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Extracellular matrix
Extracellular matrix
Extracellular matrix
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Extracellular matrix
Illustration depicting extracellular matrix (basement membrane and interstitial matrix) in relation to epithelium, endothelium and connective tissue
Details
Identifiers
Latinmatrix extracellularis
AcronymECM
MeSHD005109
THH2.00.03.0.02001
Anatomical terms of microanatomy

In biology, the extracellular matrix (ECM),[1][2] also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells.[3][4][5] 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.[6]

The animal extracellular matrix includes the interstitial matrix and the basement membrane.[7] 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.[8] 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.[9] Some single-celled organisms adopt multicellular biofilms in which the cells are embedded in an ECM composed primarily of extracellular polymeric substances (EPS).[10]

Structure

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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.[11] Once secreted, they then aggregate with the existing matrix. The ECM is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs).[citation needed]

Proteoglycans

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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.[citation needed]

Described below are the different types of proteoglycan found within the extracellular matrix.[citation needed]

Heparan sulfate

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Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan 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 protein ligands and regulates a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation, and tumour metastasis.[citation needed]

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.[citation needed]

Chondroitin sulfate

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Chondroitin sulfates contribute to the tensile strength of cartilage, tendons, ligaments, and walls of the aorta. They have also been known to affect neuroplasticity.[14]

Keratan sulfate

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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.[citation needed]

Non-proteoglycan polysaccharide

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Hyaluronic acid

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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.[15]

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.[16]

Proteins

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Collagen

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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 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.[11] The collagen can be divided into several families according to the types of structure they form:

  1. Fibrillar (Type I, II, III, V, XI)
  2. Facit (Type IX, XII, XIV)
  3. Short chain (Type VIII, X)
  4. Basement membrane (Type IV)
  5. Other (Type VI, VII, XIII)

Elastin

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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.[11]

Extracellular vesicles

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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 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.[citation needed]

Cell adhesion proteins

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Fibronectin

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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.[11]

Laminin

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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.[11]

Development

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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 the ground substance. Chondrocytes are found in cartilage and produce the cartilaginous matrix. Osteoblasts are responsible for bone formation.[citation needed]

Physiology

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Stiffness and elasticity

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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,[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 nonmuscle myosin 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.

Effect on gene expression

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Differing mechanical properties in ECM exert effects on both cell behaviour and gene expression.[27] 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.[22]

Effect on differentiation

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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.[25]

Durotaxis

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Main article: 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)[23] 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.[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 cause cytoskeletal rearrangements in order to facilitate directional migration.[citation needed]

Function

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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.[7] 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.[citation needed]

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.[7][30]

The stiffness and elasticity of the ECM has important implications in cell migration, gene expression,[31] and differentiation.[25] Cells actively sense ECM rigidity and migrate preferentially towards stiffer surfaces in a phenomenon called durotaxis.[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 of microglia.[35]

Cell adhesion

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Main article: 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.[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 as actin.[8]

Clinical significance

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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.[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 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.[37]

For medical applications, the required ECM is 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.[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) and 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.[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 called ECM Biomaterial.[citation needed]

In plants

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Plant cells are tessellated 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 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 microfibrils embedded in a 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.[15]

In Pluriformea and Filozoa

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The extracellular matrix functionality of animals (Metazoa) developed in the common ancestor of the Pluriformea and Filozoa, after the Ichthyosporea diverged.[41]

History

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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]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Extracellular matrix

View on Grokipedia
from Grokipedia
The extracellular matrix (ECM) is a complex, non-cellular network of secreted macromolecules that surrounds and supports cells within all tissues and organs, providing essential structural and biochemical signaling cues. Composed primarily of proteins, glycans, proteoglycans, and other components, the ECM forms an intricate, tissue-specific meshwork that maintains organ integrity and modulates cellular processes. The composition of the ECM varies by tissue type but generally includes fibrous proteins such as collagens and elastins for tensile strength and elasticity, as well as hydrated proteoglycans and glycosaminoglycans that create a gel-like environment for nutrient diffusion and hydration. In specialized structures like the , the ECM integrates laminins, , and nidogens to anchor epithelial and endothelial cells to underlying . These components are dynamically assembled and remodeled through cellular and enzymatic activity, ensuring adaptability to physiological demands. Beyond mechanical support, the ECM plays critical regulatory roles in , migration, proliferation, differentiation, and by interacting with cell surface receptors like , thereby transmitting biomechanical and biochemical signals that influence tissue development, , and repair. It also contributes to mechanotransduction, where physical properties such as stiffness and topography guide cellular responses in processes ranging from embryogenesis to . Dysregulation of ECM composition or remodeling is implicated in numerous diseases, including , cancer progression, and cardiovascular disorders, where altered or excessive deposition promotes pathological cell behaviors such as and . In cancer, for instance, the ECM facilitates tumor growth and by providing a supportive niche and signaling pathways that enhance . Understanding ECM dynamics thus holds significant potential for therapeutic interventions in and disease treatment.

