Abstract
Hyaluronic acid (HA) plays a vital role in the extracellular matrix of neural tissues. Originally thought to hydrate tissues and provide mechanical support, it is now clear that HA is also a complex signaling molecule that can regulate cell processes in the developing and adult nervous systems. Signaling properties are determined by molecular weight, bound proteins, and signal transduction through specific receptors. HA signaling regulates processes such as proliferation, differentiation, migration, and process extension in a variety of cell types including neural stem cells, neurons, astrocytes, microglia, and oligodendrocyte progenitors. The synthesis and catabolism of HA and the expression of HA receptors are altered in disease and influence neuroinflammation and disease pathogenesis. This review discusses the roles of HA, its synthesis and breakdown, as well as receptor expression in neurodevelopment, nervous system function and disease.
Highlights
Hyaluronic acid (HA), or hyaluronan, is a linear unsulfated glycosaminoglycan composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine that can be thousands of residues in length and megadaltons in size [1,2]
We have outlined the many known roles that HA plays in multiple cell types in the developing and adult nervous system (Figure 1)
Much work remains to be conducted to fully understand the different functions of HA in the central nervous system (CNS) and peripheral nervous system (PNS), we propose that HA acts both by signaling through
Summary
Hyaluronic acid (HA), or hyaluronan, is a linear unsulfated glycosaminoglycan composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine that can be thousands of residues in length and megadaltons in size [1,2]. HA has a diverse set of mechanical functions in tissues, such as providing elasticity in skin and acting as a lubricant between articulating bones in joints [5] This relatively simple glycosaminoglycan acts as a complex extracellular signal that can regulate a diverse set of cell processes based on its size, associated proteins, and interactions with receptors. Hyaluronan has been found to regulate cellular activities in development, homeostasis, and disease states in a variety of tissues including the nervous system, where it has been implicated in regulating neuronal and glial cell differentiation, the activity of neurons, and nervous system repair in neurodegenerative diseases and following CNS injuries These functions depend on tightly regulated changes in HA synthesis and catabolism. Covalent modifications to HA, such as the addition of the inter-α-trypsin inhibitor (IαI) heavy chain (HC) catalyzed by tumor necrosis factor stimulated gene 6 (TSG-6) changes the signaling properties of HA and can modulate neuroinflammation, HA crosslinking, and interactions between HA and receptors [31,32,33,34,35,36]
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