A New C-Xyloside Induces Modifications of GAG Expression, Structure and Functional Properties

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.

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

“…Disaccharide analysis showed that HS chains were less abundant in cells over-expressing SDC1, which may be due in part to decreased synthetic capacity of the HS biosynthetic machinery in cells over-expressing the SDC1 protein core, and in part due to the decreased amount of EXT1 and NDST1 enzymes leading to the assembly of shorter HS chains. Such a phenomenon has been observed in xyloside-treated cells [31]. In addition, SDC1 overexpression could result in the down-regulation of other HSPGs [27,29].…”

“…Preparation and purification of HS chains from cells over-expressing SDC1 and control STAV-AB cells were performed as described previously [30,31]. Briefly, cell culture medium was collected and cell layers extensively digested with trypsin (50 min at 37°C).…”

Cell surface glycans in the human stratum corneum: distribution and depth‐related changes

“…The presence of proteoglycans in the lower SC may suggest their implication in the hydration of the SC compactum , with its obvious functional consequences . Another well‐known capacity of GAGs is their interaction with other carbohydrates and proteins . Here, the potential partners within the extracellular spaces could be cell–cell junction glycoproteins and hydrophilic molecules involved in the SC processing.…”

Propolis Induces Chondroitin/Dermatan Sulphate and Hyaluronic Acid Accumulation in the Skin of Burned Wound

“…It is known that GAGs play an active role during wound healing [8] by regulating cellular adhesion, migration, and proliferation [7]. Mentioned functions are connected with GAGs and PGs ability to bind and modulate a vast repertoire of proteins, that is, growth factors, cytokines, morphogens, and enzymes [27]. The most common skin GAG is DS [28] being simultaneously the major glycan in wound fluid [29].…”