We have shown that histone H1 is a binding partner for polysialic acid (PSA) and that it improves functional recovery, axon regrowth/sprouting, and target reinnervation after mouse femoral nerve injury.
Objective:
Here, we analyzed whether histone H1 affects functional recovery, axon regrowth/sprouting, and target reinnervation after spinal cord injury of adult mice. Furthermore, we tested in vitro histone H1’s effect on astrocytic gene expression, cell shape and migration as well as on cell survival of cultured motoneurons.
Methods:
We applied histone H1 to compressed spinal cord and determined functional recovery and number of fibrillary acidic protein (GFAP)- and neuron-glial antigen 2 (NG2)- positive glial cells, which contribute to glial scarring. Histone H1’s effect on migration of astrocytes, astrocytic gene expression and motoneuronal survival was determined using scratch-wounded astroglial monolayer cultures, astrocyte cultures for microarray analysis, and motoneuron cell culture under oxidative stress conditions, respectively.
Results:
Histone H1 application improves locomotor functions and enhances monoaminergic and cholinergic reinnervation of the spinal cord. Expression levels of GFAP and NG2 around the lesion site were decreased in histone H1-treated mice relative to vehicle-treated mice six weeks after injury. Histone H1 reduced astrocytic migration, changed the shape of GFAP- and NG2-positive glial cells and altered gene expression. Gene ontology enrichment analysis indicated that in particular genes coding for proteins involved in proliferation, differentiation, migration and apoptosis are dysregulated. The up- and down-regulation of distinct genes was confirmed by qPCR and Western blot analysis. Moreover, histone H1 reduced hydrogen peroxide-induced cell death of cultured motoneurons.
Conclusions:
The combined observations indicate that histone H1 locally applied to the lesion site, improves regeneration after spinal cord injury. Some of these beneficial functions of histone H1 in vivo and in vitro can be attributed to its interaction with PSA-carrying neural cell adhesion molecule.
Adams,K.L. & Gallo,V. (2018) The diversity and disparity of the glial scar. Nature Neuroscience, 21(1), 9–15.
2.
Alonso,G. (2005) NG2 proteoglycan-expressing cells of the adult rat brain: Possible involvement in the formation of glial scar astrocytes following stab wound. Glia, 49(3), 318–338.
3.
Anderson,K.D., Guest,J.D., Dietrich,W.D., Bartlett Bunge,M., Curiel,R., Dididze,M. & A.D. (2017) Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. Journal of Neurotrauma, 34(21), 2950–2963.
4.
Anderson,M.A., Burda,J.E., Ren,Y., Ao,Y., O’Shea,T.M., Kawaguchi,R. & Sofroniew,M.V. (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature, 532(7598), 195–200.
5.
Apostolova,I., Irintchev,A. & Schachner,M. (2006) Tenascin-R restricts posttraumatic remodeling of motoneuron innervation and functional recovery after spinal cord injury in adult mice. Journal of Neuroscience, 26(30), 7849–7859.
6.
Assinck,P., Duncan,G.J., Plemel,J.R., Lee,M.J., Stratton,J.A., Manesh,S.B. & Tetzlaff,W. (2017) Myelinogenic plasticity of oligodendrocyte precursor cells following spinal cord contusion injury. Journal of Neuroscience, 37(36), 8635–8654.
7.
Basso,D.M., Fisher,L.C., Anderson,A.J., Jakeman,L.B., McTigue,D.M. & Popovich,P.G. (2006) Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. Journal of Neurotrauma, 23(5), 635–659.
8.
Beaudet,M.J., Yang,Q., Cadau,S., Blais,M., Bellenfant,S., Gros-Louis,F. & Berthod,F. (2015) High yield extraction of pure spinal motor neurons, astrocytes and microglia from single embryo and adult mouse spinal cord. Scientific Reports, 5, 16763.
9.
