Roles of Chondroitin Sulfate and Dermatan Sulfate in the Formation of a Lesion Scar and Axonal Regeneration after Traumatic Injury of the Mouse Brain

Abstract

Dermatan sulfate (DS) is synthesized from chondroitin sulfate (CS) by epimerization of glucuronic acid of CS to yield iduronic acid. In the present study, the role of CS and DS was examined in mice that received transection of nigrostriatal dopaminergic pathway followed by injection of glycosaminoglycan degrading enzymes into the lesion site. Two weeks after injury, fibrotic and glial scars were formed around the lesion, and transected axons did not regenerate beyond the fibrotic scar. Injection of chondroitinase ABC (ChABC), which degrades both CS and DS, completely suppressed the fibrotic scar formation, reduced the glial scar, and promoted the regeneration of dopaminergic axons. Injection of the DSdegrading enzyme chondroitinase B (ChB) also yielded similar results. By contrast, injection of chondroitinase AC (ChAC), a CS-degrading enzyme, did not suppress the fibrotic and glial scar formation, but reduced CS immunoreactivity and promoted the axonal regeneration. Addition of transforming growth factor-b1 (TGF-b1) to a co-culture of meningeal fibroblasts and cerebral astrocytes induces a fibrotic scar-like cell cluster. The effect of TGF-b1 on cluster formation was suppressed by treatment with ChABC or ChB, but not by ChAC. TGF-b1-induced cell cluster repelled neurites of neonatal cerebellar neurons, but addition of ChABC or ChAC suppressed the inhibitory property of clusters on neurite outgrowth. The present study is the first to demonstrate that DS and CS play different functions after brain injury: DS is involved in the lesion scar formation, and CS inhibits axonal regeneration.

Knockdown of chondroitin‐4‐sulfotransferase‐1, but not of dermatan‐4‐sulfotransferase‐1, accelerates regeneration of zebrafish after spinal cord injury

“…Germline ablation of Chst-14 reduces regeneration after mouse SCI (21), but accelerates peripheral nerve regeneration (22). DS suppresses fibrotic scar formation, reduces glial scar size, and promotes regeneration of dopaminergic axons (49). These observations underscore the difficulty in rationalizing the discrepancy, in that DS can be both beneficial and inhibitory for regeneration, a problem that is not solved by application of chondroitinase ABC (ChABC) which degrades both CS and DS.…”

“…These observations underscore the difficulty in rationalizing the discrepancy, in that DS can be both beneficial and inhibitory for regeneration, a problem that is not solved by application of chondroitinase ABC (ChABC) which degrades both CS and DS. Removal of CS and DS by ChABC treatment has been shown to enhance regeneration after nervous system injury (36,37,(49)(50)(51), demonstrating that CS and DS, at least in part, prevent the regrowth of severed axons. Injection of ChABC or ChB (DS-degrading enzyme) suppresses fibrotic scar formation, reduces glial scar size, and promotes regrowth of dopaminergic axons, whereas injection of ChAC (CS-degrading enzyme) does not suppress fibrotic and glial scar formation, but reduces CS immunoreactivity and promotes axonal regrowth (49).…”

Resveratrol Activated Sonic Hedgehog Signaling to Enhance Viability of NIH3T3 Cells in Vitro via Regulation of Sirt1

“…In the CNS，fibrogenic cells are restricted to vascular and meningeal niches. Invading meningeal fibroblast-derived cells have been proposed to actively proliferate, deposit excessive ECM proteins, contribute to the generation of connective tissue after brain trauma and form the fibrotic scar,which is believed to represent an absolute barrier for regenerating motor axons [2,50,51] . Therefore, it is important to investigate mechanism of fibroblasts for activation, proliferation, differentiation, migration in physiological or pathological state.…”

Central Nervous System Regenerative Failure: Role of Oligodendrocytes, Astrocytes, and Microglia

“…The fourth involves the restructuring of the gliotic layer into a mesh-like envelope, which changes from a radial, longitudinal orientation to an alignment largely perpendicular to the long axis of the cord and is, thus, highly obstructive to any potential regrowth of the major projection axon pathways (Bardehle et al 2013;Wanner et al 2013). In addition, there occurs the production of a variety of potently growth inhibitory extracellular matrix (ECM) molecules, among which are the lectican family of CSPGs (McKeon et al 1991(McKeon et al , 1995(McKeon et al , 1999Davies et al 1999;Yamaguchi 2000;Busch and Silver 2007;Alilain et al 2011;Brown et al 2012;Kawano et al 2012;Li et al 2013;Takeuchi et al 2013). Thus, the scar presents a physical and molecular constraint against the release of intralesional inflammatory agents, but also, unfortunately, to axon regeneration.…”