Extracellular matrix 228840 222455143 2008-06-29T12:38:08Z Epingchris 785522 /* Collagen */ [[Image:Extracellular Matrix.png|thumb|right|350px|Illustration depicting extracellular matrix ([[basement membrane]] and interstitial matrix) in relation to [[epithelium]], [[endothelium]] and [[connective tissue]]]] In [[biology]], the '''extracellular matrix''' ('''ECM''') is the [[extracellular]] part of animal tissue that usually provides structural support to the [[Cell (biology)|cells]] in addition to performing various other important functions. The extracellular matrix is the defining feature of [[connective tissue]] in animals. Extracellular matrix includes the interstitial matrix and the [[basement membrane]].<ref name="Robbins">Kumar, Abbas, Fausto; ''Robbins and Cotran: Pathologic Basis of Disease''; Elsevier; 7th ed.</ref> Interstitial matrix is present between various cells (i.e., in the intercellular spaces). Gels of [[polysaccharide]]s and fibrous proteins fill the interstitial space and act as a compression buffer against the stress placed on the ECM.<ref name=ECB>{{cite book | author = Alberts B, Bray D, Hopin K, Johnson A, Lewis J, Raff M, Roberts K, Walter P | title = Essential cell biology | chapter = Tissues and Cancer | location = New York and London | publisher = Garland Science | year = 2004 | isbn = 0-8153-3481-8}}</ref> Basement membranes are sheet-like depositions of ECM on which various [[epithelial]] cells rest. == Role and importance == Due to its diverse nature and composition, the ECM can serve many functions, such as providing support and anchorage for cells, segregating tissues from one another, and regulating intercellular communication. The ECM regulates a cell's dynamic behavior. In addition, it sequesters a wide range of cellular [[growth factor]]s, and acts as a local depot for them.<ref name="Robbins"/> Changes in physiological conditions can trigger [[protease]] activities that cause local release of such depots. This allows the rapid and local growth factor-mediated activation of cellular functions, without [[de novo synthesis]]. Formation of the extracellular matrix is essential for processes like [[growth]], [[wound healing]] and [[fibrosis]]. An understanding of ECM structure and composition also helps in comprehending the complex dynamics of [[tumor]] invasion and [[metastasis]] in [[cancer]] biology<ref name="Robbins"/> as metastasis often involves the destruction of extracellular matrix<ref>{{cite journal |author=Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S |title=Metastatic potential correlates with enzymatic degradation of basement membrane collagen |journal=Nature |volume=284 |issue=5751 |pages=67–8 |year=1980 |pmid=6243750 |url=http://www.nature.com/nature/journal/v284/n5751/abs/284067a0.html | doi = 10.1038/284067a0 }}</ref> by enzymes such as [[Serine protease|serine]] and [[Threonine protease]]s and [[Matrix metalloproteinase]].<ref name="Robbins"/> == Molecular components == Components of the ECM are produced intracellularly by resident cells, and secreted into the ECM via [[exocytosis]].<ref name=PG2007>{{cite book | author = Plopper G | title = The extracellular matrix and cell adhesion, in Cells (eds Lewin B, Cassimeris L, Lingappa V, Plopper G) | location = Sudbury, MA | publisher = Jones and Bartlett | year = 2007 | isbn = 0-7637-3905-7}}</ref> Once secreted they then aggregate with the existing matrix. The ECM is composed of an interlocking mesh of fibrous [[protein]]s and [[glycosaminoglycan]]s (GAGs). ===Proteoglycan matrix components=== [[glycosaminoglycans|GAGs]] are carbohydrate [[polymer]]s and are usually attached to extracellular matrix proteins to form [[proteoglycan]]s (hyaluronic acid is a notable exception, see below). Proteoglycans have a net negative charge that attracts water molecules, keeping the ECM and resident cells hydrated. Proteoglycans may also help to trap and store [[growth factors]] within the ECM. Described below are the different types of proteoglycan found within the extracellular matrix. ====Heparan sulfate proteoglycans==== [[Heparan sulfate]] (HS) is a linear [[polysaccharide]] found in all animal tissues. It occurs as a [[proteoglycan]] (PG) in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins.<ref>{{cite book | title=Proteoglycans: structure, biology and molecular interactions | author=Gallagher, J.T., Lyon, M. | chapter=Molecular structure of Heparan Sulfate and interactions with growth factors and morphogens | editor=Iozzo, M, V. | year=2000 | publisher=Marcel Dekker Inc. New York, New York | pages=27-59}} </ref><ref>{{cite journal | title=Matrix proteoglycans: from molecular design to cellular function | journal=Annu. Rev. Biochem. | volume=67 | pages=609–652 | author=Iozzo, R. V. | year=1998 | pmid=9759499 | doi = 10.1146/annurev.biochem.67.1.609 }}</ref> It is in this form that HS binds to a variety of protein [[ligand]]s and regulates a wide variety of biological activities, including developmental processes, [[angiogenesis]], [[blood coagulation]] and tumour [[metastasis]]. In the extracellular matrix, especially [[basement membrane]]s, the [[protein domain|multi-domain]] proteins [[perlecan]], [[agrin]] and [[type XVIII collagen|collagen XVIII]] are the main proteins to which heparan sulfate is attached. ====Chondroitin sulfate proteoglycans==== [[Chondroitin sulfate]]s contribute to the tensile strength of cartilage, [[tendon]]s, [[ligament]]s and walls of the [[aorta]]. They have also been known to affect [[neuroplasticity]].<ref>Takao K. Hensch, [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=16243601&dopt=Citation Critical Period Mechanisms in Developing Visual Cortex. Current Topics in Developmental Biology, Volume 69, 2005, Pages 215-237. DOI:oi:10.1016/S0070-2153(05)69008-4.]</ref> ====Keratan sulfate proteoglycans==== [[Keratan sulfate]]s have a variable sulfate content and unlike many other GAGs, does not contain [[uronic acid]]. It is present in the [[cornea]], cartilage, [[bone]]s and the [[Horn (anatomy)|horns]] of [[animal]]s. ===Non-proteoglycan matrix components=== ====Hyaluronic acid==== [[Hyaluronic acid]] (or "hyaluronan") is a [[polysaccharide]] consisting of alternative residues of D-glucuronic acid and N-acetylglucosamine, and unlike other GAGs is not found as a proteoglycan. Hyaluronic acid in the extracellular space confers upon tissues the ability to resist compression by providing a counteracting [[turgor]] (swelling) force by absorbing a lot of water. Hyaluronic acid is thus found in abundance in the ECM of load-bearing joints. It is also a chief component of the interstitial gel. Hyaluronic acid is found on the inner surface of the cell membrane and is translocated out of the cell during biosynthesis.<ref name=MCB>{{cite book | author = Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J | title = Molecular Cell Biology | edition = 5th | Chapter = Integrating Cells Into Tissues | location = New York | publisher = WH Freeman and Company | pages = 197–234}}</ref> Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes, [[inflammation]] and [[tumor]] development. It interacts with a specific transmembrane receptor, [[CD44]].<ref>Peach ''et al'' 1993. Identification of hyaluronic acid binding sites in the extracellular domain of CD44. The Journal of Cell Biology, Vol 122, 257-264</ref> ====Collagen==== [[Collagen]]s are, in most animals, the most abundant glycoproteins in the ECM. In fact, collagen is the most abundant protein in the human body<ref>{{cite journal |author=Di Lullo GA, Sweeney SM, Korkko J, Ala-Kokko L, San Antonio JD |title=Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen |journal=J. Biol. Chem. |volume=277 |issue=6 |pages=4223–31 |year=2002 |pmid=11704682 |doi=10.1074/jbc.M110709200}}</ref><ref>{{cite journal |author=Karsenty G, Park RW |title=Regulation of type I collagen genes expression |journal=Int. Rev. Immunol. |volume=12 |issue=2-4 |pages=177–85 |year=1995 |pmid=7650420 |doi=}}</ref> and accounts for 90% of bone matrix protein content.