Composition

Structural Proteins

The extracellular matrix (ECM) relies on structural proteins to provide tensile strength and organizational framework to tissues. Collagen, the most abundant protein in the animal kingdom, accounts for approximately one-third of the total protein content in the and is primarily synthesized by fibroblasts, which are specialized cells responsible for producing and maintaining the ECM. Collagens comprise a family of at least 28 types in vertebrates, formed by the assembly of 46 distinct chains, with fibrillar collagens such as types I, II, and III being the predominant forms that self-assemble into long, rope-like to confer mechanical stability. Network-forming collagens, including types IV and VI, create sheet-like or beaded filament structures that support basal laminae and interstitial matrices, respectively. At the molecular level, collagen molecules adopt a characteristic structure, where three polypeptide chains rich in , , and residues wind into a rigid rod approximately 300 nm long and 1.5 nm in diameter. Collagen biosynthesis begins intracellularly in fibroblasts, where procollagen chains undergo posttranslational modifications such as of and residues, followed by in the and Golgi apparatus, before secretion as a procollagen trimer into the . Extracellularly, propeptides are cleaved to initiate spontaneous into , which are then stabilized by enzymatic cross-linking mediated by lysyl oxidase, an enzyme that oxidizes residues to form allysine, enabling covalent bonds that enhance tensile strength. These typically exhibit diameters ranging from 50 to 200 nm, varying by tissue type to optimize mechanical properties. Elastin serves as the key structural protein imparting elasticity to the ECM, forming resilient fibers essential for tissues that undergo repeated deformation. Elastin fibers consist primarily of the hydrophobic protein tropoelastin, which polymerizes around a of fibrillin-rich microfibrils to create a cross-linked network capable of extending up to 150% of its length and recoiling with near-perfect reversibility. The mechanism arises from the of elastin's disordered, hydrophobic chains, which minimize conformational when stretched and rapidly recover upon release, enabling efficient and dissipation in dynamic environments. Tropoelastin monomers, synthesized by fibroblasts and cells, are secreted and self-aggregate on the cell surface before deposition onto microfibrils, where lysyl oxidase catalyzes oxidative deamination of residues to form unique tetrafunctional cross-links such as desmosine and isodesmosine. These cross-links stabilize the amorphous core, preventing degradation and ensuring long-term elasticity, with desmosine concentrations particularly high in load-bearing tissues. In stretchable tissues like arteries and lungs, fibers enable cyclic expansion and contraction; for instance, in arterial walls, they allow vessels to withstand pulsatile flow while maintaining recoil to propel forward, comprising up to 50% of the dry weight in elastic lamellae.

Glycoproteins and Proteoglycans

Glycoproteins and proteoglycans are key non-collagenous components of the extracellular matrix (ECM) that mediate dynamic interactions between cells and the structural scaffold, primarily through their moieties and protein domains. These molecules facilitate , modulate binding, and contribute to tissue organization by integrating with fibrils for enhanced mechanical stability. Unlike the rigid structural proteins, glycoproteins and proteoglycans enable adaptive responses due to their modular architectures and glycosylated extensions. Fibronectin, a prominent ECM glycoprotein, exhibits a modular structure composed of repeating type I, type II, and type III domains that enable diverse binding interactions. The type I and III domains primarily mediate into , while type II domains facilitate binding, and specific type III domains (e.g., III_{12-14}) interact with and . exists in multiple isoforms generated by , notably plasma fibronectin, which lacks the extra type III domain B (EDA) and is soluble in circulation, versus cellular fibronectin, which includes EDA and supports fibrillogenesis during tissue remodeling. These isoforms bind such as α5β1 for , types I and IV for matrix assembly, and for regulating bioavailability of signaling molecules. Laminin, another major ECM glycoprotein, forms heterotrimeric complexes with α, β, and γ chains, resulting in cross-shaped structures essential for integrity. Over 15 isoforms exist, such as (α1β1γ1), which is prevalent in early embryonic membranes and promotes epithelial cell polarization through binding to α3β1 and α6β1. The globular domains at the termini interact with nidogen (entactin) to link networks to , while the central rod-like regions enable into sheets that provide a substrate for cell attachment and migration. isoforms like (α5β1γ1) predominate in mature membranes, supporting long-term tissue stability. Proteoglycans consist of a core protein substituted with one or more () chains, covalently attached via tetrasaccharide linkers to serine residues in Ser-Gly motifs, enabling them to bridge ECM components and cells. The core proteins determine specificity; for instance, aggrecan, a large proteoglycan, features multiple GAG attachment sites and interacts with hyaluronan via its N-terminal globular domains to form massive aggregates that imbue with compressive resistance. , a small leucine-rich proteoglycan, binds fibrils via its core protein to regulate fibril diameter and spacing. Cell-associated proteoglycans include the syndecan family, which are transmembrane with and chains that cluster at cell surfaces to transduce signals, and the glypican family, anchored by (GPI) tails, which modulate gradients in the pericellular space. Specific examples include versican, a proteoglycan abundant in where it influences matrix assembly and proliferation through isoform-specific GAG content, and , a proteoglycan in basement membranes that stabilizes networks by binding and nidogen while sequestering s. Biosynthesis of proteoglycans begins in the where the core protein is synthesized and folded, followed by in the Golgi apparatus. Initiation occurs via xylosyltransferase adding to serine, extended by galactosyltransferases and glucuronyltransferase to form the linker tetrasaccharide. Elongation of chains then proceeds through alternating additions by glycosyltransferases, such as chondroitin polymerase (ChSy family) for or heparan synthase (EXT1/EXT2 complex) for , with sulfotransferases modifying the chains for functional diversity. These enzymatic steps ensure precise length and composition tailored to tissue demands.

