Versican Is Upregulated in CNS Injury and Is a Product of Oligodendrocyte Lineage Cells

Abstract

Chondroitin sulfate proteoglycan (CS-PG) expression is increased in response to CNS injury and limits the capacity for axonal regeneration. Previously we have shown that neurocan is one of the CS-PGs that is upregulated (Asher et al., 2000). Here we show that another member of the aggrecan family, versican, is also upregulated in response to CNS injury. Labeling of frozen sections 7 d after a unilateral knife lesion to the cerebral cortex revealed a clear increase in versican immunoreactivity around the lesion. Western blot analysis of extracts prepared from injured and uninjured tissue also revealed considerably more versican in the injured tissue extract. In vitro studies revealed versican to be a product of oligodendrocyte lineage cells (OLCs). Labeling was seen between the late A2B5-positive stage and the O1-positive pre-oligodendrocyte stage. Neither immature, bipolar A2B5-positive cells, nor differentiated, myelin-forming oligodendrocytes were labeled. The amount of versican in conditioned medium increased as these cells differentiated. Versican and tenascin-R colocalized in OLCs, and coimmunoprecipitation indicated that the two exist as a complex in oligodendrocyte-conditioned medium. Treatment of pre-oligodendrocytes with hyaluronidase led to the release of versican, indicating that its retention at the cell surface is dependent on hyaluronate (HA). In rat brain, approximately half of the versican is bound to hyaluronate. We also provide evidence of a role for CS-PGs in the axon growth-inhibitory properties of oligodendrocytes. Because large numbers of OLCs are recruited to CNS lesions, these results suggest that OLC-derived versican contributes to the inhospitable environment of the injured CNS.

Inhibiting cell proliferation during formation of the glial scar: effects on axon regeneration in the CNS

“…Previous studies have demonstrated that the CS-PGs produced by OPs-NG2, versican and phosphacan-are inhibitory toward axonal growth (Dou and Levine, 1994;Asher et al, 1999;Fidler et al, 1999;McKeon et al, 1999;Chen et al, 2002;Ughrin et al, 2003): in keeping with these findings, this study showed a greater number of regenerating axons in an environment depleted of NG2 OP cells.…”

“…Various CS-PGs are upregulated in the glial scar (Levine, 1994;Davies et al, 1997;Asher et al, 1999Asher et al, , 2000Fitch et al, 1999;Jones et al, 2002;Tang et al, 2003), and both in vitro and in vivo experiments have demonstrated inhibitory effects of CSPGs on axonal growth (e.g. Snow et al, 1990;McKeon et al, 1991McKeon et al, , 1995Dou and Levine, 1994;Smith-Thomas et al, 1994Fidler et al, 1999;Niederö st et al, 1999;Moon et al, 2001;Bradbury et al, 2002;Chen et al, 2002;Ughrin et al, 2003).…”

NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury

“…This distribution of versican in the white matter has also been described by others, and an axon growthinhibitory role suggested [25]. Furthermore, in vivo investigations have demonstrated an early up-regulation of this CSPG following experimental lesions, the distribution of which was compatible with a regeneration-blocking effect [22,26]. Cells of the oligodendrocytic lineage were reported to be responsible for the post-traumatic up-regulation of versican following spinal lesions.…”

Brevican isoforms associate with neural membranes

“…Like brevican, other brain ECM molecules have also been reported previously to be extractable by glycosidase digestion: hyaluronidase treatment drastically reduces brainspecific hyaluronan-binding protein Bral1 immunoreactivity in cerebellar sections (Oohashi et al 2002), solubilizes neurocan from hippocampal slices (Fö rster et al 2001) and releases versican from pre-oligodendrocytes (Asher et al 2002) indicative of HA-mediated cell surface retention of these molecules. Furthermore, glial hyaluronate binding protein is also released from brain homogenate fractions by enzymatic treatment with chondroitinase ABC (Asher et al 1991).…”