Illustration depicting extracellular matrix (basement membrane and interstitial matrix) in relation to epithelium, endothelium and connective tissue

In biology, the extracellular matrix (ECM) is the extracellular part of animal tissue that usually provides structural support to the cells in addition to performing various other important functions. The basement membrane is a structure that supports overlying Epithelial or Endothelial cells. In biology and medicine epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughout the body The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the Connective tissue is one of the four types of tissue in traditional classifications (the others being epithelial, Muscle, and Nervous tissue) Foundations of modern biology There are five unifying principles In Cell biology, Molecular biology and related fields the word extracellular (or sometimes extracellular space) means "outside the cell The cell is the structural and functional unit of all known living Organisms It is the smallest unit of an organism that is classified as living and is often called The extracellular matrix is the defining feature of connective tissue in animals. Connective tissue is one of the four types of tissue in traditional classifications (the others being epithelial, Muscle, and Nervous tissue)

Extracellular matrix includes the interstitial matrix and the basement membrane. The basement membrane is a structure that supports overlying Epithelial or Endothelial cells. ^[1] Interstitial matrix is present between various 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. Polysaccharides are relatively complex Carbohydrates They are Polymers made up of many Monosaccharides joined together by Glycosidic bonds ^[2] Basement membranes are sheet-like depositions of ECM on which various epithelial cells rest. In biology and medicine epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughout the body

Role and importance

Due to its diverse nature and composition, the ECM can serve many functions, such as providing support and anchorage for cells, segregating tissues from one another, and regulating intercellular communication. The ECM regulates a cell's dynamic behavior. In addition, it sequesters a wide range of cellular growth factors, and acts as a local depot for them. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. ^[1] Changes in physiological conditions can trigger protease activities that cause local release of such depots. A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link This allows the rapid and local growth factor-mediated activation of cellular functions, without de novo synthesis. De novo is a Latin phrase, meaning "from the new" anew or from the beginning

Formation of the extracellular matrix is essential for processes like growth, wound healing and fibrosis. Wound healing, or wound repair, is the body's natural process of regenerating dermal and epidermal tissue. Fibrosis is the formation or development of excess fibrous Connective tissue in an organ or tissue as a reparative or reactive process as opposed to a formation of Fibrous An understanding of ECM structure and composition also helps in comprehending the complex dynamics of tumor invasion and metastasis in cancer biology^[1] as metastasis often involves the destruction of extracellular matrix^[3] by enzymes such as serine and Threonine proteases and Matrix metalloproteinase. See also Cancer A tumor or tumour is the name for a swelling or lesion formed by an abnormal growth of cells (termed neoplastic Metastasis ( Greek: displacement μετά=next + στάσις=placement, plural metastases) sometimes abbreviated mets, Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled Serine proteases or serine endopeptidases (newer name are Proteases ( Enzymes that cut Peptide bonds in Proteins in which one of Matrix metalloproteinases (MMPs are Zinc -dependent Endopeptidases other family members are Adamalysins Serralysins and Astacins ^[1]

Molecular components

Components of the ECM are produced intracellularly by resident cells, and secreted into the ECM via exocytosis. Exocytosis (ek-soh-sy-TOH-sis Greek: Έξω - external and κύτος - cell is the durable process by which a cell directs secretory vesicles out of the Cell ^[4] Once secreted they then aggregate with the existing matrix. The ECM is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs). Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Glycosaminoglycans (GAGs or mucopolysaccharides are long unbranched Polysaccharides consisting of a repeating Disaccharide unit

Proteoglycan matrix components

GAGs are carbohydrate polymers and are usually attached to extracellular matrix proteins to form proteoglycans (hyaluronic acid is a notable exception, see below). Glycosaminoglycans (GAGs or mucopolysaccharides are long unbranched Polysaccharides consisting of a repeating Disaccharide unit A polymer is a large Molecule ( Macromolecule) composed of repeating Structural units typically connected by Covalent Chemical bonds Proteoglycans represent a special class of Glycoproteins that are heavily glycosylated. Proteoglycans have a net negative charge that attracts water molecules, keeping the ECM and resident cells hydrated. Proteoglycans may also help to trap and store growth factors within the ECM. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation.

