Hyaluronan-dependent pericellular matrix

doi:10.1016/j.addr.2007.08.008

Advanced Drug Delivery Reviews

Volume 59, Issue 13, 10 November 2007, Pages 1351-1365

https://doi.org/10.1016/j.addr.2007.08.008 Get rights and content

Abstract

Hyaluronan is a multifunctional glycosaminoglycan that forms the structural basis of the pericellular matrix. Hyaluronan is extruded directly through the plasma membrane by one of three hyaluronan synthases and anchored to the cell surface by the synthase or cell surface receptors such as CD44 or RHAMM. Aggregating proteoglycans and other hyaluronan-binding proteins, contribute to the material and biological properties of the matrix and regulate cell and tissue function. The pericellular matrix plays multiple complex roles in cell adhesion/de-adhesion, and cell shape changes associated with proliferation and locomotion. Time-lapse studies show that pericellular matrix formation facilitates cell detachment and mitotic cell rounding. Hyaluronan crosslinking occurs through various proteins, such as tenascin, TSG-6, inter-alpha-trypsin inhibitor, pentraxin and TSP-1. This creates higher order levels of structured hyaluronan that may regulate inflammation and other biological processes. Microvillous or filopodial membrane protrusions are created by active hyaluronan synthesis, and form the scaffold of hyaluronan coats in certain cells. The importance of the pericellular matrix in cellular mechanotransduction and the response to mechanical strain are also discussed.

Introduction

Hyaluronan, or hyaluronic acid, is a multifunctional glycosaminoglycan that forms the basis of the pericellular matrix. Hyaluronan is a linear polymer composed of repeating disaccharides of glucuronic acid and N-acetylglucosamine [-β(1,4)-GlcUA-β(1,3)-GlcNAc-]_n, and is synthesized by 3 different but related hyaluronan synthases, HAS1, HAS2 and HAS3 [1], [2]. These are enzymes with multiple transmembrane domains that synthesize hyaluronan at the inner surface of the plasma membrane. During synthesis, the growing polymer chain is extruded through the membrane into the pericellular space. This is in contrast to the mode of synthesis of other glycosaminoglycans, which are made and covalently linked to core proteins in the Golgi apparatus to make a proteoglycan, and secreted by normal exocytotic mechanisms. Hyaluronan chains can be anchored to the cell surface via the synthase enzyme or through binding to a cell surface receptor such as CD44 or RHAMM (receptor for hyaluronic acid mediated motility). Hyaluronan is cleaved by one of several hyaluronidases. There are six hyaluronidase genes in humans, encoding enzymes with different properties and different cell locations [3]. Under normal physiological conditions, hyaluronan ranges in relative molecular mass from 10⁶–10⁷ (~ 2000–25,000 disaccharides) with polymer lengths of 2–25 μm (see review by Toole [4]). Hyaluronan is capable of an amazing variety of conformations when deposited on mica surfaces; from extended chains, to relaxed coils, to condensed rods, and pearl necklaces of helical coils, rods, hairpins, and toroids [5]. Hyaluronan can also self-associate to form fibers, networks, and stacks. When retained at the cell surface, hyaluronan can form a voluminous pericellular matrix or “coat”, which has also been termed “glycocalyx”. The hyaluronan-dependent coat has multiple important roles, from serving structural and mechanochemical functions, to the regulation of cell division and motility, as well as cancer progression and metastasis. This review will discuss various aspects of hyaluronan-dependent pericellular matrix structure and function.

Section snippets

Pericellular matrix structure

Several studies have investigated the structure and formation of the pericellular matrix. One of the most widely used techniques to view the hyaluronan-dependent pericellular matrix is the particle exclusion assay, which was first utilized nearly forty years ago [6]. In this assay, a suspension of particles, usually fixed erythrocytes, is allowed to settle and a clear zone surrounding the cell is made apparent by virtue of the exclusion of the red blood cells by the gel-like hyaluronan coat (

Hyaluronan support for plasma membrane protrusions

Epithelial cells can form relatively thick pericellular coats when hyaluronan synthesis is induced by growth factors like EGF [29]. This occurs even though the cells do not express significant amounts of aggregating proteoglycans. The coat formation is even more pronounced in epithelial cells transfected with GFP-Has2 and GFP-Has3 [30], [31] (Fig. 4). The GFP-label imaged in live cells reveals that the coat is actually scaffolded by numerous elongated microvilli, on which Has accumulates (Fig. 5

