| Extracellular matrix | |
|---|---|
 Illustration depicting extracellular matrix (basement membrane and interstitial matrix) in relation toepithelium,endothelium andconnective tissue | |
| Details | |
| Identifiers | |
| Latin | matrix extracellularis |
| Acronym | ECM |
| MeSH | D005109 |
| TH | H2.00.03.0.02001 |
| Anatomical terms of microanatomy | |
Inbiology, theextracellular matrix (ECM),[1][2] also called intercellular matrix (ICM), is a network consisting ofextracellularmacromolecules and minerals, such ascollagen,enzymes,glycoproteins andhydroxyapatite that provide structural andbiochemical support to surroundingcells.[3][4][5] Becausemulticellularity 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.[6]
The animal extracellularmatrix includes theinterstitial matrix and thebasement membrane.[7] Interstitial matrix is present between variousanimal cells (i.e., in the intercellular spaces). Gels ofpolysaccharides and fibrous proteins fill theinterstitial space and act as a compression buffer against the stress placed on the ECM.[8] Basement membranes are sheet-like depositions of ECM on which variousepithelial cells rest. Each type ofconnective tissue in animals has a type of ECM:collagen fibers andbone mineral comprise the ECM ofbone tissue;reticular fibers andground substance comprise the ECM ofloose connective tissue; andblood plasma is the ECM ofblood.
The plant ECM includescell wall components, likecellulose, in addition to more complex signaling molecules.[9] Somemicroorganisms adopt multicellularbiofilms in which the cells are embedded in an ECM composed primarily ofextracellular polymeric substances (EPS).[10]
Components of the ECM are produced intracellularly by resident cells and secreted into the ECM viaexocytosis.[11] Once secreted, they then aggregate with the existing matrix. The ECM is composed of an interlocking mesh of fibrousproteins andglycosaminoglycans (GAGs).[citation needed]
Glycosaminoglycans (GAGs) arecarbohydratepolymers and mostly attached to extracellular matrix proteins to formproteoglycans (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 storegrowth factors within the ECM.[citation needed]
Described below are the different types of proteoglycan found within the extracellular matrix.[citation needed]
Heparan sulfate (HS) is a linearpolysaccharide found in all animal tissues. It occurs as aproteoglycan in which two or three HS chains are attached in close proximity to cell surface or ECM proteins.[12][13] It is in this form that HS binds to a variety of proteinligands and regulates a wide variety of biological activities, includingdevelopmental processes,angiogenesis,blood coagulation, and tumourmetastasis.[citation needed]
In the extracellular matrix, especiallybasement membranes, themulti-domain proteinsperlecan,agrin, andcollagen XVIII are the main proteins to which heparan sulfate is attached.[citation needed]
Chondroitin sulfates contribute to the tensile strength of cartilage,tendons,ligaments, and walls of theaorta. They have also been known to affectneuroplasticity.[14]
Keratan sulfates have a variable sulfate content and, unlike many other GAGs, do not containuronic acid. They are present in thecornea, cartilage,bones, and thehorns ofanimals.[citation needed]
Hyaluronic acid (or "hyaluronan") is apolysaccharide 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 counteractingturgor (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.[15]
Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes,inflammation, andtumor development. It interacts with a specific transmembrane receptor,CD44.[16]
Collagen is the most abundant protein in the ECM, and is the most abundant protein in the human body.[17][18] It accounts for 90% of bone matrix protein content.[19] Collagens are present in the ECM as fibrillar proteins and give structural support to resident cells. Collagen is exocytosed inprecursor form (procollagen), which is then cleaved by procollagenproteases to allow extracellular assembly. Disorders such asEhlers Danlos Syndrome,osteogenesis imperfecta, andepidermolysis bullosa are linked withgenetic defects in collagen-encodinggenes.[11] The collagen can be divided into several families according to the types of structure they form:
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 inblood vessels, thelungs, inskin, and theligamentum nuchae, and these tissues contain high amounts of elastins. Elastins are synthesized byfibroblasts andsmooth muscle cells. Elastins are highly insoluble, andtropoelastins are secreted inside achaperone 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 ascutis laxa andWilliams syndrome are associated with deficient or absent elastin fibers in the ECM.[11]
In 2016, Huleihel et al., reported the presence of DNA, RNA, and Matrix-bound nanovesicles (MBVs) within ECM bioscaffolds.[20] MBVs shape and size were found to be consistent with previously describedexosomes. 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.[citation needed]
Fibronectins areglycoproteins that connect cells with collagen fibers in the ECM, allowing cells to move through the ECM. Fibronectins bind collagen and cell-surfaceintegrins, causing a reorganization of the cell'scytoskeleton to facilitate cell movement. Fibronectins are secreted by cells in an unfolded, inactive form. Binding to integrins unfolds fibronectin molecules, allowing them to formdimers so that they can function properly. Fibronectins also help at the site of tissue injury by binding toplatelets duringblood clotting and facilitating cell movement to the affected area during wound healing.[11]
Laminins are proteins found in thebasal 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 andnidogens.[11]
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.[citation needed]
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 theground substance.Chondrocytes are found incartilage and produce the cartilaginous matrix.Osteoblasts are responsible for bone formation.[citation needed]
The ECM can exist in varying degrees ofstiffness andelasticity, 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 oncollagen andelastin concentrations,[4] 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.[21] This plays an important role because it helps regulate many important cellular processes including cellular contraction,[22]cell migration,[23]cell proliferation,[24]differentiation[25] and cell death (apoptosis).[26]Inhibition of nonmusclemyosin II blocks most of these effects,[25][23][22] 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.