Glycosaminoglycans and Other Polysaccharides

Glycosaminoglycans (GAGs) and other polysaccharides form a significant class of non-protein components in the extracellular matrix (ECM), primarily existing as unbound chains that contribute to tissue hydration, lubrication, and electrostatic interactions through their polyanionic properties. These molecules, including both non-sulfated and sulfated variants, create a hydrated gel-like environment in the ECM by attracting and retaining water molecules via hydrogen bonding and ionic interactions. Hyaluronic acid (HA), the principal non-sulfated , is a linear composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine linked by alternating β-1,4 and β-1,3 glycosidic bonds. With molecular weights reaching up to 10 million Da, HA exhibits exceptional viscoelastic properties essential for ECM and resilience. It is synthesized at the plasma membrane by hyaluronan synthases (HAS1, HAS2, and HAS3), which extrude the growing polymer into the without the need for core protein attachment. HA's hydrophilic nature enables it to bind up to 1000 times its weight in water, facilitating ECM hydration and space-filling functions. Sulfated GAGs, present as free chains in the ECM alongside their proteoglycan-bound forms, include heparan sulfate (HS), chondroitin sulfate (CS), and keratan sulfate (KS), each characterized by distinct sulfation patterns that enhance their polyanionic character. Heparan sulfate consists of repeating disaccharide units of uronic acid (either D-glucuronic or L-iduronic acid) and D-glucosamine, with sulfation occurring variably at the 2-O position of the uronic acid and N-, 3-O-, and 6-O positions of the glucosamine, creating domains of high and low sulfation. Chondroitin sulfate features disaccharide repeats of D-glucuronic acid and N-acetyl-D-galactosamine, sulfated predominantly at the 4-O (CS-A isomer) or 6-O (CS-C isomer) positions of the galactosamine residue, with the ratio of these isomers varying by tissue to modulate charge distribution. Keratan sulfate is composed of repeating galactose β-1,4-linked to N-acetyl-D-glucosamine units, with sulfation mainly at the 6-O position of glucosamine and occasionally at the 6-O position of galactose. Heparin-like molecules, structurally similar to highly sulfated HS, occur as free polyanionic in certain ECM contexts, exhibiting the highest degree of sulfation among GAGs and thus the greatest negative . The polyanionic nature of these sulfated GAGs and arises from their and groups, enabling them to bind substantial volumes—comparable to HA—through osmotic swelling and ion entrapment. Sulfation patterns in GAGs critically influence their , which governs interactions with cations such as Na⁺ and Ca²⁺; higher sulfation increases anionic sites, promoting stronger binding primarily to groups on uronic acids, while monovalent Na⁺ ions contribute to overall hydration shells. For instance, in , increased sulfation correlates with enhanced Ca²⁺ affinity, stabilizing compact conformations that affect ECM ion balance. These charge-based interactions underscore the role of free GAG chains in modulating ECM electrostatic environments, distinct from their occasional attachment to proteoglycans for amplified functionality.

Extracellular Vesicles and Additional Components

Extracellular vesicles (EVs) represent a diverse class of membrane-bound nanoparticles secreted by cells into the extracellular matrix (ECM), contributing to its dynamic composition beyond traditional protein and polysaccharide elements. These vesicles are categorized primarily into exosomes and microvesicles based on their biogenesis and size. Exosomes, ranging from 30 to 100 nm in diameter, originate from the endosomal pathway, where intraluminal vesicles form within multivesicular bodies that subsequently fuse with the plasma membrane for release. Microvesicles, larger at 100 to 1000 nm, arise directly from outward budding of the plasma membrane. Both types encapsulate a variety of cargo, including proteins, lipids, and microRNAs (miRNAs), which they transport to mediate intercellular communication within the ECM environment. In specialized tissues like , mineral components integrate with the organic ECM to provide rigidity and strength. , with the chemical formula , constitutes the primary inorganic phase, formed through the regulated deposition of crystals within the matrix. This mineralization process is tightly controlled by non-collagenous proteins such as and bone sialoprotein, which influence crystal , inhibit excessive growth, and ensure proper orientation of along fibrils. Additional non-structural elements in the ECM include multimeric adhesive proteins and matricellular proteins that fine-tune matrix organization without serving primary load-bearing roles. Thrombospondin, a large multimeric glycoprotein, promotes and modulates interactions between cells and ECM components like collagen and fibronectin. Matricellular proteins, exemplified by (secreted protein acidic and rich in cysteine, also known as osteonectin), act as transient regulators of ECM assembly by binding to structural proteins and growth factors, thereby influencing matrix deposition and remodeling during tissue development and repair. Recent research since 2020 has advanced understanding of EVs' contributions to ECM dynamics, particularly in remodeling processes. EVs facilitate matrix degradation and synthesis by delivering enzymes and signaling molecules that alter ECM composition in contexts like bone homeostasis. Isolation of these vesicles commonly employs ultracentrifugation, which separates them based on density gradients to yield pure populations for analysis. Furthermore, EVs hold promise as biomarkers for ECM-associated pathologies, as their protein and cargo reflects alterations in matrix integrity and can be detected non-invasively in biofluids.

Functions

Mechanical Support and Elasticity

The extracellular matrix (ECM) provides mechanical support to tissues through its structural components, enabling them to withstand physical stresses without permanent deformation. Collagen fibrils, organized in a hierarchical cable-like structure, primarily confer tensile strength to the ECM, acting as load-bearing elements that resist pulling forces. In tendons, these fibrils achieve Young's moduli ranging from 1 to 10 GPa, allowing the tissue to support high tensile loads during movement. Elasticity in the ECM arises from elastin networks, which facilitate reversible deformation and rapid recoil, essential for dynamic tissues like arteries and lungs. Elastin fibers can undergo strains up to 150% without damage, driven by entropic coiling mechanisms where random chain conformations return to a high-entropy state upon unloading. This property ensures tissues recover shape after stretching, preventing fatigue. Viscoelasticity of the ECM, combining viscous damping and elastic recovery, is contributed by (HA) and proteoglycans, which absorb energy and dissipate stress through fluid interactions and molecular friction. In HA-based hydrogels mimicking ECM, shear moduli typically range from 0.1 to 10 kPa, providing time-dependent responses that buffer sudden impacts. Tissue-specific ECM properties vary widely; for instance, bone's mineralized matrix imparts high rigidity with Young's moduli up to 10 GPa, while cartilage's proteoglycan-rich ECM enables with moduli around 100-150 kPa in superficial zones. Cross-linking density in networks significantly influences overall , as increased enzymatic cross-links enhance resistance to deformation. These mechanical behaviors often follow principles, described by : σ=Eε\sigma = E \varepsilon where σ\sigma is stress, EE is the Young's modulus, and ε\varepsilon is strain, applicable to small deformations in fibrillar ECM components.

