Hyaluronan hydrates and compartmentalises the CNS/PNS extracellular matrix and provides niche environments conducive to the optimisation of neuronal activity.

Abstract

The central nervous system/peripheral nervous system (CNS/PNS) extracellular matrix is a dynamic and highly interactive space-filling, cell-supportive, matrix-stabilising, hydrating entity that creates and maintains tissue compartments to facilitate regional ionic micro-environments and micro-gradients that promote optimal neural cellular activity. The CNS/PNS does not contain large supportive collagenous and elastic fibrillar networks but is dominated by a high glycosaminoglycan content, predominantly hyaluronan (HA) and collagen is restricted to the brain microvasculature, blood-brain barrier, neuromuscular junction and meninges dura, arachnoid and pia mater. Chondroitin sulphate-rich proteoglycans (lecticans) interactive with HA have stabilising roles in perineuronal nets and contribute to neural plasticity, memory and cognitive processes. Hyaluronan also interacts with sialoproteoglycan associated with cones and rods (SPACRCAN) to stabilise the interphotoreceptor matrix and has protective properties that ensure photoreceptor viability and function is maintained. HA also regulates myelination/re-myelination in neural networks. HA fragmentation has been observed in white matter injury, multiple sclerosis, and traumatic brain injury. HA fragments (2 × 105 Da) regulate oligodendrocyte precursor cell maturation, myelination/remyelination, and interact with TLR4 to initiate signalling cascades that mediate myelin basic protein transcription. HA and its fragments have regulatory roles over myelination which ensure high axonal neurotransduction rates are maintained in neural networks. Glioma is a particularly invasive brain tumour with extremely high mortality rates. HA, CD44 and RHAMM (receptor for HA-mediated motility) HA receptors are highly expressed in this tumour. Conventional anti-glioma drug treatments have been largely ineffective and surgical removal is normally not an option. CD44 and RHAMM glioma HA receptors can potentially be used to target gliomas with PEP-1, a cell-penetrating HA-binding peptide. PEP-1 can be conjugated to a therapeutic drug; such drug conjugates have successfully treated dense non-operative tumours in other tissues, therefore similar applications warrant exploration as potential anti-glioma treatments.