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| Image = Extracellular Matrix.png
| Caption = Illustration depicting extracellular matrix ([[basement membrane]] and interstitial matrix) in relation to [[epithelium]], [[endothelium]] and [[connective tissue]]
| Width =
| Image2 =
| Caption2 =
| Acronym = ECM
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In [[biology]], the '''extracellular matrix''' ('''ECM'''),<ref>{{cite web | url=https://www.biologyonline.com/dictionary/matrix | title=Matrix - Definition and Examples - Biology Online Dictionary | date=24 December 2021 }}</ref><ref>{{cite web |title=Body Tissues {{!}} SEER Training |url=https://training.seer.cancer.gov/anatomy/cells_tissues_membranes/tissues/ |website=training.seer.cancer.gov |access-date=12 January 2023}}</ref> also called intercellular matrix (ICM), is a network consisting of
The animal extracellular [[Matrix (biology)|matrix]] includes the [[Interstitium|interstitial]] matrix and the [[basement membrane]].<ref name="Robbins">{{cite book |last1=Kumar |last2=Abbas |last3=Fausto |title=Robbins and Cotran: Pathologic Basis of Disease |___location=Philadelphia |publisher=Elsevier |edition=7th |isbn=978-0-7216-0187-8 |title-link=Surgical sieve#Pathologic Basis Of Disease |year=2005 }}</ref> Interstitial matrix is present between various animal cells (i.e., in the intercellular spaces). Gels of [[polysaccharide]]s and fibrous proteins fill the [[Interstitial fluid|interstitial space]] and act as a compression buffer against the stress placed on the ECM.<ref name=ECB>{{cite book | vauthors = Alberts B, Bray D, Hopin K, Johnson A, Lewis J, Raff M, Roberts K, Walter P | title = Essential cell biology | chapter-url = https://archive.org/details/essentialcellbio00albe | chapter-url-access = registration | chapter = Tissues and Cancer | ___location = New York and London | publisher = [[Garland Science]] | year = 2004 | isbn = 978-0-8153-3481-1 }}</ref> Basement membranes are sheet-like depositions of ECM on which various [[epithelial]] cells rest. Each type of [[connective tissue]] in animals has a type of ECM: [[collagen]] fibers and [[bone mineral]] comprise the ECM of [[bone tissue]]; [[reticular fiber
The plant ECM includes [[cell wall]] components, like cellulose, in addition to more complex signaling molecules.<ref>{{cite journal|last=Brownlee|first=Colin|title=Role of the extracellular matrix in cell-cell signalling: paracrine paradigms|journal=[[Current Opinion in Plant Biology]]|date=October 2002|volume=5|issue=5|pages=396–401|doi=10.1016/S1369-5266(02)00286-8|pmid=12183177|bibcode=2002COPB....5..396B }}</ref> Some single-celled organisms adopt multicellular [[biofilms]] in which the cells are embedded in an ECM composed primarily of [[extracellular polymeric substance]]s (EPS).<ref>{{cite journal | vauthors = Kostakioti M, Hadjifrangiskou M, Hultgren SJ | title = Bacterial biofilms: development, dispersal, and therapeutic strategies in the dawn of the postantibiotic era | journal = Cold Spring Harbor Perspectives in Medicine | volume = 3 | issue = 4 | pages = a010306 | date = April 2013 | pmid = 23545571 | pmc = 3683961 | doi = 10.1101/cshperspect.a010306 }}</ref>
== Structure ==
[[File:Extracellular Matrix.svg|thumb|1: Microfilaments 2: Phospholipid Bilayer 3: Integrin 4: Proteoglycan 5: Fibronectin 6: Collagen 7: Elastin]]
Components of the ECM are produced intracellularly by resident cells and secreted into the ECM via [[exocytosis]].<ref name=PG2007>{{cite book | vauthors = 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 = 978-0-7637-3905-8 | url-access = registration | url = https://archive.org/details/cells0000unse }}</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).{{cn|date=April 2025}}
===Proteoglycans===
[[Glycosaminoglycan]]s (GAGs) are [[carbohydrate]] [[polymer]]s and mostly 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 positively charged sodium ions (Na<sup>+</sup>), which attracts water molecules via osmosis, keeping the ECM and resident cells hydrated. Proteoglycans may also help to trap and store [[growth factors]] within the ECM.{{cn|date=April 2025}}
Described below are the different types of proteoglycan found within the extracellular matrix.{{cn|date=April 2025}}
