-3.

Stensaas LJ: Regeneration in the spinal cord of the newt Notopthalamus (Triturus) pyrrhogaster. Spinal Cord Reconstruction. Edited by: Kao CC, Bunge RP, Reier PJ. 1983, New York: Raven Press, 121-149.

O'Hara CM, Egar MW, Chernoff EA: Reorganization of the ependyma during axolotl spinal cord regeneration: changes in intermediate filament and fibronectin expression. Dev Dyn. 1992, 193: 103-115.

Chernoff EA, Stocum DL, Nye HL, Cameron JA: Urodele spinal cord regeneration and related processes. Dev Dyn. 2003, 226: 295-307. 10.1002/dvdy.10240.

Shearer MC, Fawcett JW: The astrocyte/meningeal cell interface - a barrier to successful nerve regeneration?. Cell Tissue Res. 2001, 305: 267-273. 10.1007/s004410100384.

Bundesen LQ, Scheel TA, Bregman BS, Kromer LF: Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J Neurosci. 2003, 23: 7789-7800.

Francis ETB: The Anatomy of the Salamander. 2002, Salt Lake City: Society for the Study of Amphibians and Reptiles

Davis BM, Duffy MT, Simpson SB: Bulbospinal and intraspinal connections in normal and regenerated salamander spinal cord. Exp Neurol. 1989, 103: 41-51. 10.1016/0014-4886(89)90183-0.

Ramony Cajal S: Degeneration and Regeneration of the Nervous System. 1928, London: Oxford University Press

Tom VJ, Steinmetz MP, Miller JH, Doller CM, Silver J: Studies on the development and behavior of the dystrophic growth cone, the hallmark of regeneration failure, in an in vitro model of the glial scar and after spinal cord injury. J Neurosci. 2004, 24: 6531-6539. 10.1523/JNEUROSCI.0994-04.2004.

Becker T, Wullimann MF, Becker CG, Bernhardt RR, Schachner M: Axonal regrowth after spinal cord transection in adult zebrafish. J Comp Neurol. 1997, 377: 577-595. 10.1002/(SICI)1096-9861(19970127)377:4<577::AID-CNE8>3.0.CO;2-#.

Becker T, Becker CG: Regenerating descending axons preferentially reroute to the gray matter in the presence of a general macrophage/microglial reaction caudal to a spinal transection in adult zebrafish. J Comp Neurol. 2001, 433: 131-147. 10.1002/cne.1131.

Xie F, Zheng B: White matter inhibitors in CNS axon regeneration failure. Exp Neurol. 2008, 209: 302-312. 10.1016/j.expneurol.2007.07.005.

Tang X, Davies JE, Davies SJ: Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, versican V2, and tenascin-C during acute to chronic maturation of spinal cord scar tissue. J Neurosci Res. 2003, 71: 427-444. 10.1002/jnr.10523.

Davies SJ, Goucher DR, Doller C, Silver J: Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J Neurosci. 1999, 19: 5810-5822.

Herrmann JE, Shah RR, Chan AF, Zheng B: EphA4 deficient mice maintain astroglial-fibrotic scar formation after spinal cord injury. Exp Neurol. 2010, 223: 582-598. 10.1016/j.expneurol.2010.02.005.

Busch SA, Horn KP, Cuascut FX, Hawthorne AL, Bai L, Miller RH, Silver J: Adult NG2+ cells are permissive to neurite outgrowth and stabilize sensory axons during macrophage-induced axonal dieback after spinal cord injury. J Neurosci. 2010, 30: 255-265. 10.1523/JNEUROSCI.3705-09.2010.

Hermanns S, Reiprich P, Muller HW: A reliable method to reduce collagen scar formation in the lesioned rat spinal cord. J Neurosci Methods. 2001, 110: 141-146. 10.1016/S0165-0270(01)00427-7.

Condic ML, Lemons ML: Extracellular matrix in spinal cord regeneration: getting beyond attraction and inhibition. Neuroreport. 2002, 13: A37-48. 10.1097/00001756-200203040-00002.

McKeon RJ, Hoke A, Silver J: Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp Neurol. 1995, 136: 32-43. 10.1006/exnr.1995.1081.

