Abstract
Proteoglycans (PGs) are critically involved in major cellular processes. Most PG activities are due to the large interactive properties of their glycosaminoglycan (GAG) polysaccharide chains, whose expression and fine structural features are tightly controlled by a complex and highly regulated biosynthesis machinery. Xylosides are known to bypass PG-associated GAG biosynthesis and prime the assembly of free polysaccharide chains. These are, therefore, attractive molecules to interfere with GAG expression and function. Recently, we have developed a new xyloside derivative, C-Xyloside, that shares classical GAG-inducing xyloside activities while exhibiting improved metabolic stability. We have previously shown that C-Xyloside had beneficial effects on skin homoeostasis/regeneration using a number of models, but its precise effects on GAG expression and fine structure remained to be addressed. In this study, we have therefore investigated this in details, using a reconstructed dermal tissue as model. Our results first confirmed that C-Xyloside strongly enhanced synthesis of GAG chains, but also induced significant changes in their structure. C-Xyloside primed GAGs were exclusively chondroitin/dermatan sulfate (CS/DS) that featured reduced chain size, increased O-sulfation, and changes in iduronate content and distribution. Surprisingly, C-Xyloside also affected PG-borne GAGs, the main difference being observed in CS/DS 4-O/6-O-sulfation ratio. Such changes were found to affect the biological properties of CS/DS, as revealed by the significant reduction in binding to Hepatocyte Growth Factor observed upon C-Xyloside treatment. Overall, this study provides new insights into the effect of C-Xyloside on GAG structure and activities, which opens up perspectives and applications of such compound in skin repair/regeneration. It also provides a new illustration about the use of xylosides as tools for modifying GAG fine structure/function relationships.
Highlights
Proteoglycans (PGs) are glycoproteins abundantly found in the extracellular matrix (ECM) and at the cell surface, that are critically involved in a large array of cell functions, including cell adhesion, migration, proliferation and differentiation, embryo development, inflammation, pathogen infection or tumour growth and metastasis [1,2,3,4]
GAGs are major components of dermal ECM and participate in tissue cohesiveness and hydration. Through their ability to bind to and modulate the activity of a number of growth factors, GAGs are involved in cell adhesion and migration, as well as skin organogenesis and wound healing
The structure and integrity of GAGs is essential for skin homeostasis and regeneration, leaving open the question of a potential role of GAGs in the different skin stem cell compartments known to be involved in skin homeostasis
Summary
Proteoglycans (PGs) are glycoproteins abundantly found in the extracellular matrix (ECM) and at the cell surface, that are critically involved in a large array of cell functions, including cell adhesion, migration, proliferation and differentiation, embryo development, inflammation, pathogen infection or tumour growth and metastasis [1,2,3,4] These broad activities are mainly due to a strategic positioning at the interface between the cell and its surrounding environment, and to the ability of glycosaminoglycan (GAG) polysaccharide chains present on these proteins to bind to, and in many cases to modulate a vast repertoire of proteins (growth factors, cytokines, morphogens, enzymes, structural proteins...). These saccharide backbones can be further modified by addition of O-sulfate groups: at C-4/C-6 of GalNAc and C-2 of IdoA for CS/DS, and at C-2 of IdoA, C-6 of GlcNAc/ GlcNS and occasionally C-3 of GlcNS for HS [5,6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
