Scar-mediated inhibition and CSPG receptors in the CNS

Abstract

Severed axons in adult mammals do not regenerate appreciably after central nervous system (CNS) injury due to developmentally determined reductions in neuron-intrinsic growth capacity and extracellular environment for axon elongation. Chondroitin sulfate proteoglycans (CSPGs), which are generated by reactive scar tissues, are particularly potent contributors to the growth-limiting environment in mature CNS. Thus, surmounting the strong inhibition by CSPG-rich scar is an important therapeutic goal for achieving functional recovery after CNS injuries. As of now, the main in vivo approach to overcoming inhibition by CSPGs is enzymatic digestion with locally applied chondroitinase ABC (ChABC), but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of the molecular mechanisms underlying CSPG action is needed in order to develop more effective therapies to overcome CSPG-mediated inhibition of axon regeneration and/or sprouting. Because of their large size and dense negative charges, CSPGs were thought to act by non-specifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions. Although this may be true, recent studies indicate that two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ (PTPσ) and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibitory effects. CSPGs also may act by binding to two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3 (NgR1 and NgR3). If confirmed, it would suggest that CSPGs have multiple mechanisms by which they inhibit axon growth, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries, including spinal cord injury (SCI).

Astrocytes Grown in Alvetex® Three Dimensional Scaffolds Retain a Non-reactive Phenotype

“…CSPG upregulation is a consequence of reactive astrogliosis and a feature of glial scarring. [54,55]. We note that embryonic-derived astrocytes grown in 3D have low levels of the 2 CSPGs we measured, NG2 and SMC3, further support for these conditions supporting a less reactive, more physiologically representative phenotype.…”

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

“…Neutralizing the Inhibitory ECM-Following injury to the CNS, the lesion site becomes surrounded by reactive scar tissue, and axons interacting with this glial scar form dystrophic end bulbs and fail to regenerate; this process is reviewed in detail elsewhere (6,(192)(193)(194). Chondroitin sulfate proteoglycans (CSPGs), a class of proteins with sulfated glycosaminoglycan (CS-GAG) moieties, are deposited by macrophages, microglia, and reactive astroglia, and encompass a major component of this inhibitory environment from very early to chronic stages after injury (195).…”

The glial scar in spinal cord injury and repair

“…over the past decade, increasing evidence has attributed the failure of axonal regrowth after SCi to limited intrinsic neuronal plasticity and the local non-permissive microenvironment including myelin-associated growth inhibitors as well as the glial scar [86,87] . inhibition of glial scar formation by deleting key signals that mediate the process has shown an overt facilitation of the affected axon regrowth.…”