Bolton,S.J. & Perry,V.H. (1997) Histone H1; a neuronal protein that binds bacterial lipopolysaccharide. Journal of Neurocytology, 26(12), 823–831.
10.
Brix,K., Summa,W., Lottspeich,F. & Herzog,V. (1998) Extracellularly occurring histone H1 mediates the binding of thyroglobulin to the cell surface of mouse macrophages. Journal of Clinical Investigation, 102(2), 283–293.
11.
Bushman,J., Mishra,B., Ezra,M., Gul,S., Schulze,C., Chaudhury,S. & Loers,G. (2014) Tegaserod mimics the neurostimulatory glycan polysialic acid and promotes nervous system repair. Neuropharmacology, 79, 456–466.
12.
Casha,S., Zygun,D., McGowan,M.D., Bains,I., Yong,V.W. & Hurlbert,R.J. (2012) Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain, 135(Pt 4), 1224–1236.
13.
Chen,J., Leong,S.Y. & Schachner,M. (2005) Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury. European Journal of Neuroscience, 22(8), 1895–1906.
14.
Chen,Y., Tang,Y., Allen,V. & DeVivo,M.J. (2015) Aging and spinal cord injury: External causes of injury and implications for prevention. Topics in Spinal Cord Injury Rehabilitation, 21(3), 218–226.
15.
Chen,Y., Tang,Y., Allen,V. & DeVivo,M.J. (2016) Fall-induced spinal cord injury: External causes and implications for prevention. Journal of Spinal Cord Medicine, 39(1), 24–31.
16.
Chen,Y., Tang,Y., Vogel,L.C. & Devivo,M.J. (2013) Causes of spinal cord injury. Topics in Spinal Cord Injury Rehabilitation, 19(1), 1–8.
Cremer,H., Lange,R., Christoph,A., Plomann,M., Vopper,G., Roes,J., & et al. (1994) Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature, 367(6462), 455–459.
19.
Crutcher,K.A. & Bingham,W.G.Jr. (1978) Descending monoaminergic pathways in the primate spinal cord. American Journal of Anatomy, 153(1), 159–164.
20.
Curtis,R., Green,D., Lindsay,R.M. & Wilkin,G.P. (1993) Up-regulation of GAP-43 and growth of axons in rat spinal cord after compression injury. Journal of Neurocytology, 22(1), 51–64.
21.
Davidoff,M.S. & Irintchev,A.P. (1986) Acetylcholinesterase activity and type C synapses in the hypoglossal, facial and spinal-cord motor nuclei of rats. An electron-microscope study. Histochemistry, 84(4-6), 515–524.
Dou,C.L. & Levine,J.M. (1994) Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. Journal of Neuroscience, 14(12), 7616–7628.
24.
Fawcett,J.W. (2018) The paper that restarted modern central nervous system axon regeneration research. Trends in Neurosciences,41(5), 239–242.
25.
Fehlings,M.G., Kim,K.D., Aarabi,B., Rizzo,M., Bond,L.M., McKerracher,L. & Okonkwo,D.O. (2018) Rho inhibitor VX-210 in acute traumatic subaxial cervical spinal cord injury: Design of the SPinal cord injury Rho INhibition investiGation (SPRING) clinical trial. Journal of Neurotrauma, 35(9), 1049–1056.
26.
Fehlings,M.G., Nakashima,H., Nagoshi,N., Chow,D.S., Grossman,R.G. & Kopjar,B. (2016) Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): A randomized, double-blinded, placebo-controlled parallel multi-center trial. Spinal Cord, 54(1), 8–15.
27.
Fidler,P.S., Schuette,K., Asher,R.A., Dobbertin,A., Thornton,S.R., Calle-Patino,Y. & Fawcett,J.W. (1999) Comparing astrocytic cell lines that are inhibitory or permissive for growth: The major axon-inhibitory proteoglycan is NG2. Journal of Neuroscience, 19(20), 8778–8788.
28.