Described below are the different types of proteoglycan found within the extracellular matrix.

Heparan sulfate proteoglycans

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. Heparan sulfate (HS is a linear Polysaccharide found in all animal tissues Polysaccharides are relatively complex Carbohydrates They are Polymers made up of many Monosaccharides joined together by Glycosidic bonds It occurs as a proteoglycan (PG) in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. Proteoglycans represent a special class of Glycoproteins that are heavily glycosylated. ^[5][6] 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 Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally Angiogenesis is a physiological process involving the growth of new Blood vessels from pre-existing vessels Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby Metastasis ( Greek: displacement μετά=next + στάσις=placement, plural metastases) sometimes abbreviated mets,

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. The basement membrane is a structure that supports overlying Epithelial or Endothelial cells. A protein domain is a part of protein sequence and structure that can evolve, function and exist independently of the rest of the protein chain Heparan sulfate proteoglycan 2 ( HSPG2) is a human Gene which encodes the perlecan Protein. Agrin is a large Proteoglycan whose best characterised role is in the development of the Neuromuscular junction during Embryogenesis. Type XVIII collagen is a type of Collagen which can be cleaved to form Endostatin.

Chondroitin sulfate proteoglycans

Chondroitin sulfates contribute to the tensile strength of cartilage, tendons, ligaments and walls of the aorta. Chondroitin sulfate is a sulfated Glycosaminoglycan (GAG composed of a chain of alternating sugars ( N-acetylgalactosamine and Glucuronic acid) A tendon (or sinew) is a tough band of Fibrous connective tissue that usually connects Muscle to Bone and is capable of withstanding tension In Anatomy, the term ligament is used to denote three different types of structures Fibrous tissue that connects Bones to other bones They have also been known to affect neuroplasticity. Neuroplasticity (variously referred to as brain plasticity, cortical plasticity or cortical re-mapping) refers to the changes that occur in ^[7]

Keratan sulfate proteoglycans

Keratan sulfates have a variable sulfate content and unlike many other GAGs, does not contain uronic acid. Keratan sulfate (KS also called keratosulfate, is any of several sulfated Glycosaminoglycans (structural carbohydrates that have been found especially A uronic acid is a Sugar Acid with both a Carbonyl and a Carboxylic acid function It is present in the cornea, cartilage, bones and the horns of animals. The cornea is the transparent front part of the Eye that covers the iris, Pupil, and Anterior chamber. Bones are rigid organs that form part of the Endoskeleton of Vertebrates They function to move support and protect the various organs of the body produce A horn is a pointed projection of the Skin on the head of various Mammals consisting of a covering of horn ( Keratin and other Proteins

Non-proteoglycan matrix components

Hyaluronic acid

Hyaluronic acid (or "hyaluronan") is a polysaccharide consisting of alternative residues of D-glucuronic acid and N-acetylglucosamine, and unlike other GAGs is not found as a proteoglycan. Hyaluronan (also called hyaluronic acid or hyaluronate) is a non-sulfated Glycosaminoglycan distributed widely throughout connective, epithelial Polysaccharides are relatively complex Carbohydrates They are Polymers made up of many Monosaccharides joined together by Glycosidic bonds Hyaluronic acid in the extracellular space confers upon tissues the ability to resist compression by providing a counteracting turgor (swelling) force by absorbing a lot of water. ' Turgor pressure' or turgidity is the main pressure of the cell contents against the Cell wall in Plant cells and bacteria cells determined by the 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. ^[8]

Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes, inflammation and tumor development. Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens See also Cancer A tumor or tumour is the name for a swelling or lesion formed by an abnormal growth of cells (termed neoplastic It interacts with a specific transmembrane receptor, CD44. The CD44 Protein is a cell -surface Glycoprotein involved in cell-cell interactions cell adhesion and migration ^[9]

