Editing Extracellular matrix

{{short description|Network of proteins and molecules outside cells that provides structural support for cells}}
{{Infobox microanatomy
| Name        = Extracellular matrix
| Latin       = matrix extracellularis
| 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
}}
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  [[extracellular]] [[macromolecule]]s and minerals, such as [[collagen]], [[enzyme]]s, [[glycoprotein]]s and [[hydroxyapatite]] that provide structural and [[biochemistry|biochemical]] support to surrounding cells.<ref name="addr">{{cite journal | vauthors = Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK | title = Extracellular matrix structure | journal = Advanced Drug Delivery Reviews | volume = 97 | pages = 4–27 | date = February 2016 | pmid = 26562801 | doi = 10.1016/j.addr.2015.11.001 }}</ref><ref name="bonnans">{{cite journal | vauthors = Bonnans C, Chou J, Werb Z | title = Remodelling the extracellular matrix in development and disease | journal = Nature Reviews. Molecular Cell Biology | volume = 15 | issue = 12 | pages = 786–801 | date = December 2014 | pmid = 25415508 | pmc = 4316204 | doi = 10.1038/nrm3904 }}</ref><ref>{{cite journal | vauthors = Michel G, Tonon T, Scornet D, Cock JM, Kloareg B | title = The cell wall polysaccharide metabolism of the brown alga Ectocarpus siliculosus. Insights into the evolution of extracellular matrix polysaccharides in Eukaryotes | journal = The New Phytologist | volume = 188 | issue = 1 | pages = 82–97 | date = October 2010 | pmid = 20618907 | doi = 10.1111/j.1469-8137.2010.03374.x | doi-access = free | bibcode = 2010NewPh.188...82M }}{{open access}}</ref> Because [[Multicellular organism|multicellularity]] evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.<ref>{{cite journal | vauthors = Abedin M, King N | title = Diverse evolutionary paths to cell adhesion | journal = Trends in Cell Biology | volume = 20 | issue = 12 | pages = 734–42 | date = December 2010 | pmid = 20817460 | pmc = 2991404 | doi = 10.1016/j.tcb.2010.08.002 | bibcode = 2010TCBio..20..734A }}</ref>

The animal extracellular [[Matrix (biology)|matrix]] includes the 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]]s and [[ground substance]] comprise the ECM of [[loose connective tissue]]; and [[blood plasma]] is the ECM of [[blood]].

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]–59 |isbn=9780824703349 }}</ref><ref>{{cite journal | vauthors = Iozzo RV | s2cid = 14638091 | title = Matrix proteoglycans: from molecular design to cellular function | journal = Annual Review of Biochemistry | volume = 67 | issue = 1 | pages = 609–52 | year = 1998 | pmid = 9759499 | doi = 10.1146/annurev.biochem.67.1.609 | doi-access = free }}{{closed access}}</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]].{{cn|date=April 2025}}

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====
[[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>{{cite book |doi=10.1016/S0070-2153(05)69008-4 |pmid=16243601 |chapter=Critical Period Mechanisms in Developing Visual Cortex |title=Neural Development |volume=69 |pages=215–237 |series=Current Topics in Developmental Biology |year=2005 |last1=Hensch |first1=Takao K. |isbn=978-0-12-153169-0 }}</ref>

====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]–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>{{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>

===Proteins===
====Collagen====
[[Collagen]] is the most abundant protein in the ECM, and is the most abundant protein in the human body.<ref>{{cite journal | vauthors = 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 = The Journal of Biological Chemistry | volume = 277 | issue = 6 | pages = 4223–31 | date = February 2002 | pmid = 11704682 | doi = 10.1074/jbc.M110709200 | doi-access = free }}{{open access}}</ref><ref>{{cite journal | vauthors = Karsenty G, Park RW | title = Regulation of type I collagen genes expression | journal = International Reviews of Immunology | volume = 12 | issue = 2–4 | pages = 177–85 | year = 1995 | pmid = 7650420 | doi = 10.3109/08830189509056711 }}{{closed access}}</ref> It accounts for 90% of bone matrix protein content.<ref>{{cite journal | vauthors = Kern B, Shen J, Starbuck M, Karsenty G | title = Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes | journal = The Journal of Biological Chemistry | volume = 276 | issue = 10 | pages = 7101–7 | date = March 2001 | pmid = 11106645 | doi = 10.1074/jbc.M006215200 | doi-access = free }}{{open access}}</ref> Collagens are present in the ECM as fibrillar proteins and give structural support to resident cells. Collagen is exocytosed in [[Precursor (chemistry)|precursor]] form ([[procollagen]]), which is then cleaved by procollagen [[protease]]s to allow extracellular assembly. Disorders such as [[Ehlers Danlos Syndrome]], [[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)

