Cell Science at a Glance 4195 The extracellular matrix at a glance Introduction The extracellular matrix (ECM) is the non- Christian Frantz1, Kathleen M. Stewart1 and Valerie M. Weaver1,2,* cellular component present within all tissues and 1Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California San organs, and provides not only essential physical Francisco, San Francisco, CA 94143, USA scaffolding for the cellular constituents but also 2 Department of Anatomy, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad initiates crucial biochemical and biomechanical Center of Regeneration Medicine and Stem Cell Research at UCSF, UCSF Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA cues that are required for tissue morphogenesis, *Author for correspondence ([email protected]) differentiation and homeostasis. The importance Journal of Cell Science 123, 4195-4200 of the ECM is vividly illustrated by the wide © 2010. Published by The Company of Biologists Ltd range of syndromes, which can be anything doi:10.1242/jcs.023820 from minor to severe, that arise from genetic abnormalities in ECM proteins (Jarvelainen et al., 2009). Although, fundamentally, the ECM is composed of water, proteins and The Extracellular Matrix at a Glance polysaccharides, each tissue has an ECM with Christian Frantz, Kathleen M. Stewart and Valerie M. Weaver a unique composition and topology that is 1 ECM macromolecules generated during tissue development through Examples of proteoglycans Fibrous proteins a dynamic and reciprocal, biochemical Glycosaminoglycan hydrogel Modular PGs SLRPs Cell-surface PGs Syndecan Glypican and biophysical dialogue between the Fibrous collagens Core protein Decorin Lumican Fibronectin Tenascin Elastins Laminin Glycosamino- Cell membrane various cellular components (e.g. epithelial, glycan chains Perlecan Aggrecan fibroblast, adipocyte, endothelial elements) 2 ECM structure and function and the evolving cellular and protein Normal Aged Wounded or fibrotic Tumor Loss of cell−cell adhesion Loss of apical−basal polarity Loss of apical–basal polarity microenvironment. Indeed, the physical, Cell proliferation Cell migration topological, and biochemical composition of the Thinner BM BM ECM is not only tissue-specific, but is also Metastatic markedly heterogeneous. Cell adhesion to the cell migration EMT Epithelial cell Inflammatory cell Senescent fibroblast (growth arrest, ECM is mediated by ECM receptors, such as (apical−basal polarity) (infiltration from blood resistant to apoptotic signals) and lymph vessels) Fibrin blood clot Fibroblast (secreting ECM Growth factors MMP precursors and reorganizing Myofibroblast integrins, discoidin domain receptors and the ECM) Non-enzymatic crosslinking (differentiated fibroblast) Proteoglycans (PGs) Adipocyte (each and glycosaminoglycan Activated infiltrated Transformed Differentiated fibroblasts surrounded by a secreted chains cell (peritumoral fibroblasts, reactive syndecans (Harburger and Calderwood, 2009; inflammatory cell thick basal lamina) stroma fibroblasts, cancer-associated Col I Epithelial-to-mesenchymal fibroblasts and myofibroblasts) EMT Myoepithelial cell transition Humphries et al., 2006; Leitinger and (in contact with BM) Fibronectin Collagen-crosslinking enzymes Hohenester, 2007; Xian et al., 2010). Adhesion Molecular composition mediates cytoskeletal coupling to the ECM and Col I Fibronectin Elastin Degenerated elastin network ↑ Fibronectin ↑ Col types I, III ↑ Fibronectin ↑ Col types I, III and IV ↑ Fibronectin ↑ Elastin is involved in cell migration through the ECM PGs (examples) (Schmidt and Friedl, 2010). Moreover, the ↑ HA ↑ Fibrin ↑ PGs (decorin, biglycan, lumican, fibromodulin…) ↓ Total PGs ↑ Decorin Journal of Cell Science ECM is a highly dynamic structure that is HA Decorin Aggrecan Perlecan constantly being remodeled, either Biological and mechanical properties enzymatically or non-enzymatically, and its Compliant meshwork, β TGF-β and VEGF ↑ EGF-like GFs Unbound TGF , VGEF, G resists tensile and G G G promote vessel G CH G recruits inflammatory cells molecular components are subjected to a myriad compressive stress ↓ Tensile strength growth and inflammation CHCH PAI G ↑ TGF-β, PDGF, bFGF, G GFs: EGF, TGF-β, bFGF G ↑ β G ↑ Stiffness VEGF TGF- , VEGF, PDGF, ROSS ROS G EGF, bFGF, HGF G of post-translational modifications. Through G CH CH ↓ Mechanical stability, G G PAI G G tensile strength, elasticity ROS ECM stiffening, G CH reduced elasticity G ↑ G Stiffness these physical and biochemical characteristics G G G CCH G G G G CH the ECM generates the biochemical and G Glycosaminoglycan- ROS G G bound growth factor G PAII CH G (GH) G G CH G mechanical properties of each