Spatiotemporal diversity and regulation of glycosaminoglycans in cell homeostasis and human disease

Abstract

Glycosaminoglycans (GAGs) are long, linear polysaccharides that are ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These complex carbohydrates play important roles in many cellular processes and have been implicated in many disease states, including cancer, inflammation, and genetic disorders. GAGs are among the most complex molecules in biology with enormous information content and extensive structural and functional heterogeneity. GAG biosynthesis is a non-template driven process facilitated by a large group of biosynthetic enzymes that have been extensively characterized over the past few decades. Interestingly, the expression of the enzymes and the consequent structure and function of the polysaccharide chains can vary temporally and spatially during development and under certain pathophysiological conditions, suggesting their assembly is tightly regulated in cells. Due to their many key roles in cell homeostasis and disease, there is much interest in targeting the assembly and function of GAGs as a therapeutic approach. Recent advances in genomics and GAG analytical techniques have pushed the field and generated new perspectives on the regulation of mammalian glycosylation. This review highlights the spatiotemporal diversity of GAGs and the mechanisms guiding their assembly and function in human biology and disease.

HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

“…HS-PG interactions with neural cell surface cell attachment glycoproteins provide synaptic stabilization [ 104 , 105 , 106 ] and the signalling properties of neural networks [ 106 ]. The specific contributions of neurexin synaptic HS-PGs to neural stabilization and function [ 104 ] and the relatively recently identified dystroglycan interactive photoreceptor basement membrane HS-PGs Pikachurin [ 107 , 108 , 109 ] and Eyes shut (EYS) [ 110 , 111 ] also show the important tissue organizational functional properties that HS-PGs convey to specific tissues [ 24 , 44 ].…”

“…Ovarian GAGs promote gonadotropin-induced follicle development in the mouse acting through stimulation of angiogenesis consistent with roles assigned to perlecan in the development of a number of these tissues [ 182 , 183 ]. Transcriptomics has also been used to examine the spatiotemporal diversity and regulation of GAG biosynthesis in normal homeostatic tissues and in those undergoing disease processes [ 24 ].…”

“…The diversity of the GAG side chains attached to PG core proteins at the cell surface contributes to their cell instructive and ECM interactive properties, allowing interaction with growth factors, chemokines, morphogens, proteases, and protease inhibitory proteins, and facilitating cell responsive cues delivered by the ECM [ 24 , 27 ]. The Wnt signalling pathway has important roles to play in embryonic tissue development and the homeostasis of adult tissue.…”

“…Wnt binds to the LDLR domain II of perlecan and this acts as a Wnt delivery vehicle in tissue development [ 29 , 30 ]. HS-PGs are also pericellular and basement membrane ECM components and have roles in synapse stabilization in neural tissues important in synaptic plasticity and neuron interactivity within neural networks of the central and peripheral nervous systems (CNS & PNS, respectively) [ 24 , 27 ]. HS-PGs fine tune tissue development [ 31 , 32 , 33 ] and regulate physiological processes in mature tissues [ 34 , 35 ].…”

Immunotherapeutic Targeting of NG2/CSPG4 in Solid Organ Cancers

“…Choosing the PG-chondroitin sulfate chain as the putative target of CAR-T cells to allow the targeting of NG2/CSPG4-expressing cell membrane microdomains by targeted therapies may be a selective and powerful approach to eliminate cancers. Therefore, the chondroitin sulfate chain [ 76 , 77 ] as a surface antigen derived from NG2/CSPG4 on the cell membrane should be a focal point for further developing immunotherapeutic approaches exploiting this PG subchain (PG-subChain) in solid organ cancers, such as HCC and PDAC. Except for those target antibodies or vaccines, using microarray analyses to evaluate NG2/CSPG4 expression in solid organ cancers is also compelling ( Table 1 ).…”