Cell Adhesion and Migration

The extracellular matrix (ECM) facilitates cell adhesion primarily through integrin receptors, which are transmembrane αβ heterodimers that bind specific motifs in ECM proteins such as the arginine-glycine-aspartic acid (RGD) sequence found in fibronectin and certain laminin isoforms. These integrins, including α5β1 for fibronectin and α3β1 or α6β1 for laminin, undergo conformational changes upon ligand binding, enabling intracellular connections to the actin cytoskeleton. This binding initiates the assembly of focal adhesions, dynamic multiprotein complexes where talin links the integrin β-subunit tail to actin filaments, recruiting vinculin to reinforce the linkage and stabilize adhesion under mechanical stress. Focal adhesions thus serve as sites for force transmission, allowing cells to sense and respond to ECM topography and rigidity. Beyond focal adhesions, specialized adhesion complexes further mediate ECM interactions during attachment and motility. Hemidesmosomes, prominent in epithelial tissues, anchor basal to the via α6β4 binding laminin-332, coupled to intermediate filaments through plectin and BP230 proteins for robust, stable attachment resistant to shear forces. In contrast, invadopodia are transient, actin-rich protrusions formed by invasive cells, such as metastatic cancer cells, that locally degrade ECM through recruitment of metalloproteases like MT1-MMP, enabling directional penetration and migration. These structures highlight the ECM's role in balancing stable with dynamic remodeling. Cell migration on the ECM involves guided motility modes, including durotaxis, where cells preferentially move toward regions of increasing substrate stiffness via clustering and reinforcement on stiffer matrices, as observed in fibroblasts navigating tissue gradients. Haptotaxis directs migration along gradients of ECM adhesiveness, such as varying densities, prompting cells to follow higher ligand concentrations through biased lamellipodial extension. Matrix metalloproteinases (MMPs), secreted by migrating cells, degrade ECM barriers to create paths, with MMP-2 and MMP-9 cleaving and to facilitate while exposing cryptic binding sites that promote further . These dynamics are exemplified in , where and fibroblasts migrate collectively across provisional fibronectin-rich matrices, remodeling ECM to close gaps, and in embryonic development, where cells traverse basement membranes via integrin-MMP interactions to reach target sites. Quantitatively, (AFM) measurements reveal that individual integrin-ECM bonds withstand rupture forces of 20-40 piconewtons (pN), sufficient for cells to generate traction during migration without bond failure under physiological loads. This adhesion strength scales with cluster size in focal adhesions, enabling cells to exert forces up to several nanonewtons for effective .

Biochemical Signaling

The extracellular matrix (ECM) plays a pivotal role in biochemical signaling by acting as a and presenter of growth factors, sequestering them to regulate their and spatiotemporal to cells. (HS) proteoglycans, key ECM components, bind and stabilize growth factors such as (FGF) and (VEGF), preventing their diffusion and degradation while facilitating high-affinity interactions with cell surface receptors upon localized release. These interactions are modulated by the sulfation patterns of HS chains, which confer specificity to binding and signaling . Release of sequestered growth factors occurs primarily through enzymatic degradation of the ECM, involving proteases that cleave HS proteoglycans and liberate bioactive molecules to influence processes like and tissue remodeling. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases exemplified by MMP-2 (gelatinase A) and MMP-9 (gelatinase B), drive much of this signaling by cleaving ECM components to release bound s and generate bioactive fragments known as matrikines. These matrikines, derived from proteins like and , function as signaling peptides that bind specific receptors on cells, promoting responses such as , proliferation, and independent of growth factor release. MMP activity is precisely regulated by endogenous inhibitors, including tissue inhibitors of metalloproteinases (TIMPs), which form complexes with active MMPs to prevent excessive ECM degradation and maintain signaling . Dysregulation of MMPs and TIMPs has been implicated in pathological signaling, where unbalanced matrikine production contributes to disease progression. Beyond release, ECM proteolysis unmasks cryptic sites—sequestered sequences within structural proteins like —that become exposed and bioactive upon cleavage, thereby initiating novel signaling cascades. For example, MMP-mediated breakdown of type IV reveals hidden motifs that interact with and receptors, amplifying cellular responses to injury or stress. This exposure of cryptic sites transforms the ECM from a passive scaffold into a dynamic signaling platform, where fragmented act as endogenous regulators of cell behavior. Specific examples illustrate the ECM's signaling versatility: transforming growth factor-β (TGF-β) is stored in a latent complex with its latency-associated (LAP), which covalently binds to microfibrils in the ECM, controlling TGF-β through mechanical or proteolytic cues that disrupt the LAP- interaction. Similarly, HS proteoglycans modulate Wnt signaling by clustering Wnt ligands and co-receptors on the cell surface, enhancing gradient formation and pathway specificity during development and ; distinct HS sulfation patterns differentially regulate versus non-canonical Wnt branches.