Filous,A.R., Tran,A., Howell,C.J., Busch,S.A., Evans,T.A., Stallcup,W.B. & Silver,J. (2014) Entrapment via synaptic-like connections between NG2 proteoglycan+cells and dystrophic axons in the lesion plays a role in regeneration failure after spinal cord injury. Journal of Neuroscience, 34(49), 16369–16384.
29.
Frosch,M., Gorgen,I., Boulnois,G.J., Timmis,K.N. & Bitter-Suermann,D. (1985) NZB mouse system for production of monoclonal antibodies to weak bacterial antigens: Isolation of an IgG antibody to the polysaccharide capsules of Escherichia coli K1 and group B meningococci. Proceedings of the National Academy of Sciences of the United States of America, 82(4), 1194–1198.
30.
Gaudet,A.D. & Fonken,L.K. (2018) Glial cells shape pathology and repair after spinal cord injury. Neurotherapeutics, 15(3), 554–577.
31.
Ghosh,M., Tuesta,L.M., Puentes,R., Patel,S., Melendez,K., El Maarouf,A. & Pearse,D.D. (2012) Extensive cell migration, axon regeneration, and improved function with polysialic acid-modified Schwann cells after spinal cord injury. Glia, 60(6), 979–992.
32.
Grossman,S.D., Rosenberg,L.J. & Wrathall,J.R. (2001) Temporal-spatial pattern of acute neuronal and glial loss after spinal cord contusion. Experimental Neurology, 168(2), 273–282.
33.
Hackett,A.R. & Lee,J.K. (2016) Understanding the NG2 glial scar after spinal cord injury. Frontiers in Neurology, 7, 199.
34.
Hampton,D.W., Rhodes,K.E., Zhao,C., Franklin,R.J. & Fawcett,J.W. (2004) The responses of oligodendrocyte precursor cells, astrocytes and microglia to a cortical stab injury, in the brain. Neuroscience, 127(4), 813–820.
35.
Hampton,R.Y., Golenbock,D.T. & Raetz,C.R. (1988) Lipid A binding sites in membranes of macrophage tumor cells. Journal of Biological Chemistry, 263(29), 14802–14807.
Heckman,C.J., Lee,R.H. & Brownstone,R.M. (2003) Hyperexcitable dendrites in motoneurons and their neuromodulatory control during motor behavior. Trends in Neurosciences, 26(12), 688–695.
38.
Henriquez,J.P., Casar,J.C., Fuentealba,L., Carey,D.J. & Brandan,E. (2002) Extracellular matrix histone H1 binds to perlecan, is present in regenerating skeletal muscle and stimulates myoblast proliferation. Journal of Cell Science, 115(Pt 10), 2041–2051.
39.
Hildebrandt,H., Becker,C., Gluer,S., Rosner,H., Gerardy-Schahn,R. & Rahmann,H. (1998) Polysialic acid on the neural cell adhesion molecule correlates with expression of polysialyltransferases and promotes neuroblastoma cell growth. Cancer Res, 58(4), 779–784.
40.
Hildebrandt,H., Dityatev,A. (2015) Polysialic acid in brain development and synaptic plasticity. Topics in Current Chemistry, 366, 55–96.
41.
Holtje,M., Hoffmann,A., Hofmann,F., Mucke,C., Grosse,G., Van Rooijen,N. & Ahnert-Hilger,G. (2005) Role of Rho GTPase in astrocyte morphology and migratory response during in vitro wound healing. Journal of Neurochemistry, 95(5), 1237–1248.
42.
Hu,H.Z., Granger,N., Pai,S.B., Bellamkonda,R.V. & Jeffery,N.D. (2018) Therapeutic efficacy of microtube-embedded chondroitinase ABC in a canine clinical model of spinal cord injury. Brain, 141(4), 1017–1027.
43.
Jakovcevski,I., Djogo,N., Holters,L.S., Szpotowicz,E. & Schachner,M. (2013) Transgenic overexpression of the cell adhesion molecule L1 in neurons facilitates recovery after mouse spinal cord injury. Neuroscience, 252, 1–12.