====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]], in [[skin]], and the [[ligamentum nuchae]], and these tissues 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. Disorders such as [[cutis laxa]] and [[Williams syndrome]] are associated with deficient or absent elastin fibers in the ECM.<ref name=PG2007/>

===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==
=== Fibronectin ===
[[Fibronectin]]s are [[glycoproteins]] 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]] to facilitate cell movement. Fibronectins are secreted by cells in an unfolded, inactive form. Binding to integrins unfolds fibronectin molecules, allowing them to form [[protein dimer|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/>

=== 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 and [[nidogen]]s.<ref name=PG2007/>

==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==
===Stiffness and elasticity===
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.

====Effect on gene expression====
Differing mechanical properties in ECM exert effects on both cell behaviour and [[gene expression]].<ref>{{cite journal |last1=Wahbi |first1=Wafa |last2=Naakka |first2=Erika |last3=Tuomainen |first3=Katja |last4=Suleymanova |first4=Ilida |last5=Arpalahti |first5=Annamari |last6=Miinalainen |first6=Ilkka |last7=Vaananen |first7=Juho |last8=Grenman |first8=Reidar |last9=Monni |first9=Outi |last10=Al-Samadi |first10=Ahmed |last11=Salo |first11=Tuula |title=The critical effects of matrices on cultured carcinoma cells: Human tumor-derived matrix promotes cell invasive properties |journal=Experimental Cell Research |date=February 2020 |volume=389 |issue=1 |pages=111885 |doi=10.1016/j.yexcr.2020.111885 |pmid=32017929 |hdl=10138/325579 |s2cid=211035510 |url=http://urn.fi/urn:nbn:fi-fe2020051435636 |hdl-access=free }}</ref> Although the mechanism by which this is done has not been thoroughly explained, [[Hemidesmosome|adhesion complexes]] and the [[actin]]-[[myosin]] [[cytoskeleton]], whose contractile forces are transmitted through transcellular structures are thought to play key roles in the yet to be discovered molecular pathways.<ref name="DischerDE"/>

====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 local growth-factor-mediated activation of cellular functions without ''[[De novo synthesis|de novo]]'' synthesis.{{cn|date=April 2025}}

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>

In the brain, [[hyaluronan]] serves as the primary component of the extracellular matrix, contributing to both structural integrity and signaling functions. High-molecular-weight hyaluronan forms a diffusional barrier that regulates local extracellular diffusion. When the ECM undergoes degradation, hyaluronan fragments are released into the extracellular space, where they act as pro-inflammatory molecules, influencing immune cell responses, including those of [[microglia]].<ref name="SoriaFN">{{cite journal | vauthors = Soria FN, Paviolo C, Doudnikoff E, Arotcarena ML, Lee A, Danné N, Mandal AK, Gosset P, Dehay B, Groc L, Cognet L, Bezard E | title = Synucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling | journal = Nature Communications | volume = 11 | pages = 3440 | date = July 2020 | issue = 1 | pmid = 32651387| doi = 10.1038/s41467-020-17328-9 | pmc = 7351768 | bibcode = 2020NatCo..11.3440S | doi-access = free }}{{Open access}}</ref>

===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/>

==Clinical significance==
{{See also|Regenerative medicine}}
Extracellular matrix has been found to cause regrowth and healing of tissue. Although the mechanism of action by which extracellular matrix promotes constructive remodeling of tissue is still unknown, researchers now believe that Matrix-bound nanovesicles (MBVs) are a key player in the healing process.<ref name="Huleihel e1600502"/><ref>{{Cite web|url=https://www.eurekalert.org/pub_releases/2016-07/uops-prs072816.php|title=Pitt researchers solve mystery on how regenerative medicine works|website=EurekAlert!|language=en|access-date=2017-03-01}}</ref> 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.<ref name="telegraph">[https://www.telegraph.co.uk/news/1915228/Pixie-dust-helps-man-grow-new-finger.html 'Pixie dust' helps man grow new finger]</ref>