Biological Roles

In Development and Morphogenesis

During embryonic development, the extracellular matrix (ECM) undergoes dynamic temporal changes to support tissue patterning and organ formation. Initially, a provisional ECM rich in and (HA) predominates, providing a flexible scaffold that facilitates and proliferation in the early . As development progresses, this provisional matrix is remodeled into a mature, collagen-rich structure that offers greater mechanical stability for tissue maturation. membranes, specialized ECM sheets, assemble through of laminins and type IV collagens, crosslinked by nidogens and proteoglycans, to separate epithelial layers from underlying and guide . In morphogenetic processes, ECM components direct branching morphogenesis in organs such as the and . Laminin gradients within the regulate ureteric bud branching in the and epithelial tip outgrowth in the , influencing directional and invasion. Similarly, neural crest cells migrate along fibronectin-rich ECM tracks, where dynamic assembly of fibrillar by leader cells creates haptotactic cues that coordinate collective stream migration during craniofacial and development. ECM remodeling is mediated by specific enzymes that enable tissue shaping. Members of the ADAMTS family, such as ADAMTS-12, cleave versican and other proteoglycans in the provisional matrix, promoting proliferation and matrix organization during skeletal development. Hyaluronidases, including TMEM2, degrade HA to reduce matrix viscosity, facilitating mesenchymal cell expansion and tissue hydration in expanding embryonic structures like the heart and . Genetic models highlight ECM's essential roles in development. Knockout of collagen XVIII in mice disrupts eye morphogenesis, leading to abnormal hyaloid vessel regression, retinal vascular outgrowth defects, and anterior segment anomalies due to impaired basement membrane integrity in ocular tissues. In species comparisons, Drosophila's basement membrane analogs, composed of collagen IV and laminin, support epithelial morphogenesis and organ shaping, with hemocyte-secreted components reinforcing ECM assembly akin to vertebrate processes. Key developmental events rely on ECM dynamics for patterning. During , localized ECM remodeling, including fibrillogenesis, coordinates mesendoderm and convergent extension movements in vertebrates like . In somitogenesis, ECM components such as and contribute to somite boundary formation, ensuring periodic segmentation of the vertebral column.

In Tissue Homeostasis and Repair

The extracellular matrix (ECM) maintains tissue through a balanced process of continuous synthesis and degradation, ensuring structural integrity and functional adaptability in mature tissues. In steady-state conditions, fibroblasts remain largely quiescent, producing ECM components at a rate that matches their enzymatic breakdown by matrix metalloproteinases (MMPs) and other proteases. For instance, , a major ECM protein in , exhibits a of approximately 15 years, reflecting the slow turnover necessary for long-term tissue stability. This equilibrium prevents excessive accumulation or loss of matrix, supporting organ function without overt remodeling. Disruptions in this balance, such as altered protease activity, can lead to pathological changes, underscoring the ECM's role in physiological maintenance. In wound repair, the ECM dynamically participates across overlapping phases to restore tissue integrity. During the inflammatory phase, recruited immune cells release MMPs that degrade damaged ECM, clearing debris and facilitating leukocyte infiltration to control infection. In the subsequent proliferative phase, fibroblasts deposit a provisional matrix rich in , , and hyaluronan, which provides a scaffold for formation and . The remodeling phase, lasting weeks to months, involves collagen cross-linking and realignment by lysyl oxidase, culminating in formation that replaces the provisional matrix with a more organized but often less elastic structure. These ECM-mediated events parallel developmental processes in their orchestration of cellular responses, though adapted for adult recovery. The ECM also sustains niches critical for tissue renewal. In the (HSC) niche within , —a ECM component secreted by osteoblasts—acts as a negative regulator, limiting HSC proliferation and maintaining quiescence to preserve the pool. Similarly, in intestinal crypts, gradients of isoforms in the ECM guide positioning and differentiation, with higher concentrations at the crypt base promoting self-renewal while lower levels toward the villus apex favor maturation. These niche-specific ECM cues ensure controlled regeneration without exhaustion of pools. Aging impairs ECM homeostasis through progressive stiffening and loss of elasticity, primarily driven by (AGEs). AGEs form via non-enzymatic of long-lived proteins like , creating irreversible cross-links that increase matrix rigidity and disrupt fibril assembly. In , for example, age-associated ECM stiffening correlates directly with elevated AGE adducts and collagen content, compromising tissue compliance and contributing to reduced regenerative capacity. These changes accumulate over decades, altering mechanotransduction and exacerbating functional decline in multiple organs. Recent advances post-2020 have leveraged ECM components for enhanced tissue repair strategies. ECM-derived hydrogels, incorporating decellularized matrix from dermal or adipose sources, serve as bioactive dressings that promote moist , reduce , and accelerate re-epithelialization in chronic wounds. For instance, collagen-based hydrogels functionalized with have demonstrated improved outcomes in diabetic ulcers by mimicking native matrix signaling. Complementing this, decellularized ECM scaffolds in preserve native architecture and bioactive cues, enabling vascularized constructs for skin and cardiac regeneration with demonstrated and reduced compared to synthetic alternatives. As of 2025, ongoing clinical trials are expanding dECM applications to and regeneration.