44.
Jakovcevski,I., Siering,J., Hargus,G., Karl,N., Hoelters,L., Djogo,N. & Irintchev,A. (2009) Close homologue of adhesion molecule L1 promotes survival of Purkinje and granule cells and granule cell migration during murine cerebellar development. Journal of Comparative Neurology, 513(5), 496–510.
45.
Jakovcevski,I., Wu,J., Karl,N., Leshchyns’ka,I., Sytnyk,V., Chen,J. & Schachner,M. (2007) Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury. Journal of Neuroscience, 27(27), 7222–7233.
46.
Jungnickel,J., Bramer,C., Bronzlik,P., Lipokatic-Takacs,E., Weinhold,B., Gerardy-Schahn,R. & Grothe,C. (2009) Level and localization of polysialic acid is critical for early peripheral nerve regeneration. Molecular and Cellular Neuroscience, 40(3), 374–381.
47.
Kataria,H., Lutz,D., Chaudhary,H., Schachner,M. & Loers,G. (2016) Small molecule agonists of cell adhesion molecule L1 mimic L1 functions in vivo. Molecular Neurobiology, 53(7), 4461–4483.
48.
Kilkenny,C., Browne,W., Cuthill,I.C., Emerson,M. & Altman,D.G. (2010) Animal research: Reporting in vivo experiments: The ARRIVE guidelines. Journal of Gene Medicine, 12(7), 561–563.
Kloos,A.D., Fisher,L.C., Detloff,M.R., Hassenzahl,D.L. & Basso,D.M. (2005) Stepwise motor and all-or-none sensory recovery is associated with nonlinear sparing after incremental spinal cord injury in rats. Experimental Neurology, 191(2), 251–265.
51.
Kucher,K., Johns,D., Maier,D., Abel,R., Badke,A., Baron,H. & Curt,A. (2018) First-in-man intrathecal application of neurite growth-promoting anti-Nogo-A antibodies in acute spinal cord injury. Neurorehabilitation and Neural Repair, 32(6-7), 578–589.
52.
Lang,B.T., Cregg,J.M., DePaul,M.A., Tran,A.P., Xu,K., Dyck,S.M. & Silver,J. (2015) Modulation of the proteoglycan receptor PTPsigma promotes recovery after spinal cord injury. Nature, 518(7539), 404–408.
53.
Lee,H.J., Bian,S., Jakovcevski,I., Wu,B., Irintchev,A. & Schachner,M. (2012) Delayed applications of L1 and chondroitinase ABC promote recovery after spinal cord injury. Journal of Neurotrauma, 29(10), 1850–1863.
54.
Lee,J.Y., Maeng,S., Kang,S.R., Choi,H.Y., Oh,T.H., Ju,B.G. & Yune,T.Y. (2014) Valproic acid protects motor neuron death by inhibiting oxidative stress and endoplasmic reticulum stress-mediated cytochrome C release after spinal cord injury. Journal of Neurotrauma, 31(6), 582–594.
55.
Levine,J. (2016) The reactions and role of NG2 glia in spinal cord injury. Brain Research, 1638(Pt B), 199–208.
56.
Li,R., Sahu,S. & Schachner,M. (2018) Phenelzine, a small organic compound mimicking the functions of cell adhesion molecule L1, promotes functional recovery after mouse spinal cord injury. Restorative Neurology and Neuroscience, 36(4), 469–483.
57.
Li,Y., Li,D., Ibrahim,A., Raisman,G. (2012) Repair involves all three surfaces of the glial cell. Progress in Brain Research, 201, 199–218.
58.
Liang,C.C., Park,A.Y. & Guan,J.L. (2007) In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nature Protocols, 2(2), 329–333.
59.
Loers,G., Chen,S., Grumet,M. & Schachner,M. (2005) Signal transduction pathways implicated in neural recognition molecule L1 triggered neuroprotection and neuritogenesis. Journal of Neurochemistry, 92(6), 1463–1476.