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.<ref name="telegraph" />

For medical applications, the required ECM is usually extracted from [[pig bladder]]s, 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?] In 2009, the St. Francis Heart Center announced the use of the extracellular matrix technology in [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/07-08-2009/0005056423&EDATE=valve repair surgery]. {{webarchive |url=https://web.archive.org/web/20070310205604/http://health.howstuffworks.com/extracellular-matrix.htm |date=March 10, 2007 }}</ref>

Not all ECM devices come from the bladder. Extracellular matrix coming from pig small intestine submucosa are being used to repair "atrial septal defects" (ASD), "patent foramen ovale" (PFO) and [[inguinal hernia repair|inguinal hernia]]. After one year, 95% of the collagen ECM in these patches has been replaced by the body with the normal soft tissue of the heart.<ref>{{cite web
  | title = First Ever Implantation of Bioabsorbable Biostar Device at DHZB
  | quote = The almost transparent collagen matrix consists of medically purified pig intestine, which is broken down by the scavenger cells (macrophages) of the immune system. After about 1 year the collagen has been almost completely (90-95%) replaced by normal body tissue: only the tiny metal framework remains. An entirely absorbable implant is currently under development.
  | publisher = DHZB NEWS
  | date = December 2007
  | url = http://www.dhzb.de/international_services/dhzb_aktuell/detail/ansicht/pressedetail/290/
  | access-date = 2008-08-05
  | archive-date = 2008-12-11
  | archive-url = https://web.archive.org/web/20081211051327/http://www.dhzb.de/international_services/dhzb_aktuell/detail/ansicht/pressedetail/290/
  | url-status = dead
  }}</ref>

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==
[[Plant]] cells are [[Tessellation|tessellated]] to form [[Tissue (biology)|tissue]]s. The [[cell wall]] is the relatively rigid structure surrounding the [[plant cell]]. The cell wall provides lateral strength to resist [[osmotic]] [[turgor pressure]], but it 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 (biology)|matrix]] of [[glycoproteins]], including [[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/>

==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 |page=39 |doi=10.1186/s12915-020-0762-1 |pmid=32272915 |pmc=7147346 |doi-access=free }}</ref>

==History==
The importance of the extracellular matrix has long been recognized (Lewis, 1922), but the usage of the term is more recent (Gospodarowicz et al., 1979).<ref>{{cite journal | last1 = Lewis|first1= WH | name-list-style=vanc| year = 1922 | title = The adhesive quality of cells | url =https://zenodo.org/record/1424513 | journal = Anat Rec | volume = 23 | issue = 7| pages = 387–392 | doi=10.1002/ar.1090230708|s2cid= 84566330 }}</ref><ref>{{cite book | vauthors = Gospodarowicz D, Vlodovsky I, Greenburg G, Johnson LK | veditors = Sato GH, Ross R |title=Hormones and Cell Culture | year = 1979 | url = https://archive.org/details/hormonescellcult0000unse | url-access = registration |publisher=Coldspring Harbor Laboratory |page=561 |chapter=Cellular shape is determined by the extracellular matrix and is responsible for the control of cellular growth and function| isbn = 9780879691257 }}</ref><ref>{{cite book |editor1-last=Mecham |editor1-first=Robert |title=The extracellular matrix: an overview |date=2011 |publisher=Springer |isbn=9783642165559 |url=https://books.google.com/books?id=ZltDVlFx6K8C| name-list-style=vanc}}{{page number needed|date=August 2018}}</ref><ref>{{cite book |last1=Rieger |first1=Rigomar |last2=Michaelis |first2=Arnd |last3=Green |first3=Melvin M. | name-list-style = vanc |title=Glossary of Genetics: Classical and Molecular |publisher=Springer-Verlag |location=Berlin |isbn=9783642753336 |page=553 |edition=5th| date=2012-12-06 }}</ref>

== See also ==
* [[Anoikis]]
* [[Interstitium]]
* [[Perineuronal net]]
* [[Temporal feedback]]

== References ==
{{Reflist|2}}

== Further reading ==
* [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]
* [https://web.archive.org/web/20110719215952/http://soundmedicine.iu.edu/segment.php4?seg=2108 Sound Medicine - Heart Tissue Regeneration] - July 19 interview discussing ECM and its uses in cardiac tissue repair (requires MP3 playback).

{{Connective tissue}}
{{Fibrous proteins}}
{{Authority control}}

{{DEFAULTSORT:Extracellular Matrix}}
[[Category:Extracellular matrix| ]]
[[Category:Matrices (biology)]]
[[Category:Tissues (biology)]]