Mechanical Sensing and Response

Cells sense the mechanical properties of the extracellular matrix (ECM) through mechanotransduction, a process where physical forces from the ECM are converted into biochemical signals that influence cellular behavior and . This sensing primarily occurs via integrin-mediated adhesions, which connect the ECM to the , allowing cells to probe matrix stiffness and topography. Upon engagement with ECM ligands, cluster to form focal adhesions, where mechanical forces activate downstream signaling pathways. A key mechanotransduction pathway involves focal adhesion kinase (FAK), which is activated by tensile forces transmitted through and talin-vinculin linkages at s. Force application unfolds FAK's autoinhibitory domains, enabling autophosphorylation at tyrosine 397 and recruitment of Src kinase, which amplifies signaling to regulate and survival. Parallel to FAK, the Hippo pathway effectors YAP and TAZ are mechanosensitive; on stiff matrices, nuclear translocation of YAP/TAZ is promoted via -FAK-RhoA-actin signaling, driving transcription of genes involved in proliferation and differentiation. In contrast, soft matrices retain YAP/TAZ in the through Hippo activation, favoring other fates. Matrix stiffness profoundly affects gene expression and cell fate. For instance, mesenchymal stem cells (MSCs) on stiff matrices (25–40 kPa, mimicking ) upregulate , a master osteogenic transcription factor, via YAP/TAZ and ERK signaling, promoting osteogenesis. Conversely, soft matrices (0.1–1 kPa, akin to tissue) suppress RUNX2 and activate neurogenic markers like β-III tubulin through mechanosensitive ion channels and reduced YAP activity, directing . In myogenesis, aligned ECM topography enhances myoblast fusion into multinucleated myotubes by orienting cytoskeletal tension and signaling, as seen in fibronectin-coated substrates. Adipogenesis is favored on compliant substrates (1–10 kPa), where low stiffness limits YAP nuclear entry, allowing PPARγ upregulation and lipid accumulation in preadipocytes. Cells exhibit durotaxis, a directed migration toward stiffer ECM regions, driven by differential adhesion strengthening and actomyosin contractility on stiffness gradients, which is crucial for and cancer invasion. ECM thixotropy, the reversible under , facilitates by temporarily reducing matrix viscosity, allowing and cytoskeletal pushing without permanent remodeling. These behaviors are studied using (PAAm) hydrogels, tunable from 0.1 kPa (soft) to 40 kPa (stiff) by varying and bis-acrylamide concentrations, coated with ECM proteins like or to mimic physiological cues. (AFM) enables nanoscale stiffness mapping of native ECM, revealing heterogeneous that correlate with cellular responses in tissues. In focal adhesions, force balance is often modeled using , where the applied force FF equals the spring constant kk times displacement dd: F=k⋅dF = k \cdot d This equation describes how adhesions act as viscoelastic springs, with kk reflecting ECM stiffness and linkage compliance, balancing cellular contractility against matrix resistance to propagate signals.

Clinical Significance

Role in Diseases

Alterations in the extracellular matrix (ECM) play a central role in various pathologies, where dysregulated remodeling leads to tissue dysfunction and disease progression. In fibrotic conditions, excessive deposition of ECM components, particularly , disrupts normal tissue architecture and impairs organ function. For instance, in liver cirrhosis and (IPF), fibroblasts differentiate into under the influence of transforming growth factor-β (TGF-β), driving persistent synthesis and matrix stiffening. This TGF-β-mediated sustains myofibroblast persistence, creating a feed-forward loop that exacerbates and hinders resolution. In cancer, ECM remodeling contributes to tumor progression through desmoplasia, where stromal fibroblasts deposit dense collagen networks that stiffen the surrounding matrix and facilitate invasion. In breast cancer, accumulation of hyaluronic acid (HA) in the tumor microenvironment enhances cell motility and promotes metastatic spread by altering matrix compliance. Furthermore, ECM stiffening supports the formation of pre-metastatic niches, where primary tumor-derived factors prime distant sites for colonization via extracellular vesicle-mediated remodeling. Genetic disorders often arise from direct defects in ECM structural proteins, leading to connective tissue fragility. Ehlers-Danlos syndrome (EDS) is characterized by mutations in genes, such as COL5A1 and COL5A2, resulting in abnormal assembly and reduced matrix integrity that manifests as skin hyperextensibility and joint hypermobility. stems from mutations in the FBN1 gene encoding fibrillin-1, a key ECM , which disrupts formation and stability, predisposing individuals to aortic aneurysms. involves mutations in genes (COL1A1 or COL1A2), causing brittle bones due to defective ECM mineralization and reduced secretion. Inflammatory diseases like (RA) feature ECM degradation driven by matrix metalloproteinases (MMPs), which are upregulated in synovial fibroblasts and macrophages. MMP-1, MMP-3, and MMP-9 target s and proteoglycans, leading to erosion and joint destruction in RA. Recent insights post-2020 highlight ECM involvement in emerging conditions. In severe , viral infection triggers excessive ECM deposition in the lungs, with elevated and contributing to post-acute through activation and TGF-β signaling. In (IBD), gut commensal bacteria, such as those enriched in dysbiotic microbiomes, degrade ECM components like IV via microbial proteases, exacerbating mucosal barrier breakdown and chronic inflammation.