<ref>{{cite journal |author=Kern B, Shen J, Starbuck M, Karsenty G |title=Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes |journal=J. Biol. Chem. |volume=276 |issue=10 |pages=7101–7 |year=2001 |pmid=11106645 |doi=10.1074/jbc.M006215200}}</ref> Collagens are present in the ECM as fibrillar proteins and give structural support to resident cells. Collagen is exocytosed in [[precursor]] form ([[procollagen]]), which is then cleaved by procollagen [[proteinase]]s to allow extracellular assembly. Diseases such as [[osteogenesis imperfecta]] and [[epidermolysis bullosa]] are linked with [[genetic defect]]s in collagen-encoding [[gene]]s.<ref name=PG2007/>The collagen can be divided into several families according to the types of structure they form: # Fibrillar (Type I,II,III,V,XI) # Facit (Type IX,XII,XIV) # Short chain (Type VIII,X) # Basement membrane (Type IV) # Other (Type VI,VII, XIII) ====Fibronectin==== [[Fibronectin]]s are proteins that connect cells with collagen fibers in the ECM, allowing cells to move through the ECM. Fibronectins bind collagen and cell surface [[integrin]]s, causing a reorganization of the cell's [[cytoskeleton]] and facilitating cell movement. Fibronectins are secreted by cells in an unfolded, inactive form. Binding to integrins unfolds fibronectin molecules, allowing them to form [[dimer]]s so that they can function properly. Fibronectins also help at the site of tissue injury by binding to [[platelet]]s during [[blood clotting]] and facilitating cell movement to the affected area during wound healing.<ref name=PG2007/> ====Elastin==== [[Elastin]]s, in contrast to collagens, give elasticity to tissues, allowing them to stretch when needed and then return to their original state. This is useful in [[blood vessels]], the [[lungs]] and in [[skin]], and these organs contain high amounts of elastins. Elastins are synthesized by [[fibroblast]]s and [[smooth muscle]] cells. Elastins are highly insoluble, and [[tropoelastin]]s are secreted inside a [[chaperone molecule]], which releases the precursor molecule upon contact with a fiber of mature elastin. Tropoelastins are then deaminated to become incorporated into the elastin strand. Diseases such as [[cutis laxa]] and [[Williams syndrome]] are associated with deficient or absent elastin fibers in the ECM.<ref name=PG2007/> ====Laminin==== [[Laminin]]s are proteins found in the [[basal lamina]]e of virtually all animals. Rather than forming collagen-like fibers, laminins form networks of web-like structures that resist tensile forces in the basal lamina. They also assist in cell adhesion. Laminins bind other ECM components such as collagens, nidogens, and [[entactin]]s.<ref name=PG2007/> == Cell adhesion to the ECM == Many cells bind to components of the extracellular matrix. This cell-to-ECM adhesion is regulated by specific cell surface [[cellular adhesion molecule]]s (CAM) known as [[integrins]]. Integrins are cell surface proteins that bind cells to ECM structures, such as fibronectin and laminin, and also to integrin proteins on the surface of other cells. Fibronectins bind to ECM macromolecules and facilitate their binding to transmembrane integrins. The attachment of fibronectin to the extracellular domain initiates intracellular signaling pathways as well as association with the cellular cytoskeleton via a set of adaptor molecules such as [[actin]].