====Heparan sulfate====
[[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 ECM proteins.<ref>{{cite book | title=Proteoglycans: structure, biology and molecular interactions | url=https://archive.org/details/proteoglycansstr00iozz | url-access=limited | vauthors = Gallagher JT, Lyon M | chapter=Molecular structure of Heparan Sulfate and interactions with growth factors and morphogens | veditors = Iozzo RV | year=2000 | publisher=Marcel Dekker Inc. New York, New York | pages=[https://archive.org/details/proteoglycansstr00iozz/page/n41 27]
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.{{cn|date=April 2025}}
====Chondroitin sulfate====
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====Keratan sulfate====
[[Keratan sulfate]]s have a variable sulfate content and, unlike many other GAGs, do not contain [[uronic acid]]. They are present in the [[cornea]], cartilage, [[bone]]s, and the [[Horn (anatomy)|horns]] of [[animal]]s.{{cn|date=April 2025}}
===Non-proteoglycan polysaccharide===
====Hyaluronic acid====
[[Hyaluronic acid]] (or "hyaluronan") is a [[polysaccharide]] consisting of alternating 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 significant amounts 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 |vauthors=Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J | title = Molecular Cell Biology |year=2008 |url=https://archive.org/details/molecularcellbio00harv_624 |url-access=limited | edition = 5th | chapter = Integrating Cells Into Tissues | ___location = New York | publisher = WH Freeman and Company | pages = [https://archive.org/details/molecularcellbio00harv_624/page/n193 197]
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>{{cite journal | vauthors = Peach RJ, Hollenbaugh D, Stamenkovic I, Aruffo A | title = Identification of hyaluronic acid binding sites in the extracellular ___domain of CD44 | journal = The Journal of Cell Biology | volume = 122 | issue = 1 | pages = 257–64 | date = July 1993 | pmid = 8314845 | pmc = 2119597 | doi = 10.1083/jcb.122.1.257 }}{{open access}}</ref>
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===Proteins===
====Collagen====
[[Collagen]]
# Fibrillar (Type I, II, III, V, XI)
# Facit (Type IX, XII, XIV)
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===Extracellular vesicles===
In 2016, Huleihel et al., reported the presence of DNA, RNA, and Matrix-bound nanovesicles (MBVs) within ECM bioscaffolds.<ref name="Huleihel e1600502">{{cite journal | vauthors = Huleihel L, Hussey GS, Naranjo JD, Zhang L, Dziki JL, Turner NJ, Stolz DB, Badylak SF | title = Matrix-bound nanovesicles within ECM bioscaffolds | journal = Science Advances | volume = 2 | issue = 6 | pages = e1600502 | date = June 2016 | pmid = 27386584 | pmc = 4928894 | doi = 10.1126/sciadv.1600502 | bibcode = 2016SciA....2E0502H }}</ref> MBVs shape and size were found to be consistent with previously described [[Exosome (vesicle)|exosomes]]. MBVs cargo includes different protein molecules, lipids, DNA, fragments, and miRNAs. Similar to ECM bioscaffolds, MBVs can modify the activation state of macrophages and alter different cellular properties such as; proliferation, migration and cell cycle. MBVs are now believed to be an integral and functional key component of ECM bioscaffolds.{{cn|date=April 2025}}
==Cell adhesion proteins==
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==Development==
There are many cell types that contribute to the development of the various types of extracellular matrix found in the plethora of tissue types. The local components of ECM determine the properties of the connective tissue.{{cn|date=April 2025}}
[[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 cartilaginous matrix. [[Osteoblast]]s are responsible for bone formation.{{cn|date=April 2025}}
==Physiology==
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The ECM can exist in varying degrees of [[stiffness]] and [[elasticity (physics)|elasticity]], from soft brain tissues to hard bone tissues. The elasticity of the ECM can differ by several orders of magnitude. This property is primarily dependent on [[collagen]] and [[elastin]] concentrations,<ref name=bonnans/> and it has recently been shown to play an influential role in regulating numerous cell functions.
