Heparan sulfate: decoding a dynamic multifunctional cell regulator

Turnbull, Jeremy E.; Powell, Andrew K.; Guimond, Scott E.

doi:10.1016/s0962-8924(00)01897-3

Cited by 442 publications

(376 citation statements)

References 51 publications

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“…A primary biological function of GAGs is to recognize and bind ECM proteins for regulating cellular activities, including cell adhesion, extracellular matrix modelling and fibrillogenesis 46 . Therefore, GAG's such as HA, CS, DS and heparin sulfate (HS) are often incorporated through doping into conducting polymers with the intention of promoting favourable interactions with proteins to improve biocompatibility 38,45 .…”

Section: Resultsmentioning

confidence: 99%

Quantifying fibronectin adhesion with nanoscale spatial resolution on glycosaminoglycan doped polypyrrole using Atomic Force Microscopy

Gelmi

Higgins

Wallace

2013

Biochimica et Biophysica Acta (BBA) - General Subjects

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The interaction of ECM proteins is critical in determining the performance of materials used in biomedical applications such as tissue regeneration, implantable bionics and biosensing. Methods: To improve our understanding of ECM protein-conducting polymer interactions, we have used Atomic Force Microscopy (AFM) to elucidate the interactions of fibronectin (FN) on polypyrrole (PPy) doped with different glycosaminoglycans. Results: We were able to classify four main types of FN interactions, including those related to 1) non-specific adhesion, 2) protein unfolding and subsequent unbinding from the surface, 3) desorption and 4) interactions with no adhesion. FN adhesion on PPy/hyaluronic acid showed a significantly lower density of surface adhesion with the adhesion restricted to nodule structures, as opposed to their peripheries, of the polymer morphology. In contrast, PPy/chondroitin sulfate showed a significantly higher density of surface adhesion to the point where the distribution of adhesion effectively masked the topography. Through conductive AFM imaging, we found that the conductive regions correlated with regions of FN adhesion. Conclusions: Given that the conductivity requires doping of the polymer, these findings suggest that FN adhesion is mediated by interactions with chondroitin sulfate and hyaluronic acid at the polymer surface and may be indicative of specific interactions due to contributions from electrostatic attraction between the FN and sulfate/anionic groups of the dopants. General significance: This study demonstrates the ability of AFM to resolve the protein-conducting polymer interactions at the molecular and nanoscale level, which will be important for interfacing these polymer materials with biological systems. This article is part of a Special Issue entitled Organic Bioelectronics -Novel Applications in Biomedicine.

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Section: Resultsmentioning

confidence: 99%

Quantifying fibronectin adhesion with nanoscale spatial resolution on glycosaminoglycan doped polypyrrole using Atomic Force Microscopy

Gelmi

Higgins

Wallace

2013

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…These selective interactions with certain proteins results in regulation of protein activities (Cool & Nurcombe 2005). HS thus acts as a co-receptor, binding to heparin-binding growth factors such as FGF and BMP2, both protecting them from proteolytic degradation and promoting binding to their high affinity receptors (Turnbull et al 2001). HS has a low affinity yet high capacity for its ligands, drawing them onto the cell surface with their high-affinity cognate receptors, which then transduce the appropriate signal into the cells (Lyon et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Sustained release and osteogenic potential of heparan sulfate-doped fibrin glue scaffolds within a rat cranial model

et al. 2007

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This paper explores the potential therapeutic role of the naturally occurring sugar heparan sulfate for the augmentation of bone repair. Scaffolds comprising fibrin glue loaded with 5 µg of embryonically-derived heparan sulfate were assessed, firstly as a releasereservoir, and secondly as a scaffold to stimulate bone regeneration in a critical size rat cranial defect. We show heparan sulfate-loaded scaffolds have a uniform distribution of heparan sulfate, which was readily released with a typical burst phase, quickly followed by a prolonged delivery lasting several days. Importantly, the released heparan sulfate contributed to improved wound healing over a 3 month period as determined by µCT scanning, histology, histomorphometry and PCR for osteogenic markers. In all cases, only minimal healing was observed after 1 and 3 months in the absence of heparan sulfate. In contrast, marked healing was observed by 3 months following heparan sulfate treatment, with nearly full closure of the defect site. PCR analysis showed significant increases in the gene expression of the osteogenic markers Runx2, alkaline phosphatase and osteopontin in the heparin sulfate group compared with controls. These results further emphasize the important role heparan sulfate plays in augmenting wound healing, and its successful delivery in a hydrogel provides a novel alternative to autologous bone graft and growth factor-based therapies.

