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.image

CNS/PNS proteoglycans functionalize neuronal and astrocyte niche microenvironments optimizing cellular activity by preserving membrane polarization dynamics, ionic microenvironments, ion fluxes, neuronal activation, and network neurotransductive capacity

“…CNS PGs serve a particularly important structural role, since these tissues do not contain the stabilizing collagen and elastin fibril networks found elsewhere in the human body. The brain is one of the softest tissues in the human body and PGs and hyaluronan (HA) have important tissue stabilization properties (Melrose, 2023). This study illustrates how PG interactions with ECM components provide matrix stabilization, niche environments, ion fluxes, and ion‐gradients that instruct neuronal and astrocytic cellular behavior and maintain tissue homeostasis.…”

“…CD44 is a major HA receptor in the CNS/PNS and has roles in HA localization which aids in tissue hydration, compartmentalization, and functional properties (Melrose, 2023). It is important that brain HA levels are maintained, tissues which have deficient HA levels detrimentally impact normal neuronal functional properties, these cells may display an epileptic phenotype and are more likely to undergo seizures (Arranz et al., 2014; Balashova et al., 2019; Perkins et al., 2017).…”

“…The GAG side chains of PGs also equip them with interactive properties with a diverse range of ligands including growth factors, morphogens, and structural ECM glycoproteins which allows them to participate in a range of processes in tissue development and physiological processes that control cellular behavior. In the specific context of the brain, tissue stabilization, cellular regulation, control of ionic environments, compartmentalization, and hydration are particularly important beneficial traits displayed by PGs (Dityatev et al., 2010; Farrugia & Melrose, 2023; Hayes & Melrose, 2023; Melrose, 2023, 2024a; Melrose et al., 2021).…”

“…CSPGs (lecticans, hyalectans) form specialized ECM structures in brain tissues known as perineuronal nets (PNNs) through networks formed with HA stabilized by link protein (Bral1), tenascin‐R and tenascin‐C. These are neuroprotective structures that provide synaptic plasticity (Testa et al., 2019), and promote cognitive processes, learning, and memory (Bosiacki et al., 2019; Fawcett et al., 2022; Melrose, 2023, 2024b; Nojima et al., 2021; Sinha et al., 2023). PGs also contribute to the function of neuromuscular junction (NMJ) structures (Guarino et al., 2020; Rushton et al., 2020) in motor neurons that control muscular movement, and are integral components of the blood–brain barrier (BBB) basement membrane maintaining its permeable integrity (Nakamura et al., 2019; Steiner et al., 2014).…”

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

“…CD44 and integrins attached to neural cells generate focal adhesion complexes that generate traction forces and cell spreading, as well as glioma cell invasion [ 106 , 107 ]. The entrapment of HA by CD44 is important in the hydration and space-filling properties of the CNS/PNS ECM, which maintain ionic gradients and hydration and compartmentalization of neural tissues, preserving neural niches and stem cell viability [ 108 , 109 , 110 , 111 ]. MMPs can lead to the shedding of CD44 from the cell surface [ 112 ], while soluble CD44 antagonizes CD44-mediated cellular binding to HA and can modulate or inhibit tumor development [ 113 ] and tumor cell migration [ 114 ].…”