Cells can sense the mechanical properties of their environment by applying forces and measuring the resulting backlash.<ref name="PlotnikovSV">{{cite journal | vauthors = Plotnikov SV, Pasapera AM, Sabass B, Waterman CM | title = Force fluctuations within focal adhesions mediate ECM-rigidity sensing to guide directed cell migration | journal = Cell | volume = 151 | issue = 7 | pages = 1513–27 | date = December 2012 | pmid = 23260139 | pmc = 3821979 | doi = 10.1016/j.cell.2012.11.034 }}{{Closed access}}</ref> This plays an important role because it helps regulate many important cellular processes including cellular contraction,<ref name="DischerDE">{{cite journal | vauthors = Discher DE, Janmey P, Wang YL | title = Tissue cells feel and respond to the stiffness of their substrate | journal = Science | volume = 310 | issue = 5751 | pages = 1139–43 | date = November 2005 | pmid = 16293750 | doi = 10.1126/science.1116995 | citeseerx = 10.1.1.318.690 | bibcode = 2005Sci...310.1139D | s2cid = 9036803 }}{{Closed access}}</ref> [[cell migration]],<ref name="LoCM"/> [[cell proliferation]],<ref>{{cite journal | vauthors = Hadjipanayi E, Mudera V, Brown RA | title = Close dependence of fibroblast proliferation on collagen scaffold matrix stiffness | journal = Journal of Tissue Engineering and Regenerative Medicine | volume = 3 | issue = 2 | pages = 77–84 | date = February 2009 | pmid = 19051218 | doi = 10.1002/term.136 | s2cid = 174311 | doi-access = free }}{{Closed access}}</ref> [[Cellular differentiation|differentiation]]<ref name="EnglerAJ"/> and cell death ([[apoptosis]]).<ref name="WangHB">{{cite journal | vauthors = Wang HB, Dembo M, Wang YL | title = Substrate flexibility regulates growth and apoptosis of normal but not transformed cells | journal = American Journal of Physiology. Cell Physiology | volume = 279 | issue = 5 | pages = C1345-50 | date = November 2000 | pmid = 11029281 | doi = 10.1152/ajpcell.2000.279.5.C1345 }}{{Closed access}}</ref>
Inhibition of nonmuscle [[myosin II]] blocks most of these effects,<ref name="EnglerAJ"/><ref name="LoCM"/><ref name="DischerDE"/> indicating that they are indeed tied to sensing the mechanical properties of the ECM, which has become a new focus in research during the past decade.
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====Effect on differentiation====
ECM elasticity can direct [[cellular differentiation]], the process by which a cell changes from one cell type to another. In particular, naive [[mesenchymal stem cells]] (MSCs) have been shown to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. MSCs placed on soft matrices that mimic the brain differentiate into [[neuron]]-like cells, showing similar shape, [[RNAi]] profiles, cytoskeletal markers, and [[transcription factor]] levels. Similarly stiffer matrices that mimic muscle are myogenic, and matrices with stiffnesses that mimic collagenous bone are osteogenic.<ref name="EnglerAJ"/>
====Durotaxis====
{{Main|Durotaxis}}
Stiffness and elasticity also guide [[cell migration]], this process is called [[durotaxis]]. The term was coined by Lo CM and colleagues when they discovered the tendency of single cells to migrate up rigidity gradients (towards more stiff substrates)<ref name="LoCM"/> and has been extensively studied since. The molecular mechanisms behind [[durotaxis]] are thought to exist primarily in the [[focal adhesion]], a large [[protein complex]] that acts as the primary site of contact between the cell and the ECM.<ref>{{cite journal | vauthors = Allen JL, Cooke ME, Alliston T | title = ECM stiffness primes the TGFβ pathway to promote chondrocyte differentiation | journal = Molecular Biology of the Cell | volume = 23 | issue = 18 | pages = 3731–42 | date = September 2012 | pmid = 22833566 | pmc = 3442419 | doi = 10.1091/mbc.E12-03-0172 }}</ref> This complex contains many proteins that are essential to durotaxis including structural anchoring proteins ([[integrins]]) and signaling proteins (adhesion kinase ([[PTK2|FAK]]), [[talin protein|talin]], [[vinculin]], [[paxillin]], [[α-actinin]], [[GTPases]] etc.) which cause changes in cell shape and actomyosin contractility.