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“…3-OST-4 is specifically expressed in brain tissues and may play a role in neuronal development (14). The delineation of sulfated motifs on the HS chain of proteoglycans will shed light on how cells interact with extracellular proteins, respond to extracellular signals, and initiate signaling cascade beginning on the cell membrane (15). This strategy relies on introducing a stable isotope of sulfate into specific sites on the HS chain by 3-OST-4.…”

mentioning

confidence: 99%

Determining Heparan Sulfate Structure in the Vicinity of Specific Sulfotransferase Recognition Sites by Mass Spectrometry

Lech

Beeler

et al. 2004

Journal of Biological Chemistry

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Sulfated motifs on heparan sulfate (HS) are involved in various extracellular processes from cell signaling to enzymatic regulation, but the structures of these motifs are obscure. We have developed a strategy to determine the structure of sulfotransferase recognition sites which constitute these motifs. Stable isotope is first introduced into specific sites on HS with HS sulfotransferases and the modified HS is then digested into oligosaccharides of differing sizes. The overlapping oligosaccharides containing the introduced stable isotope are identified by changes in the m/z profiles by mass spectrometry, and their relationships are elucidated. In this way, the HS structures in the vicinity of the sulfotransferase recognition site are quickly determined and groups on precursor structures of HS that direct the action of HS sulfotransferases are pinpointed.Heparan sulfate (HS) 1 is one major polysaccharide found on proteoglycans. HS chains are first synthesized in the Golgi apparatus as repeated units of the disaccharide of a glucuronic acid and an N-acetylated glucosamine (GlcA-GlcNAc) n (1). The glucuronic acid can be epimerized to iduronic acid (IdoA). Incomplete sulfation at the 2-O positions of the uronic acids, and the 3-O, 6-O, and N positions of the glucosamine by various sulfotransferases results in structural diversity within HS (1, 2). The sulfate groups usually cluster in small regions and form sulfated motifs.The sulfated motifs can bind to growth factors, cytokines, and morphogens as well as proteases in the extracellular matrix and regulate their activities (3); thus HS plays critical roles in organ development (4 -6), morphogenesis (7, 8), angiogenesis (2), blood coagulation (2), inflammation (1), wound healing, and cancer progression (9). These sulfated motifs also play roles in pathological processes, such as functioning as receptors for viral entry (10 -13).Although HS plays important roles in various biological processes, the structures of these biological motifs are obscure, due to the difficulties involved in obtaining homogeneous components and determining their structures. Cloning, expressing, and sequencing biopolymers have tremendously advanced our understanding of DNA and protein, but no similar methods are available for studying HS.In this report, we describe a novel strategy that permits us to quickly determine specific HS structures in the vicinity of the sulfotransferase recognition site for 3-OST-4. HS 3-OSTs are rare modification enzymes that helps to generate binding sites for proteins such as antithrombin III (2) and herpes simplex virus glycoprotein D (11). 3-OST-4 is specifically expressed in brain tissues and may play a role in neuronal development (14). The delineation of sulfated motifs on the HS chain of proteoglycans will shed light on how cells interact with extracellular proteins, respond to extracellular signals, and initiate signaling cascade beginning on the cell membrane (15). This strategy relies on introducing a stable isotope of sulfate into specific sites on the...

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Heparan sulfate: decoding a dynamic multifunctional cell regulator

Cited by 442 publications

References 51 publications

Quantifying fibronectin adhesion with nanoscale spatial resolution on glycosaminoglycan doped polypyrrole using Atomic Force Microscopy

Quantifying fibronectin adhesion with nanoscale spatial resolution on glycosaminoglycan doped polypyrrole using Atomic Force Microscopy

Sustained release and osteogenic potential of heparan sulfate-doped fibrin glue scaffolds within a rat cranial model

Determining Heparan Sulfate Structure in the Vicinity of Specific Sulfotransferase Recognition Sites by Mass Spectrometry

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