Hyaluronan crosslinking

Several different mechanisms of crosslinking hyaluronan have been identified that can influence pericellular matrix assembly and material properties [32]. For example, the C-terminal lectin-like domain of versican has been shown to bind to multimeric tenascin-R and tenascin-C in a calcium-dependent manner, creating the possibility of crosslinking hyaluronan through non-covalent versican–tenascin–versican interactions [33], [34]. Other studies have implicated inter-alpha trypsin inhibitor (IαI)

Role of the pericellular matrix in ECM assembly

The hyaluronan-dependent pericellular matrix may be involved directly or indirectly in the assembly of other ECM components, either by serving as a scaffold or through interactions of pericellular matrix constituents with other matrix proteins. For example, fibronectin and collagen were found in the pericellular matrix of fibroblasts [52]. Thus the cell coat may serve to retain newly secreted collagen and fibronectin prior to assembly. Elastic fiber formation may also be regulated by the

Role for the pericellular matrix in cell proliferation and migration

Hyaluronan and versican have been found to play a role in the maintenance of proliferative and migratory phenotypes in various cells following growth factor treatment or injury [15], [56], [57], [58], [59], [60], [61], [62], [63]. Hyaluronan is localized in tissues and cell cultures using a highly specific biotinylated hyaluronan binding protein (bHABP) preparation from cartilage [64]. The probe is prepared from trypsin digests of cartilage extracts and is isolated using a hyaluronan affinity

Pericellular matrix regulation of cell adhesion

Work from a number of laboratories shows that hyaluronan and/or proteoglycan in the pericellular matrix can have both adhesive and anti-adhesive properties, which are regulated on several levels. Evidence for an anti-adhesive role of the pericellular matrix comes from several studies indicating that hyaluronan promotes cell detachment [72], [73], [74]. Surface coatings of purified hyaluronan and chondroitin sulfate proteoglycans are generally anti-adhesive and can form barriers to cell movement

Role of the pericellular matrix in mechanotransduction and cell response to strain

The stiffness of crosslinked hyaluronan gels is important for cellular adhesion and spreading in bioengineering applications [108]. This suggests that local variations in Young's modulus of the native pericellular matrix may dictate its inherent signal transduction potential, whether it promotes cell adhesion and spreading, or promotes cell detachment and rounding, or contributes to the metastatic potential of cancer cells. Growing evidence that structured hyaluronan is closely associated with

Conclusions

The hyaluronan-dependent pericellular matrix is a multifunctional regulator of cell adhesion, cell shape and behavior. Hyaluronan-binding proteoglycans and other associated proteins in the cell coat contribute to a wide variety of structural morphologies and material properties of the pericellular matrix, and add complexity to the biological functions of the matrix. Greater levels of structure and crosslinking of hyaluronan contribute to important processes such as ovulation and inflammation.

Acknowledgements

The authors would like to thank Dr. Virginia Green for careful reading and editing of the manuscript. Support was provided through NIH grant P01 HL018645-31 (SPE & TNW) and The Academy of Finland and Sigrid Juselius Foundation (RHT & MIT). We also want to thank Dr. Kirsi Rilla and Anne Kultti, MSc for the images of the GFP-Has transfected cells.

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^☆: This review is part of the Advanced Drug Delivery Reviews theme issue on “Natural and Artificial Cellular Microenvironments for Soft Tissue Repair”.

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Hyaluronan-dependent pericellular matrix☆

Abstract

Introduction

Section snippets

Pericellular matrix structure

Hyaluronan support for plasma membrane protrusions

Hyaluronan crosslinking

Role of the pericellular matrix in ECM assembly

Role for the pericellular matrix in cell proliferation and migration

Pericellular matrix regulation of cell adhesion

Role of the pericellular matrix in mechanotransduction and cell response to strain

Conclusions

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

Biophys. J.

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biomech.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Immunol.

Structure

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

J. Biol. Chem.

Blood

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Kidney Int.

Biochim. Biophys. Acta

Am. J. Pathol.

J. Biol. Chem.

Biomaterials

Exp. Cell Res.

J. Biol. Chem.

Arch. Biochem. Biophys.

Int. J. Biochem.

Dev. Biol.

Exp. Cell Res.

Matrix Biol.

Exp. Cell Res.

Exp. Cell Res.

Exp. Neurol.

Exp. Neurol.

Blood

Matrix Biol.

J. Biol. Chem.

Biophys. J.

J. Biol. Chem.

Immunity

J. Biol. Chem.

Mammalian hyaluronidases

Hyaluronan: from extracellular glue to pericellular cue

Nat. Rev., Cancer

Hyaluronan receptor-directed assembly of chondrocyte pericellular matrix

J. Cell Biol.

Proteoglycans and vascular cell proliferation

Am. Rev. Respir. Dis.

Lecticans: organizers of the brain extracellular matrix

Cell. Mol. Life Sci.