Differing mechanical properties in ECM exert effects on both cell behaviour andgene expression.[27] Although the mechanism by which this is done has not been thoroughly explained,adhesion complexes and theactin-myosincytoskeleton, whose contractile forces are transmitted through transcellular structures are thought to play key roles in the yet to be discovered molecular pathways.[22]
ECM elasticity can directcellular differentiation, the process by which a cell changes from one cell type to another. In particular, naivemesenchymal 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 intoneuron-like cells, showing similar shape,RNAi profiles, cytoskeletal markers, andtranscription factor levels. Similarly stiffer matrices that mimic muscle are myogenic, and matrices with stiffnesses that mimic collagenous bone are osteogenic.[25]
Stiffness and elasticity also guidecell migration, this process is calleddurotaxis. 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)[23] and has been extensively studied since. The molecular mechanisms behinddurotaxis are thought to exist primarily in thefocal adhesion, a largeprotein complex that acts as the primary site of contact between the cell and the ECM.[28] 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.[29] These changes are thought to causecytoskeletal rearrangements in order to facilitate directionalmigration.[citation needed]
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 cellulargrowth factors and acts as a local store for them.[7] Changes in physiological conditions can triggerprotease activities that cause local release of such stores. This allows the rapid local growth-factor-mediated activation of cellular functions withoutde novo synthesis.[citation needed]
Formation of the extracellular matrix is essential for processes like growth,wound healing, andfibrosis. An understanding of ECM structure and composition also helps in comprehending the complex dynamics oftumor invasion andmetastasis incancer biology as metastasis often involves the destruction of extracellular matrix by enzymes such asserine proteases,threonine proteases, andmatrix metalloproteinases.[7][30]
Thestiffness andelasticity of the ECM has important implications incell migration, gene expression,[31] anddifferentiation.[25] Cells actively sense ECM rigidity and migrate preferentially towards stiffer surfaces in a phenomenon calleddurotaxis.[23] 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.[32] The biochemical and biomechanical properties of tumor ECM differ from those of normal tissues, and could be used for cancer diagnosis and therapy.[33][34]
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 ofmicroglia.[35]
Many cells bind to components of the extracellular matrix. Cell adhesion can occur in two ways; byfocal adhesions, connecting the ECM toactin filaments of the cell, andhemidesmosomes, connecting the ECM to intermediate filaments such askeratin. This cell-to-ECM adhesion is regulated by specific cell-surfacecellular adhesion molecules (CAM) known asintegrins. 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.[citation needed]
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 asactin.[8]
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.[20][36] 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.[37]
In terms of injury repair andtissue 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.[37]
For medical applications, the required ECM is usually extracted frompig 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.[38]
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) andinguinal 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.[39]
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.[40]
A class of biomaterials derived from processing human or animal tissues to retain portions of the extracellular matrix are calledECM Biomaterial.[citation needed]
Plant cells aretessellated to formtissues. Thecell wall is the relatively rigid structure surrounding theplant cell. The cell wall provides lateral strength to resistosmoticturgor 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 ofcellulosemicrofibrils embedded in amatrix ofglycoproteins, includinghemicellulose,pectin, andextensin. The components of the glycoprotein matrix help cell walls of adjacent plant cells to bind to each other. Theselective 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.[15]
The extracellular matrix functionality of animals (Metazoa) developed in the common ancestor of thePluriformea andFilozoa, after theIchthyosporea diverged.[41]
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).[42][43][44][45]
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.