Caubit X, Riou JF, Coulon J, Arsanto JP, Benraiss A, Boucaut JC, Thouveny Y: Tenascin expression in developing, adult and regenerating caudal spinal cord in the urodele amphibians. Int J Dev Biol. 1994, 38: 661-672.

Larrivee B, Freitas C, Suchting S, Brunet I, Eichmann A: Guidance of vascular development: lessons from the nervous system. Circ Res. 2009, 104: 428-441. 10.1161/CIRCRESAHA.108.188144.

Mey J, D JM, Brook G, Liu RH, Zhang YP, Koopmans G, McCaffery P: Retinoic acid synthesis by a population of NG2-positive cells in the injured spinal cord. Eur J Neurosci. 2005, 21: 1555-1568. 10.1111/j.1460-9568.2005.03928.x.

Li Y, Field PM, Raisman G: Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells. J Neurosci. 1998, 18: 10514-10524.

Lakatos A, Smith PM, Barnett SC, Franklin RJ: Meningeal cells enhance limited CNS remyelination by transplanted olfactory ensheathing cells. Brain. 2003, 126: 598-609. 10.1093/brain/awg055.

Harty M, Neff AW, King MW, Mescher AL: Regeneration or scarring: an immunologic perspective. Dev Dyn. 2003, 226: 268-279. 10.1002/dvdy.10239.

Fitch MT, Doller C, Combs CK, Landreth GE, Silver J: Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci. 1999, 19: 8182-8198.

Horn KP, Busch SA, Hawthorne AL, van Rooijen N, Silver J: Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J Neurosci. 2008, 28: 9330-9341. 10.1523/JNEUROSCI.2488-08.2008.

Donnelly DJ, Popovich PG: Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 2008, 209: 378-388. 10.1016/j.expneurol.2007.06.009.

Simpson SB: Fasciculation and guidance of regenerating central axons by the ependyma. Spinal Cord Reconstruction. Edited by: Kao CC, Bunge RP, Reier PJ. 1983, New York: Raven Press, 151-162.

Schonbach C: The neuroglia in the spinal cord of the newt, Triturus viridescens. J Comp Neurol. 1969, 135: 93-120. 10.1002/cne.901350107.

Ghashghaei HT, Lai C, Anton ES: Neuronal migration in the adult brain: are we there yet?. Nat Rev Neurosci. 2007, 8: 141-151. 10.1038/nrn2074.

Ferguson MW, O'Kane S: Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond B Biol Sci. 2004, 359: 839-850. 10.1098/rstb.2004.1475.

Borrell V, Marin O: Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling. Nat Neurosci. 2006, 9: 1284-1293. 10.1038/nn1764.

Siegenthaler JA, Ashique AM, Zarbalis K, Patterson KP, Hecht JH, Kane MA, Folias AE, Choe Y, May SR, Kume T, Napoli JL, Peterson AS, Pleasure SJ: Retinoic acid from the meninges regulates cortical neuron generation. Cell. 2009, 139: 597-609. 10.1016/j.cell.2009.10.004.

Shearer MC, Niclou SP, Brown D, Asher RA, Holtmaat AJ, Levine JM, Verhaagen J, Fawcett JW: The astrocyte/meningeal cell interface is a barrier to neurite outgrowth which can be overcome by manipulation of inhibitory molecules or axonal signalling pathways. Mol Cell Neurosci. 2003, 24: 913-925. 10.1016/j.mcn.2003.09.004.

Clagett-Dame M, McNeill EM, Muley PD: Role of all-trans retinoic acid in neurite outgrowth and axonal elongation. J Neurobiol. 2006, 66: 739-756. 10.1002/neu.20241.

Wang G, Scott SA: Retinoid signaling is involved in governing the waiting period for axons in chick hindlimb. Dev Biol. 2008, 321: 216-226. 10.1016/j.ydbio.2008.06.021.

Becker CG, Becker T, Meyer RL, Schachner M: Tenascin-R inhibits the growth of optic fibers in vitro but is rapidly eliminated during nerve regeneration in the salamander Pleurodeles waltl. J Neurosci. 1999, 19: 813-827.