Diagnostic and Therapeutic Applications

The extracellular matrix (ECM) serves as a valuable source of biomarkers for diagnosing fibrotic and degenerative diseases, enabling non-invasive monitoring of tissue remodeling. Circulating collagen fragments, such as PRO-C3—a neo-epitope marker of type III collagen synthesis—have been established as predictors of fibrosis progression in conditions like liver fibrosis, correlating with disease severity and clinical outcomes in multiple cohorts. Similarly, elevated levels of hyaluronic acid (HA) in synovial fluid indicate ECM disruption in osteoarthritis, reflecting increased turnover and inflammation that correlates with joint degeneration and pain severity. Advanced imaging techniques exploit ECM components for precise visualization of tissue architecture and pathology. Second harmonic generation (SHG) provides label-free imaging of fibers within the ECM, revealing fibrillar organization changes in tumors and fibrotic tissues, which aids in assessing disease progression without exogenous dyes. (MRI), particularly T2 and T1ρ mapping, quantifies ECM alterations in , such as loss and matrix degradation, offering a non-invasive tool for early detection and monitoring therapeutic responses. Therapeutic strategies targeting the ECM focus on modulating its remodeling to halt pathological progression. Matrix metalloproteinase (MMP) inhibitors like doxycycline have shown promise in preclinical studies by reducing ECM degradation in connective tissue disorders, such as hypermobile Ehlers-Danlos syndrome, where they restore collagen organization and mitigate fibroblast dysfunction. Anti-fibrotic agents, including pirfenidone, inhibit ECM deposition in pulmonary fibrosis models by suppressing collagen synthesis and fibril formation, leading to reduced lung stiffness and improved function in preclinical and clinical settings. ECM-mimicking scaffolds composed of collagen and HA composites support tissue repair by providing biomechanical cues and promoting cell adhesion, as demonstrated in dermal and cartilage regeneration applications. In , decellularized ECM (dECM) derived from native tissues serves as a bioactive scaffold for culture, preserving matrix proteins to enhance differentiation and organ-specific functionality in models of liver and intestinal regeneration. Three-dimensional ( using methacryloyl (GelMA) hydrogels incorporates ECM motifs to fabricate vascularized constructs, improving cell viability and matrix deposition for applications in and repair. Emerging post-2020 approaches leverage and gene editing for precise ECM modulation. Nanomedicine platforms, such as enzyme-loaded nanoparticles, enable targeted ECM degradation in tumor microenvironments, enhancing penetration and immune cell infiltration in solid cancers like pancreatic ductal . /Cas9-based editing of genes affecting ECM composition in stem cells alters matrix properties in engineered tissues, offering potential for personalized regenerative therapies.

ECM in Diverse Organisms

In Animals

In animals, the extracellular matrix (ECM) exhibits remarkable diversity across tissues, tailored to specific mechanical and functional demands. In , the ECM is predominantly composed of mineralized collagen fibrils, primarily , which provide rigidity and tensile strength through crystal deposition, enabling load-bearing functions. ECM, in contrast, is rich in aggrecan proteoglycans and , forming a hydrated that resists compressive forces while allowing flexibility in joints. Vascular tissues feature lamellae within the ECM of arterial walls, facilitating and maintaining blood flow dynamics under pulsatile pressure. Evolutionarily, the ECM in animals shows deep conservation, with basement membranes—thin sheets of type IV collagen, laminins, and nidogens—present from sponges (Porifera) to mammals, underscoring their role in epithelial organization since the emergence of metazoa. Invertebrate ECMs are largely collagenous, as seen in the fibrous networks of cnidarians and echinoderms, though arthropods incorporate as a key in their exoskeletal matrices for structural reinforcement. This collagen-centric framework predates more complex innovations, highlighting progressive elaboration in multicellular animals. Comparatively, the ECM in fish scales consists of layered collagen and , which dictate skin innervation patterns and vascular distribution, differing from the mammalian where and fibers support dermal-epidermal interactions and . In regeneration, the limb ECM undergoes dynamic turnover, with matrix metalloproteinases degrading pre-existing structures to form a provisional matrix that guides formation and tissue repatterning, enabling scar-free regrowth absent in most mammals. Pre-metazoan origins of animal-like ECM are evident in , the clade including choanoflagellates, where ECM-like structures such as siliceous loricae and adhesive glycoproteins facilitate colonial aggregation and substrate adhesion, suggesting proto-ECM components that preceded full metazoan multicellularity.

In Plants and Fungi

In , the extracellular matrix is manifested primarily through the , a rigid structure that provides mechanical support and withstands to prevent cell rupture while enabling controlled expansion. Primary cell walls, formed during active growth, consist of microfibrils (15–40%) embedded in a matrix of hemicelluloses such as xyloglucans (20–30%) and pectic (30–50%), along with lesser amounts of arabinoxylans and structural proteins. Secondary cell walls, deposited in mature cells for enhanced rigidity, incorporate alongside and hemicelluloses, contributing to strength and overall plant architecture. Hydroxyproline-rich glycoproteins like extensins function as structural analogs to animal ECM proteins, cross-linking to reinforce wall integrity and extensibility during development. The apoplastic fluid in intercellular spaces contains secreted proteins, including cell wall-modifying enzymes, oxidoreductases, and stress-related factors, facilitating signaling and nutrient exchange akin to ECM functions. In fungi, the acts as the primary extracellular matrix, comprising a -β-glucan scaffold embedded with mannoproteins that form a protective outer layer. microfibrils and branched β-1,3-glucans constitute the inner rigid framework, cross-linked via β-1,6-glucans, while mannoproteins—glycoproteins with up to 50% content—provide and regulation. During hyphal growth, fungi secrete ECM-like matrices rich in and proteins, supporting formation and environmental adaptation. These matrices enable hyphal to substrates and host tissues, contrasting with the more dynamic, collagen-dominated animal ECM by emphasizing rigidity for osmotic stability and protection. Plant and fungal matrices share functional parallels with animal ECM in structural support and signaling but differ in composition and interaction mechanisms; for example, plants lack integrins and instead use wall-associated kinases (WAKs)—receptor-like kinases spanning the plasma membrane—to detect wall perturbations and trigger responses like cell expansion or defense. Recent post-2020 studies reveal dynamic roles in stress adaptation: in plants, apoplastic remodeling under drought involves peroxidase-mediated ROS modulation in the cell wall to maintain integrity and enhance tolerance, as seen in maize where ZmPrx25 regulates extracellular oxidative balance. In fungi, hyphal ECM secretions in biofilms bolster pathogenesis by encapsulating virulence factors and evading host immunity, with Paracoccidioides species demonstrating polysaccharide-rich matrices that promote tissue invasion.

