extracellular matrix extracellular matrix in biology, the extracellular matrix (ecm), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. because 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. extracellular matrixillustration depicting extracellular matrix (basement membrane and interstitial matrix) in relation to epithelium, endothelium and connective tissuedetailsidentifierslatinmatrix extracellularisacronym(s)ecmmeshd005109thh2.00.03.0.02001 anatomical terms of microanatomy the animal extracellular matrix includes the interstitial matrix and the basement membrane. interstitial matrix is present between various animal cells (i.e., in the intercellular spaces). gels of polysaccharides and fibrous proteins fill the interstitial space and act as a compression buffer against the stress placed on the ecm. 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 fibers 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. some single-celled organisms adopt multicellular biofilms in which the cells are embedded in an ecm composed primarily of extracellular polymeric substances (eps). structure 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. once secreted, they then aggregate with the existing matrix. the ecm is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (gags). proteoglycans glycosaminoglycans (gags) are carbohydrate polymers and mostly attached to extracellular matrix proteins to form proteoglycans (hyaluronic acid is a notable exception; see below). proteoglycans have a net negative charge that attracts positively charged sodium ions (na+), 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. described below are the different types of proteoglycan found within the extracellular matrix. 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. it is in this form that hs binds to a variety of protein ligands and regulates a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation, and tumour metastasis. in the extracellular matrix, especially basement membranes, the multi-domain proteins perlecan, agrin, and collagen xviii are the main proteins to which heparan sulfate is attached. chondroitin sulfate chondroitin sulfates contribute to the tensile strength of cartilage, tendons, ligaments, and walls of the aorta. they have also been known to affect neuroplasticity. keratan sulfate keratan sulfates have a variable sulfate content and, unlike many other gags, do not contain uronic acid. they are present in the cornea, cartilage, bones, and the horns of animals. 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. 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. collagen collagens are the most abundant protein in the ecm. in fact, collagen is the most abundant protein in the human body and accounts for 90% of bone matrix protein content. 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 proteases to allow extracellular assembly. disorders such as ehlers danlos syndrome, osteogenesis imperfecta, and epidermolysis bullosa are linked with genetic defects in collagen-encoding genes. 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 elastins, 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 fibroblasts and smooth muscle cells. elastins are highly insoluble, and tropoelastins 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. extracellular vesicles in 2016, huleihel et al., reported the presence of dna, rna, and matrix-bound nanovesicles (mbvs) within ecm bioscaffolds. mbvs shape and size were found to be consistent with previously described 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. cell adhesion proteins fibronectin fibronectins are glycoproteins that connect cells with collagen fibers in the ecm, allowing cells to move through the ecm. fibronectins bind collagen and cell-surface integrins, 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 dimers so that they can function properly. fibronectins also help at the site of tissue injury by binding to platelets during blood clotting and facilitating cell movement to the affected area during wound healing. laminin laminins are proteins found in the basal laminae 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 nidogens. 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. fibroblasts 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. chondrocytes are found in cartilage and produce the cartilaginous matrix. osteoblasts are responsible for bone formation. physiology stiffness and elasticity the ecm can exist in varying degrees of stiffness and 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, 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. this plays an important role because it helps regulate many important cellular processes including cellular contraction, cell migration, cell proliferation, differentiation and cell death (apoptosis). inhibition of nonmuscle myosin ii blocks most of these effects, 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. although the mechanism by which this is done has not been thoroughly explained, 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. 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 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. 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) 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. this complex contains many proteins that are essential to durotaxis including structural anchoring proteins (integrins) and signaling proteins (adhesion kinase (fak), talin, vinculin, paxillin, α-actinin, gtpases etc.) which cause changes in cell shape and actomyosin contractility. these changes are thought to cause cytoskeletal rearrangements in order to facilitate directional migration. 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 factors and acts as a local store for them. changes in physiological conditions can trigger protease activities that cause local release of such stores. 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 as metastasis often involves the destruction of extracellular matrix by enzymes such as serine proteases, threonine proteases, and matrix metalloproteinases. the stiffness and elasticity of the ecm has important implications in cell migration, gene expression, and differentiation. cells actively sense ecm rigidity and migrate preferentially towards stiffer surfaces in a phenomenon called durotaxis. 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. in the brain, where hyaluronan is the main ecm component, the matrix display both structural and signaling properties. high-molecular weight hyaluronan acts as a diffusional barrier that can modulate diffusion in the extracellular space locally. upon matrix degradation, hyaluronan fragments are released to the extracellular space, where they function as pro-inflammatory molecules, orchestrating the response of immune cells such as microglia. 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 molecules (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 signalling pathways as well as association with the cellular cytoskeleton via a set of adaptor molecules such as actin. clinical significance