60.
Loers,G., Cui,Y.F., Neumaier,I., Schachner,M. & Skerra,A. (2014) A Fab fragment directed against the neural cell adhesion molecule L1 enhances functional recovery after injury of the adult mouse spinal cord. Biochemical Journal, 460(3), 437–446.
61.
Luo,J., Bo,X., Wu,D., Yeh,J., Richardson,P.M. & Zhang,Y. (2011) Promoting survival, migration, and integration of transplanted Schwann cells by over-expressing polysialic acid. Glia, 59(3), 424–434.
62.
Marino,P., Norreel,J.C., Schachner,M., Rougon,G. & Amoureux,M.C. (2009) A polysialic acid mimetic peptide promotes functional recovery in a mouse model of spinal cord injury. Experimental Neurology, 219(1), 163–174.
63.
Mehanna,A., Jakovcevski,I., Acar,A., Xiao,M., Loers,G., Rougon,G. & Schachner,M. (2010) Polysialic acid glycomimetic promotes functional recovery and plasticity after spinal cord injury in mice. Molecular Therapy, 18(1), 34–43.
64.
Mehanna,A., Mishra,B., Kurschat,N., Schulze,C., Bian,S., Loers,G. & Schachner,M. (2009) Polysialic acid glycomimetics promote myelination and functional recovery after peripheral nerve injury in mice. Brain, 132(Pt 6), 1449–1462.
65.
Middeldorp,J., Hol,E.M. (2011) GFAP in health and disease. Progress in Neurobiology, 93(3), 421–443.
66.
Mishra,B., von der Ohe,M., Schulze,C., Bian,S., Makhina,T., Loers,G. & Schachner,M. (2010) Functional role of the interaction between polysialic acid and extracellular histone H1. Journal of Neuroscience, 30(37), 12400–12413.
67.
Moeendarbary,E., Weber,I.P., Sheridan,G.K., Koser,D.E., Soleman,S., Haenzi,B. & Franze,K. (2017) The soft mechanical signature of glial scars in the central nervous system. Naure. Communications, 8, 14787.
68.
Muhlenhoff,M., Oltmann-Norden,I., Weinhold,B., Hildebrandt,H. & Gerardy-Schahn,R. (2009) Brain development needs sugar: The role of polysialic acid in controlling NCAM functions. Biological Chemistry, 390(7), 567–574.
69.
Niehaus,A., Stegmuller,J., Diers-Fenger,M. & Trotter,J. (1999) Cell-surface glycoprotein of oligodendrocyte progenitors involved in migration. Journal of Neuroscience, 19(12), 4948–4961.
70.
Okada,S., Hara,M., Kobayakawa,K., Matsumoto,Y. & Nakashima,Y. (2018) Astrocyte reactivity and astrogliosis after spinal cord injury. Neuroscience Research, 126, 39–43.
71.
Pan,H.C., Shen,Y.Q., Loers,G., Jakovcevski,I. & Schachner,M. (2014) Tegaserod, a small compound mimetic of polysialic acid, promotes functional recovery after spinal cord injury in mice. Neuroscience, 277, 356–366.
72.
Papastefanaki,F., Chen,J., Lavdas,A.A., Thomaidou,D., Schachner,M. & Matsas,R. (2007) Grafts of Schwann cells engineered to express PSA-NCAM promote functional recovery after spinal cord injury. Brain, 130(Pt 8), 2159–2174.
Parseghian,M.H. & Luhrs,K.A. (2006) Beyond the walls of the nucleus: The role of histones in cellular signaling and innate immunity. Biochemistry and Cell Biology, 84(4), 589–604.
75.
Potempska,A., Ramakrishna,N., Wisniewski,H.M. & Miller,D.L. (1993) Interaction between the beta-amyloid peptide precursor and histones. Archives of Biochemistry and Biophysics, 304(2), 448–453.