<ref>{{cite journal | vauthors = Kanchanawong P, Shtengel G, Pasapera AM, Ramko EB, Davidson MW, Hess HF, Waterman CM | title = Nanoscale architecture of integrin-based cell adhesions | journal = Nature | volume = 468 | issue = 7323 | pages = 580–4 | date = November 2010 | pmid = 21107430 | pmc = 3046339 | doi = 10.1038/nature09621 | bibcode = 2010Natur.468..580K }}</ref> These changes are thought to cause [[cytoskeleton|cytoskeletal]] rearrangements in order to facilitate directional [[cell migration|migration]].{{cn|date=April 2025}}
== Function ==
Due to its diverse nature and composition, the ECM can serve many functions, such as providing support, segregating tissues from one another, and regulating intercellular communication. The extracellular matrix regulates a cell's dynamic behavior. In addition, it sequesters a wide range of cellular [[growth factor]]s and acts as a local store for them.<ref name="Robbins"/> Changes in physiological conditions can trigger [[protease]] activities that cause local release of such stores. This allows the rapid
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 [[Oncology|cancer biology]] as metastasis often involves the destruction of extracellular matrix by enzymes such as [[serine protease]]s, [[threonine protease]]s, and [[matrix metalloproteinase]]s.<ref name="Robbins"/><ref>{{cite journal | vauthors = Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S | s2cid = 4356057 | title = Metastatic potential correlates with enzymatic degradation of basement membrane collagen | journal = Nature | volume = 284 | issue = 5751 | pages = 67–8 | date = March 1980 | pmid = 6243750 | doi = 10.1038/284067a0 | bibcode = 1980Natur.284...67L }}{{Closed access}}</ref>
The [[stiffness]] and [[elasticity (physics)|elasticity]] of the ECM has important implications in [[cell migration]], gene expression,<ref name="WangJHC">{{cite journal | vauthors = Wang JH, Thampatty BP, Lin JS, Im HJ | title = Mechanoregulation of gene expression in fibroblasts | journal = Gene | volume = 391 | issue = 1–2 | pages = 1–15 | date = April 2007 | pmid = 17331678 | pmc = 2893340 | doi = 10.1016/j.gene.2007.01.014 }}{{Closed access}}</ref> and [[Cellular differentiation|differentiation]].<ref name="EnglerAJ">{{cite journal | vauthors = Engler AJ, Sen S, Sweeney HL, Discher DE | s2cid = 16109483 | title = Matrix elasticity directs stem cell lineage specification | journal = Cell | volume = 126 | issue = 4 | pages = 677–89 | date = August 2006 | pmid = 16923388 | doi = 10.1016/j.cell.2006.06.044 | doi-access = free }}{{Closed access}}</ref> Cells actively sense ECM rigidity and migrate preferentially towards stiffer surfaces in a phenomenon called [[durotaxis]].<ref name="LoCM">{{cite journal | vauthors = Lo CM, Wang HB, Dembo M, Wang YL | title = Cell movement is guided by the rigidity of the substrate | journal = Biophysical Journal | volume = 79 | issue = 1 | pages = 144–52 | date = July 2000 | pmid = 10866943 | pmc = 1300921 | doi = 10.1016/S0006-3495(00)76279-5 | bibcode = 2000BpJ....79..144L }}{{Closed access}}</ref> They also detect elasticity and adjust their gene expression accordingly, which has increasingly become a subject of research because of its impact on differentiation and cancer progression.