organ, such as its G G G G G Unbound GH G CH ROSS G ROS Glycosaminoglycan G MMP activity G Newly secreted GH ROS G tensile and compressive strength and elasticity, G chain 500 Pa 3000 Pa and also mediates protection by a buffering Increased stiffness Extrinsic and intrinsic forces action that maintains extracellular homeostasis Tensional ECM resistance Reciprocal ECM resistance Reciprocal ECM resistance homeostasis Migrating and and water retention. In addition, the ECM dividing cells ECM-contracting Stiff crosslinked PG-modified collagen fibers collagen and myofibroblast elastin fibers directs essential morphological organization Stiff crosslinked collagen fibers Solid stress Solid stress Proliferating Weak basement transformed and physiological function by binding growth Basement membrane epithelium membrane Stiff crosslinked collagen fibers factors (GFs) and interacting with cell-surface Exerted ECM-contracting force myofibroblast receptors to elicit signal transduction and 3 Natural and synthetic engineered ECMs regulate gene transcription. The biochemical Natural Modified or synthetic Soft rBM gel (e.g. Matrigel™) (Kleinman et al., Col I (Friess, 1998) Functionalized HA (Serban and Prestwich, 2008) PEG hydrogels and biomechanical, protective and 1986; Kleinman and Martin, 2005) (Lutolf and Hubbell, 2005) Self-assembling peptides (Hauser and Zhang, 2010) R R Conjugated Multi-arm macromers conjugated R RGD peptides, G R with RGD, LDV, YIGSR Self-assembled peptide-amphiphiles. RRRR R organizational properties of the ECM in a given R Col I, laminin, G Functionalized with RGF, RGD, LDV, fibronectin G R YIGSR. Fiber diameter~50 nm R G Integrin ligands R R G R R G Adhesion receptor Collagen concentration G ligands tissue can vary tremendously from one tissue to G R SIS scaffold (Badylak, 2007) Fibrin gel (fibrinogen + thrombin) Key (Blombäck and Bark, 2004) Electrospun biomaterial (silk, lactic acid and glycolic acid Functionalized polyacrylamide gel (Pelham and Wang, 1997) another (e.g. lungs versus skin versus bone) and R Remodeling sites polymers) (Zhang et al., 2009; McCullen et al., 2009) R G Col I, laminin, GFs Crosslinked with ECM R R G Embedded growth factors G R and fibronectin R molecules and peptides R R R Fiber diameter 50 nm−300 μm. even within one tissue (e.g. renal cortex versus R R G Mixed with Col I, fibrin, HA Thrombin mg/ml (See accompanying article for full citations.) renal medulla), as well as from one physiological state to another (normal versus Abbreviations: bFGF, basic fibroblast growth factor; BM, basement membrane; CH, chemokines; Col, collagen; EGF, endothelial growth factor; HGH, human growth hormone; HA, hyaluronic acid; MMP, matrix metalloproteinase; LDV, Leu-Asp-Val; PAI, plasminogen activator inhibitor; PDGF, platelet-derived growth factor; PEG, polyethyleneglycol; rBM, reconstituted basement membrane; RGD, Arg-Gly-Asp; ROS, reactive oxygen species; SIS, small intestinal submucosa; SRLPs, small leucine- cancerous). In this Cell Science at a Glance rich proteoglycans; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor; © Journal of Cell Science 2010 (123, pp. 4195–4200) YIGSR, article, we briefly describe the main molecular (See poster insert) components of the ECM and then compare and 4196 Journal of Cell Science 123 (24) contrast the ECM within a normal simple epithelial tissue with that found within a Box 1. Structure and function of proteoglycans pathologically modified tissue, as exemplified Proteoglycans (PGs) are composed of glycosaminoglycan (GAG) chains covalently linked in aged tissue, wounded or fibrotic tissue and to a specific protein core (with the exception of hyaluronic acid) (Iozzo and Murdoch, 1996; tumors. We particularly focus on the Schaefer and Schaefer, 2010). PGs have been classified according to their core proteins, localization and GAG composition. The three main families are: small leucine-rich composition and architecture of the ECM and proteoglycans (SLRPs), modular proteoglycans and cell-surface proteoglycans (Schaefer interactions with its cellular constituents, and Schaefer, 2010). The GAG chains on the protein core are unbranched polysaccharide and describe in detail common post- chains composed of repeating disaccharide units [sulfated N-aceltylglucosamine or translational modifications that evoke defined N-acetylgalactosamine, D-glucuronic or L-iduronic acid and galactose (–4 N- topological and viscoelasticity changes in the acetylglucosamine-1,3-galactose-1)] that can be divided further into sulfated (chondroitin tissue. We thereafter discuss the functional sulfate, heparan sulfate and keratan sulfate) and non-sulfated (hyaluronic acid) GAGs consequences of ECM remodeling