76.
Quraishe,S., Forbes,L.H. & Andrews,M.R. (2018) The extracellular environment of the CNS: Influence on plasticity, sprouting, and axonal regeneration after spinal cord injury. Neural Plasticity, 2018, 2952386.
77.
Renault-Mihara,F., Okada,S., Shibata,S., Nakamura,M., Toyama,Y. & Okano,H. (2008) Spinal cord injury: Emerging beneficial role of reactive astrocytes’ migration. International Journal of Biochemistry and Cell Biology, 40(9), 1649–1653.
78.
Rolls,A., Shechter,R. & Schwartz,M. (2009) The bright side of the glial scar in CNS repair. Nature Reviews: Neuroscience, 10(3), 235–241.
Rutishauser,U. (2008) Polysialic acid in the plasticity of the developing and adult vertebrate nervous system. Nature Reviews: Neuroscience, 9(1), 26–35.
81.
Saadoun,S., Papadopoulos,M.C., Watanabe,H., Yan,D., Manley,G.T. & Verkman,A.S. (2005) Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. Journal of Cell Science, 118(Pt 24), 5691–5698.
82.
Saini,V., Loers,G., Kaur,G., Schachner,M. & Jakovcevski,I. (2016) Impact of neural cell adhesion molecule deletion on regeneration after mouse spinal cord injury. European Journal of Neuroscience, 44(1), 1734–1746.
83.
Saini,V., Lutz,D., Kataria,H., Kaur,G., Schachner,M. & Loers,G. (2016) The polysialic acid mimetics 5-nonyloxytryptamine and vinorelbine facilitate nervous system repair. Scientific Reports, 6, 26927.
84.
Schwab,J.M., Brechtel,K., Mueller,C.A., Failli,V., Kaps,H.P., Tuli,S.K. & Schluesener,H.J. (2006) Experimental strategies to promote spinal cord regeneration - an integrative perspective. Progress in Neurobiology, 78(2), 91–116.
85.
Selvarajah,S., Hammond,E.R., Haider,A.H., Abularrage,C.J., Becker,D., Dhiman,N. & Schneider,E.B. (2014) The burden of acute traumatic spinal cord injury among adults in the United States: An update. Journal of Neurotrauma, 31(3), 228–238.
Storms,S.D. & Rutishauser,U. (1998) A role for polysialic acid in neural cell adhesion molecule heterophilic binding to proteoglycans. J Biol Chem, 273(42), 27124–27129.
90.
Sun,D. & Jakobs,T.C. (2012) Structural remodeling of astrocytes in the injured CNS. Neuroscientist, 18(6), 567–588.
Tan,A.M., Colletti,M., Rorai,A.T., Skene,J.H. & Levine,J.M. (2006) Antibodies against the NG2 proteoglycan promote the regeneration of sensory axons within the dorsal columns of the spinal cord. Journal of Neuroscience, 26(18), 4729–4739.
93.
Theis,T., Yoo,M., Park,C.S., Chen,J., Kugler,S., Gibbs,K.M. & Schachner,M. (2017) Lentiviral delivery of miR-133b improves functional recovery after spinal cord injury in mice. Molecular Neurobiology, 54(6), 4659–4671.
94.
Tran,A.P., Warren,P.M. & Silver,J. (2018) The biology of regeneration failure and success after spinal cord injury. Physiological Reviews, 98(2), 881–917.
95.
Ughrin,Y.M., Chen,Z.J. & Levine,J.M. (2003) Multiple regions of the NG2 proteoglycan inhibit neurite growth and induce growth cone collapse. Journal of Neuroscience, 23(1), 175–186.
96.
Vulovic,M., Divac,N., Jakovcevski,I. (2018) Confocal synaptology: Synaptic rearrangements in neurodegenerative disorders and upon nervous system injury. Frontiers in Neuroanatomy, 12, 11.
97.