History

Early Discoveries

In the late 18th and early 19th centuries, the foundations of understanding the extracellular matrix were laid through histological descriptions of s. French anatomist Marie François Xavier Bichat, often regarded as a pioneer of tissue pathology, systematically classified structures into 21 distinct tissue types in his 1801 Anatomie générale appliquée à la physiologie à la médecine, including "cellular tissue" which encompassed what is now identified as providing structural support to organs. Bichat's work, conducted without , emphasized the integration of these tissues in organ formation and pathology, shifting focus from organs to their compositional elements. Building on this, German pathologist advanced the concept in his seminal 1858 lectures compiled as Cellular Pathology, where he described the "ground substance" as an intercellular matrix originating from cells but distinct from them, serving as the medium in which cells are embedded. Virchow viewed this amorphous ground substance as a product of cellular activity, integral to tissue integrity and pathological changes, thereby integrating it into his cellular theory of disease. This recognition marked a pivotal shift, portraying the extracellular material not merely as passive filler but as a dynamic component influenced by cellular processes. Entering the early , improved optical techniques enabled more precise visualization of matrix components. In the 1920s, polarization revealed the fibrillar structure of , demonstrating its birefringent properties due to aligned molecular chains, which distinguished it from other tissue elements. This method, applied to connective tissues, highlighted 's organized, rope-like fibrils as key to tensile strength. Concurrently, was isolated in a relatively pure form in 1925 through studies, confirming its distinct and elastic properties separate from . Key contributions in the 1930s further characterized matrix elements. Pioneering cell biologist Albert Claude, through early tissue fractionation techniques at the Rockefeller Institute, developed methods for separating cellular components, laying groundwork for later understanding of matrix-cell interactions via . Simultaneously, the discovery of glycosaminoglycans (GAGs), then termed mucopolysaccharides, occurred in the 1930s when Karl Meyer and colleagues identified sulfated polysaccharides like in and other matrices, revealing their acidic, hydrated nature essential for tissue resilience. The advent of electron microscopy in the 1950s provided ultrastructural insights, particularly into basement membranes. Researchers such as David C. Pease and in 1950, followed by Krakower and Greenspon in 1951, used to visualize the as a distinct, electron-dense layer approximately 300-500 nm thick, separating epithelial and endothelial cells in renal tissues. These observations confirmed basement membranes as specialized matrix sheets composed of intertwined filaments, foundational to epithelial barriers. By the 1960s, the first purification of proteoglycans—complexes of GAGs bound to core proteins—was achieved, including isolations from bovine nasal cartilage, elucidating their macromolecular structure and role in matrix hydration.

Modern Advances

The marked a pivotal shift in extracellular matrix (ECM) research with the identification and sequencing of key glycoproteins, including the isolation of as a major basement membrane component in 1979. , first isolated from fibroblasts in the early , was sequenced through cDNA efforts that revealed its modular structure comprising repeating domains essential for and migration. By the late , partial sequencing confirmed fibronectin's role in linking cells to the ECM, laying groundwork for understanding tissue organization. The 1980s brought molecular breakthroughs, including the discovery of as transmembrane receptors mediating cell-ECM interactions. were first identified in the mid-1980s through studies on platelet aggregation and leukocyte adhesion, with the receptor (α5β1 integrin) cloned and shown to bind specific ECM motifs like the Arg-Gly-Asp sequence. Concurrently, matrix metalloproteinases (MMPs) were cloned, revealing their zinc-dependent proteolytic activity against ECM components such as and ; the first human MMP (MMP-1, ) cDNA was isolated in 1986, highlighting MMPs' role in ECM remodeling during development and . In the 1990s and 2000s, genetic models illuminated ECM functions in biology and tissue development. mice targeting ECM genes, such as the 1995 generation of β2-deficient mutants, demonstrated severe glomerular defects and , underscoring laminin's structural and signaling roles in basement membranes. These models, alongside studies showing ECM stiffness directing differentiation into lineages like osteoblasts on rigid substrates versus adipocytes on soft ones, established the ECM as a niche regulator of stem cell fate and self-renewal. The completion of the in 2003 accelerated ECM research by enabling comprehensive annotation of matrisome genes—over 1,000 protein-coding genes encoding ECM and ECM-associated proteins—facilitating genotype-phenotype mapping in diseases. This genomic resource supported large-scale analyses linking ECM variants to conditions like and cancer, transforming ECM from a structural scaffold to a dynamically regulated network. The saw the rise of technologies in ECM profiling, with approaches defining the matrisome across tissues. Mass spectrometry-based methods, refined since 2010, identified over 200 core matrisome proteins in human organs, revealing tissue-specific compositions and post-translational modifications that influence bioavailability and function. Mechanobiology advanced concurrently, with YAP/TAZ transcription factors emerging as key sensors of ECM mechanics; studies from 2011 onward showed that stiff ECM promotes YAP/TAZ nuclear translocation via integrin-actin linkages, driving proliferation and . Post-2020 developments integrated advanced tools for dissecting ECM dynamics. Single-molecule force spectroscopy using has quantified ECM protein unfolding forces, such as collagen's tensile strength exceeding 100 pN, providing atomic-scale insights into mechanical stability during tissue stress. models now simulate ECM remodeling, with algorithms predicting stiffness-induced signaling cascades and matrisome alterations in aging tissues based on multi-omics data. In , ECM dysregulation has been linked to , where fragmented collagens accumulate and impair rejuvenation; interventions modulating ECM composition show potential to extend lifespan in model organisms. Yoshinori Ohsumi's 2016 Nobel Prize in Physiology or Medicine for elucidating mechanisms has implications for ECM turnover, as contributes to degrading misfolded ECM proteins and regulating lysosomal pathways in fibroblasts to help prevent fibrotic accumulation. These advances underscore the ECM's integration with cellular , paving the way for targeted therapies in .

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