<ref name=ECB/> == Cell types involved in ECM formation == There are many cell types that contribute to the development of the various types of extracellular matrix found in plethora of tissue types. The local components of ECM determine the properties of the connective tissue. [[Fibroblast]]s are the most common cell type in connective tissue ECM, in which they synthesize, maintain and provide a structural framework; fibroblasts secrete the precursor components of the ECM, including the [[ground substance]]. [[Chondrocyte]]s are found in [[cartilage]] and produce the cartilagenous matrix. [[Osteoblast]]s are responsible for bone formation. ==Extracellular matrix in plants== Plant cells are tesselated to form tissues. The [[cell wall]] is the relatively rigid structure surrounding the plant cell. The cell wall provides lateral strength to resist osmotic turgor pressure, but is flexible enough to allow cell growth when needed; it also serves as a medium for intercellular communication. The cell wall comprises multiple laminate layers of [[cellulose]] [[microfibril]]s embedded in a matrix of glycoproteins such as [[hemicellulose]], [[pectin]], and [[extensin]]. The components of the glycoprotein matrix help cell walls of adjacent plant cells to bind to each other. The [[selective permeability]] of the cell wall is chiefly governed by pectins in the glycoprotein matrix. [[Plasmodesmata]] (''singular'': plasmodesma) are pores that traverse the cell walls of adjacent plant cells. These channels are tightly regulated and selectively allow molecules of specific sizes to pass between cells.<ref name=MCB/> == Medical Applications == Extracellular Matrix cells have been found to cause regrowth and healing of tissue. In human fetuses, for example, the extracellular matrix works with stem cells to grow and regrow all parts of the human body, and fetuses can regrow anything that gets damaged in the womb. Scientists have long believed that the matrix stops functioning after full development. It has been used in the past to help horses heal torn ligaments, but it is being researched further as a device for tissue regeneration in humans. In terms of injury repair and [[tissue engineering]], the extracellular matrix serves two main purposes. First, it prevents the immune system from triggering from the injury and responding with inflammation and scar tissue. Next, it facilitates the surrounding cells to repair the tissue instead of forming scar tissue. For medical applications, the cells required are usually extracted from pig bladders, an easily accessible and relatively unused source. It is currently being used regularly to treat ulcers by closing the hole in the tissue that lines the stomach, but further research is currently being done by many universities as well as the U.S. Government for wounded soldier applications. As of early 2007, testing was being carried out on a military base in Texas. Scientists are using a powdered form on Iraq War veterans whose hands were damaged in the war.<ref>HowStuffWorks, [http://health.howstuffworks.com/extracellular-matrix.htm Humans Can Regrow Fingers?]</ref> == References == {{reflist}} ==External links== * {{MeshName|Extracellular+matrix}} * [http://cellbiology.med.unsw.edu.au/units/science/lecture08.htm ANAT3231 Lecture 08 Extracellular Matrix] - Lecture about extracellular matrix from UNSW Cell Biology website. * [http://www.worldwidewounds.com/2005/august/Schultz/Extrace-Matric-Acute-Chronic-Wounds.html Extracellular matrix: review of its roles in acute and chronic wounds] * [http://health.howstuffworks.com/extracellular-matrix.htm Usage of Extracellular Matrix from pigs to regrow human extremities] * [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.section.3532 "The Extracellular Matrix of Animals", from Chapter 19 of ''The Molecular Biology of the Cell'', 4th edition, Alberts ''et al.''] * [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/ECM.html Biology], John W. Kimball. An online Biology textbook. * [http://news.bbc.co.uk/1/hi/health/7354458.stm], The man who grew a finger, By Matthew Price, BBC News {{Connective tissue}} [[Category:Tissues]] [[ar:نسيج خارج الخلية]] [[bg:Извънклетъчен матрикс]] [[de:Extrazelluläre Matrix]] [[el:Εξωκυττάριος Χώρος]] [[es:Matriz extracelular]] [[eo:Eksterĉela matrico]] [[fr:Matrice extracellulaire]] [[it:Matrice extracellulare]] [[ja:細胞外マトリックス]] [[pl:Macierz pozakomórkowa]] [[pt:Matriz extracelular]] [[ru:Внеклеточный матрикс]] [[sr:Екстрацелуларни матрикс]] [[fi:Soluväliaine]] [[sv:Extracellulär matrix]] [[tr:Hücrelerarası madde]] [[zh:细胞外间质]]