<ref name="ProvenzanoPP">{{cite journal | vauthors = Provenzano PP, Inman DR, Eliceiri KW, Keely PJ | title = Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage | journal = Oncogene | volume = 28 | issue = 49 | pages = 4326–43 | date = December 2009 | pmid = 19826415 | pmc = 2795025 | doi = 10.1038/onc.2009.299 }}{{Closed access}}</ref> The biochemical and biomechanical properties of tumor ECM differ from those of normal tissues, and could be used for cancer diagnosis and therapy.<ref>{{Cite journal |last1=Klabukov |first1=I. |last2=Smirnova |first2=A. |last3=Yakimova |first3=A. |last4=Kabakov |first4=A.E. |last5=Atiakshin |first5=D. |last6=Petrenko |first6=D. |last7=Shestakova |first7=V.A. |last8=Sulina |first8=Yana |last9=Yatsenko |first9=E. |last10=Stepanenko |first10=V.N. |last11=Ignatyuk |first11=M. |last12=Evstratova |first12=E. |last13=Krasheninnikov |first13=M. |last14=Sosin |first14=D. |last15=Baranovskii |first15=D. |date=2024 |title=Oncomatrix: Molecular Composition and Biomechanical Properties of the Extracellular Matrix in Human Tumors |journal=Journal of Molecular Pathology |volume=5 |issue=4 |pages=437–453 |doi=10.3390/jmp5040029 |doi-access=free |issn=2673-5261}}</ref><ref>{{Cite journal |last1=Sleeboom |first1=Jelle J. F. |last2=van Tienderen |first2=Gilles S. |last3=Schenke-Layland |first3=Katja |last4=van der Laan |first4=Luc J. W. |last5=Khalil |first5=Antoine A. |last6=Verstegen |first6=Monique M. A. |date=2024 |title=The extracellular matrix as hallmark of cancer and metastasis: From biomechanics to therapeutic targets |journal=Science Translational Medicine |volume=16 |issue=728 |pages=eadg3840 |doi=10.1126/scitranslmed.adg3840 |issn=1946-6242 |pmid=38170791}}</ref>
In the brain,
===Cell adhesion
{{Main|Cell adhesion}}
Many cells bind to components of the extracellular matrix. Cell adhesion can occur in two ways; by [[focal adhesions]], connecting the ECM to [[actin]] filaments of the cell, and [[hemidesmosomes]], connecting the ECM to intermediate filaments such as [[keratin]]. 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.{{cn|date=April 2025}}
Fibronectins bind to ECM macromolecules and facilitate their binding to transmembrane integrins. The attachment of fibronectin to the extracellular ___domain initiates intracellular signalling pathways as well as association with the cellular cytoskeleton via a set of adaptor molecules such as [[actin]].<ref name=ECB/>
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Extracellular matrix proteins are commonly used in cell culture systems to maintain stem and precursor cells in an undifferentiated state during cell culture and function to induce differentiation of epithelial, endothelial and smooth muscle cells in vitro. Extracellular matrix proteins can also be used to support 3D cell culture in vitro for modelling tumor development.<ref>{{cite journal | vauthors = Kleinman HK, Luckenbill-Edds L, Cannon FW, Sephel GC | title = Use of extracellular matrix components for cell culture | journal = Analytical Biochemistry | volume = 166 | issue = 1 | pages = 1–13 | date = October 1987 | pmid = 3314585 | doi = 10.1016/0003-2697(87)90538-0 }}</ref>
A class of biomaterials derived from processing human or animal tissues to retain portions of the extracellular matrix are called [[ECM Biomaterial]].{{cn|date=April 2025}}
==In plants==
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==In Pluriformea and Filozoa==
The extracellular matrix functionality of animals (Metazoa) developed in the common ancestor of the [[Pluriformea]] and [[Filozoa]], after the [[Ichthyosporea]] diverged.<ref>{{cite journal |last1=Tikhonenkov |first1=Denis V. |title=Insights into the origin of metazoan multicellularity from predatory unicellular relatives of animals |journal=BMC Biology |date=2020 |volume=18 |issue=39 |
==History==
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* [[Perineuronal net]]
* [[Temporal feedback]]
* [[Advanced glycation end-product]]
== References ==
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