Wang,K., Bekar,L.K., Furber,K. & Walz,W. (2004) Vimentin-expressing proximal reactive astrocytes correlate with migration rather than proliferation following focal brain injury. Brain Research, 1024(1-2), 193–202.
98.
Wang,S., Cesca,F., Loers,G., Schweizer,M., Buck,F., Benfenati,F. & Kleene,R. (2011) Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. Journal of Neuroscience, 31(20), 7275–7290.
99.
Wang,W., Qi,B., Lv,H., Wu,F., Liu,L., Wang,W. & Wang,Y. (2017) A new method of isolating spinal motor neurons from fetal mouse. Journal of Neuroscience Methods, 288, 57–61.
100.
Watson,K., Edwards,R.J., Shaunak,S., Parmelee,D.C., Sarraf,C., Gooderham,N.J. & Davies,D.S. (1995) Extra-nuclear location of histones in activated human peripheral blood lymphocytes and cultured T-cells. Biochemical Pharmacology, 50(3), 299–309.
101.
Watson,K., Gooderham,N.J., Davies,D.S. & Edwards,R.J. (1999) Nucleosomes bind to cell surface proteoglycans. Journal of Biological Chemistry, 274(31), 21707–21713.
102.
Wu,B., Matic,D., Djogo,N., Szpotowicz,E., Schachner,M. & Jakovcevski,I. (2012) Improved regeneration after spinal cord injury in mice lacking functional T- and B-lymphocytes. Experimental Neurology, 237(2), 274–285.
103.
Wu,J., Wrathall,J.R. & Schachner,M. (2010) Phosphatidylinositol 3-kinase/protein kinase Cdelta activation induces close homolog of adhesion molecule L1 (CHL1) expression in cultured astrocytes. Glia, 58(3), 315–328.
104.
Xu,J., Hu,C., Jiang,Q., Pan,H., Shen,H. & Schachner,M. (2017) Trimebutine, a small molecule mimetic agonist of adhesion molecule L1, contributes to functional recovery after spinal cord injury in mice. Disease Models and Mechanisms, 10(9), 1117–1128.
105.
Xu,J.C., Bernreuther,C., Cui,Y.F., Jakovcevski,I., Hargus,G., Xiao,M.F. & Schachner,M. (2011) Transplanted L1 expressing radial glia and astrocytes enhance recovery after spinal cord injury. Journal of Neurotrauma, 28(9), 1921–1937.
106.
Xu,W., Chi,L., Xu,R., Ke,Y., Luo,C., Cai,J. & Liu,R. (2005) Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury. Spinal Cord, 43(4), 204–213.
107.
Yang,Z. & Wang,K.K. (2015) Glial fibrillary acidic protein: From intermediate filament assembly and gliosis to neurobiomarker. Trends in Neurosciences, 38(6), 364–374.
108.
Yoo,J.Y., Hwang,C.H. & Hong,H.N. (2016) A model of glial scarring analogous to the environment of a traumatically injured spinal cord using kainate. Annals of Rehabilitation Medicine, 40(5), 757–768.
109.
Yoo,M., Khaled,M., Gibbs,K.M., Kim,J., Kowalewski,B., Dierks,T. & Schachner,M. (2013) Arylsulfatase B improves locomotor function after mouse spinal cord injury. PloS One, 8(3), e57415.
110.
Yuan,Y.M. & He,C. (2013) The glial scar in spinal cord injury and repair. Neuroscience Bulletin, 29(4), 421–435.
111.
Zhang,Y., Zhang,X., Wu,D., Verhaagen,J., Richardson,P.M., Yeh,J. & Bo,X. (2007) Lentiviral-mediated expression of polysialic acid in spinal cord and conditioning lesion promote regeneration of sensory axons into spinal cord. Molecular Therapy, 15(10), 1796–1804.
112.
Zhou,X., He,X. & Ren,Y. (2014) Function of microglia and macrophages in secondary damage after spinal cord injury. Neural Regeneration Research, 9(20), 1787–1795.