Condic ML, Snow DM, Letourneau PC: Embryonic neurons adapt to the inhibitory proteoglycan aggercan by increasing integrin expression. J Neurosci. 1999, 19: 10036-10043.

Lemons ML, Barua S, Abanto ML, Halfter W, Condic ML: Adaptation of sensory neurons to hyalectin and decorin proteoglycans. J Neurosci. 2005, 25: 4964-4973. 10.1523/JNEUROSCI.0773-05.2005.

Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP: Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science. 2007, 318: 772-777. 10.1126/science.1147710.

Tennant M, Beazley LD: A breakdown of the blood-brain barrier is associated with optic nerve regeneration in the frog. Vis Neurosci. 1992, 9: 149-155. 10.1017/S0952523800009615.

Reier PJ, Stensaas LJ, Guth L: The astrocytic scar as an impediment to regeneration in the central nervous system. Spinal Cord Reconstruction. Edited by: Kao CC, Bunge RP, Reier PJ. 1983, New York: Raven Press, 163-196.

Ferretti P, Zhang F, O'Neill P: Changes in spinal cord regenerative ability through phylogenesis and development: lessons to be learnt. Dev Dyn. 2003, 226: 245-256. 10.1002/dvdy.10226.

Odelberg SJ: Cellular plasticity in vertebrate regeneration. Anat Rec B New Anat. 2005, 287: 25-35.

Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z: PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 2010, 13: 1075-1081. 10.1038/nn.2603.

McLean IW, Nakane PK: Periodate-lysine-paraformaldehyde fixative. A new fixation for immunoelectron microscopy. J Histochem Cytochem. 1974, 22: 1077-1083.

Kardon G: Muscle and tendon morphogenesis in the avian hind limb. Development. 1998, 125: 4019-4032.

Klymkowsky MW, Hanken J: Whole-mount staining of Xenopus and other vertebrates. Methods in Cell Biology. 1991, Academic Press, Inc, 36: 419-441. full_text.

Zukor KA, Kent DT, Odelberg SJ: Fluorescent whole-mount method for visualizing 3-dimensional relationships in intact and regenerating adult newt spinal cords. Dev Dyn.

Tokuyasu KT: Use of poly(vinylpyrrolidone) and poly(vinyl alcohol) for cryoultramicrotomy. Histochem J. 1989, 21: 163-171. 10.1007/BF01007491.

Wei Y, Yang EV, Klatt KP, Tassava RA: Monoclonal antibody MT2 identifies the urodele alpha 1 chain of type XII collagen, a developmentally regulated extracellular matrix protein in regenerating newt limbs. Dev Biol. 1995, 168: 503-513. 10.1006/dbio.1995.1098.

Onda H, Goldhamer DJ, Tassava RA: An extracellular matrix molecule of newt and axolotl regenerating limb blastemas and embryonic limb buds: immunological relationship of MT1 antigen with tenascin. Development. 1990, 108: 657-668.

Nace JD, Tassava RA: Examination of fibronectin distribution and its sources in the regenerating newt limb by immunocytochemistry and in situ hybridization. Dev Dyn. 1995, 202: 153-164.

Bader HL, Keene DR, Charvet B, Veit G, Driever W, Koch M, Ruggiero F: Zebrafish collagen XII is present in embryonic connective tissue sheaths (fascia) and basement membranes. Matrix Biol. 2009, 28: 32-43. 10.1016/j.matbio.2008.09.580.

Reichenberger E, Baur S, Sukotjo C, Olsen BR, Karimbux NY, Nishimura I: Collagen XII mutation disrupts matrix structure of periodontal ligament and skin. J Dent Res. 2000, 79: 1962-1968. 10.1177/00220345000790120701.

ImageJ. [http://rsb.info.nih.gov/ij/]

Anderson JR, Jones BW, Yang JH, Shaw MV, Watt CB, Koshevoy P, Spaltenstein J, Jurrus EUVK, Whitaker RT, Mastronarde D, Tasdizen T, Marc RE: A computational framework for ultrastructural mapping of neural circuitry. PLoS Biol. 2009, 7: e1000074-10.1371/journal.pbio.1000074.

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