Traumatic spinal cord injury results in severe and irreversible loss of function. The injury triggers a complex cascade of inflammatory and pathological processes, culminating in formation of a scar. While traditionally referred to as a glial scar, the spinal injury scar in fact comprises multiple cellular and extracellular components. This multidimensional nature should be considered when aiming to understand the role of scarring in limiting tissue repair and recovery. In this Review we discuss recent advances in understanding the composition and phenotypic characteristics of the spinal injury scar, the oversimplification of defining the scar in binary terms as good or bad, and the development of therapeutic approaches to target scar components to enable improved functional outcome after spinal cord injury.

Brain and spinal cord injury can result in permanent cognitive, motor, sensory and autonomic deficits. The central nervous system (CNS) has a poor intrinsic capacity for regeneration, although some functional recovery does occur. This is mainly in the form of sprouting, dendritic remodelling and changes in neuronal coding, firing and synaptic properties; elements collectively known as plasticity. An important approach to repair the injured CNS is therefore to harness, promote and refine plasticity. In the adult, this is partly limited by the extracellular matrix (ECM). While the ECM typically provides a supportive framework to CNS neurones, its role is not only structural; the ECM is homeostatic, actively regulatory and of great signalling importance, both directly via receptor or coreceptor-mediated action and via spatially and temporally relevant localization of other signalling molecules. In an injury or disease state, the ECM represents a key environment to support a healing and/or regenerative response. However, there are aspects of its composition which prove suboptimal for recovery: some molecules present in the ECM restrict plasticity and limit repair. An important therapeutic concept is therefore to render the ECM environment more permissive by manipulating key components, such as inhibitory chondroitin sulphate proteoglycans. In this review we discuss the major components of the ECM and the role they play during development and following brain or spinal cord injury and we consider a number of experimental strategies which involve manipulations of the ECM, with the aim of promoting functional recovery to the injured brain and spinal cord.

Chondroitinase is a promising preclinical therapy for restoring function after spinal cord injury. Burnside et al. engineer an immune-evasive vector system that allows delivery of chondroitinase under the control of an on/off switch to regulate expression. Switching on chondroitinase helps spinal-injured rats to recover reaching and grasping movements.

Highlights d RhoA has opposing roles in neurons and astrocytes during CNS regeneration d Neuronal RhoA prevents axon regeneration by mechanisms that recapitulate polarization d Astrocytic RhoA drives actin compaction to activate YAP, restricting astrogliosis d Axon regeneration is only stimulated when RhoA is ablated specifically in neurons

Chondroitin sulfate proteoglycans (CSPGs) act as potent inhibitors of axonal growth and neuroplasticity after spinal cord injury (SCI). Here we reveal that CSPGs also play a critical role in preventing inflammation resolution by blocking the conversion of pro-inflammatory immune cells to a pro-repair phenotype in rodent models of SCI. We demonstrate that enzymatic digestion of CSPG glycosaminoglycans enhances immune cell clearance and reduces pro-inflammatory protein and gene expression profiles at key resolution time points. Analysis of phenotypically distinct immune cell clusters revealed CSPG-mediated modulation of macrophage and microglial subtypes which, together with T lymphocyte infiltration and composition changes, suggests a role for CSPGs in modulating both innate and adaptive immune responses after SCI. Mechanistically, CSPG activation of a pro-inflammatory phenotype in pro-repair immune cells was found to be TLR4-dependent, identifying TLR4 signalling as a key driver of CSPG-mediated immune modulation. These findings establish CSPGs as critical mediators of inflammation resolution failure after SCI in rodents, which leads to prolonged inflammatory pathology and irreversible tissue destruction.