CS-4,6 is differentially upregulated in glial scar and is a potent inhibitor of neurite extension

Department of Biomedical Engineering, Biomaterials, Cell and Tissue Engineering Laboratory, Case Western Reserve University, Cleveland, OH 44106-7207, USA.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 09/2005; 29(4):545-58. DOI: 10.1016/j.mcn.2005.04.006
Source: PubMed


The precise contribution of different CS-GAGs to CSPG-mediated inhibition of axonal growth after CNS injury is unknown. Quantification of the CS-GAGs in uninjured and injured brain (scar tissue) using fluorophore-assisted carbohydrate electrophoresis (FACE) demonstrated that the dominant CS-GAG in the uninjured brain is CS-4 whereas, in glial scar, CS-2, CS-6, and CS-4,6 were over-expressed. To determine if the pattern of sulfation influenced neurite extension, we compared the effects of CS-GAGs with dominant CS-4, CS-6, or CS-4,6 sulfation to intact CSPG (aggrecan), chondroitin (CS-0), and hyaluronan on chick DRG neurite outgrowth. We report that CS-4,6 GAG, one of the upregulated CS-GAGs in astroglial scar, is potently inhibitory and is comparable to intact aggrecan, a CSPG with known inhibitory properties. Thus, a specific CS-GAG that is differentially over-expressed in astroglial scar is a potent inhibitor of neurite extension. These results may influence the design of more specific strategies to enhance CNS regeneration after injury.

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Available from: Ryan Gilbert, Oct 08, 2015
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    • "While the contribution of CSPGs to the inhibitory nature of the glial scar has been known for many years (see review by Silver and Miller, 2004), mechanistic explanation as to how CSPGs inhibit advancing growth cones was lacking—until recently. For years it was posited that CSPGs exert inhibition through relatively nonspecific mechanisms such as substrate occlusion (McKeon et al., 1995), or presentation of a negatively charged boundary that repels growing axons (Gilbert et al., 2005). This view has changed considerably with the discovery of several receptors that directly bind sulfated glycosaminoglycan moieties (Dickendesher et al., 2012; Fisher et al., 2011; Shen et al., 2009) (Fig. 5H). "
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    ABSTRACT: Astrocytes react to CNS injury by building a dense wall of filamentous processes around the lesion. Stromal cells quickly take up residence in the lesion core and synthesize connective tissue elements that contribute to fibrosis. Oligodendrocyte precursor cells proliferate within the lesion and help to entrap dystrophic axon tips. Here we review evidence that this aggregate scar acts as the major barrier to regeneration of axons after injury. We also consider several exciting new interventions that allow axons to regenerate beyond the glial scar, and discuss the implications of this work for the future of regeneration biology.
    Experimental Neurology 01/2014; 253. DOI:10.1016/j.expneurol.2013.12.024 · 4.70 Impact Factor
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    • "After lesions, CSPGs are upregulated several-fold, peaking at between 10 to 14 days post-lesion [2] . Together with activated glial cells, the CSPGs form a dense layer of glial scar inhibitory to axon growth, and much of this inhibition is due to the activity of the glycosaminoglycan (GAG) chains [3] . in addition, CSPGs are major components of the perineuronal nets (PNNs), which are dense ECM structures that form around many neuronal cell bodies and dendrites late in development [4] [5] . in the spinal cord, PNNs surround ~30% of motoneurons in the ventral horn, 50% of large interneurons in the intermediate grey, and 20% of neurons in the dorsal horn [4] , while in the brain they are particularly associated with inhibitory GABAergic interneurons. The PNNs in the visual cortex form in the second week of postnatal development, which coincides with closure of the critical period for visual functions [6] . "
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    ABSTRACT: After spinal cord injury (SCi), re-establishing functional circuitry in the damaged central nervous system (CNS) faces multiple challenges including lost tissue volume, insufficient intrinsic growth capacity of adult neurons, and the inhibitory environment in the damaged CNS. Several treatment strategies have been developed over the past three decades, but successful restoration of sensory and motor functions will probably require a combination of approaches to address different aspects of the problem. Degradation of the chondroitin sulfate proteoglycans with the chondroitinase ABC (ChABC) enzyme removes a regeneration barrier from the glial scar and increases plasticity in the CNS by removing perineuronal nets. its mechanism of action does not clash or overlap with most of the other treatment strategies, making ChABC an attractive candidate as a combinational partner with other methods. in this article, we review studies in rat SCi models using ChABC combined with other treatments including cell implantation, growth factors, myelin-inhibitory molecule blockers, and ion channel expression. We discuss possible ways to optimize treatment protocols for future combinational studies. To date, combinational therapies with ChABC have shown synergistic effects with several other strategies in enhancing functional recovery after SCi. These combinatorial approaches can now be developed for clinical application.
    Neuroscience Bulletin 07/2013; 29(4). DOI:10.1007/s12264-013-1359-2 · 2.51 Impact Factor
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    • "Like C4S, C6S increases in the spinal cord after injury [20] and inhibits axonal regeneration in cortical brain lesions [21]. However, other studies reported that C4S is neither up-regulated after cortical injury nor inhibitory to dorsal root ganglion axon outgrowth in vitro, and suggested C4, 6S (CS-E) is a potentially inhibitory molecule [26]. C6S binding peptides, obtained from a peptide phage display library, can block C6S and enhance cortical neurite outgrowth [22], [23], suggesting an inhibitory role of C6S for cortical neurons. "
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    ABSTRACT: Bacterial chondroitinase ABC (ChaseABC) has been used to remove the inhibitory chondroitin sulfate chains from chondroitin sulfate proteoglycans to improve regeneration after rodent spinal cord injury. We hypothesized that the mammalian enzyme arylsulfatase B (ARSB) would also enhance recovery after mouse spinal cord injury. Application of the mammalian enzyme would be an attractive alternative to ChaseABC because of its more robust chemical stability and reduced immunogenicity. A one-time injection of human ARSB into injured mouse spinal cord eliminated immunoreactivity for chondroitin sulfates within five days, and up to 9 weeks after injury. After a moderate spinal cord injury, we observed improvements of locomotor recovery assessed by the Basso Mouse Scale (BMS) in ARSB treated mice, compared to the buffer-treated control group, at 6 weeks after injection. After a severe spinal cord injury, mice injected with equivalent units of ARSB or ChaseABC improved similarly and both groups achieved significantly more locomotor recovery than the buffer-treated control mice. Serotonin and tyrosine hydroxylase immunoreactive axons were more extensively present in mouse spinal cords treated with ARSB and ChaseABC, and the immunoreactive axons penetrated further beyond the injury site in ARSB or ChaseABC treated mice than in control mice. These results indicate that mammalian ARSB improves functional recovery after CNS injury. The structural/molecular mechanisms underlying the observed functional improvement remain to be elucidated.
    PLoS ONE 03/2013; 8(3):e57415. DOI:10.1371/journal.pone.0057415 · 3.23 Impact Factor
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