Collagen

Collagens are, in most animals, the most abundant glycoproteins in the ECM. Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein In fact, collagen is the most abundant protein in the human body^[10][11] and accounts for 90% of bone matrix protein content. ^[12] 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 proteinases to allow extracellular assembly. Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link Diseases such as osteogenesis imperfecta and epidermolysis bullosa are linked with genetic defects in collagen-encoding genes. Osteogenesis imperfecta ( OI and sometimes known as Brittle Bone Disease) is a genetic bone disorder Epidermolysis Bullosa ( EB) is a rare Genetic disease characterized by the presence of extremely fragile Skin and recurrent Blister A genetic disorder is a condition caused by abnormalities in Genes or Chromosomes While some diseases such as Cancer, are due to genetic abnormalities acquired History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance ^[4]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

Fibronectin

Fibronectins are proteins that connect cells with collagen fibers in the ECM, allowing cells to move through the ECM. Fibronectin is a high-molecular-weight extracellular matrix Glycoprotein containing about 5% Carbohydrate that binds to membrane spanning Receptor proteins Fibronectins bind collagen and cell surface integrins, causing a reorganization of the cell's cytoskeleton and facilitating cell movement. Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. cytoskeleton (also CSK is a cellular " Scaffolding " or " Skeleton " contained within the Cytoplasm. 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. A dimer is a Chemical or Biological entity consisting of two subunits called Monomers which are held together by either Intramolecular forces 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. Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby ^[4]

Elastin

Elastins, in contrast to collagens, give elasticity to tissues, allowing them to stretch when needed and then return to their original state. Elastin is a Protein in Connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting This is useful in blood vessels, the lungs and in skin, and these organs contain high amounts of elastins. The blood vessels are part of the Circulatory system and function to transport Blood throughout the body lung is the essential Respiration organ in air-breathing Animals including most Tetrapods a few Fish and a few Snails The most primitive The skin is the outer covering of living tissue of an animal (or plant Elastins are synthesized by fibroblasts and smooth muscle cells. A fibroblast is a type of cell that synthesizes and maintains the Extracellular matrix of many Animal tissues Smooth muscle is a type of non- Striated muscle, found within the Tunica media layer of large and small Arteries and Veins, the bladder 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. Tropoelastin is a water-soluble Molecule with a Molecular weight of approximately 70000 daltons. This article is about the protein For other uses see Chaperone, a disambiguation page Tropoelastins are then deaminated to become incorporated into the elastin strand. Diseases such as cutis laxa and Williams syndrome are associated with deficient or absent elastin fibers in the ECM. Cutis laxa (also called elastolysis) is a group of rare Connective tissue disorders in which the Skin becomes inelastic and hangs loosely in folds Williams syndrome ( WS; also Williams-Beuren syndrome or WBS) is a rare Neurodevelopmental disorder caused by a deletion of about 26 genes from ^[4]

Laminin

Laminins are proteins found in the basal laminae of virtually all animals. Laminin is the major non-collagenous component of the Basal lamina, such as those on which cells of an Epithelium sit The basal lamina is a layer of extracellular matrix on which Epithelium sits and which is secreted by the epithelial cells 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, nidogens, and entactins. Entactin (or nidogen) is a component of the Basement membrane alongside other components such as Collagen type IV Proteoglycans ( heparan sulfate ^[4]

Cell adhesion to the ECM

Many cells bind to components of the extracellular matrix. This cell-to-ECM adhesion is regulated by specific cell surface cellular adhesion molecules (CAM) known as integrins. Cell Adhesion Molecules ( CAM s are Proteins located on the cell surface involved with the Binding with other cells or with the Extracellular Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. 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 signaling pathways as well as association with the cellular cytoskeleton via a set of adaptor molecules such as actin. Actin is a globular roughly 42-kDa Protein found in all eukaryotic cells (except for Nematode sperm where it may be present at concentrations of ^[2]

Cell types involved in ECM formation

There are many cell types that contribute to the development of the various types of extracellular matrix found in 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. A fibroblast is a type of cell that synthesizes and maintains the Extracellular matrix of many Animal tissues Ground substance is a term for the non-collagenous components of Extracellular matrix. Chondrocytes are found in cartilage and produce the cartilagenous matrix. Chondrocytes (from Greek chondros cartilage + kytos cell are the only cells found in Cartilage. Cartilage is a type of dense Connective tissue. It is composed of specialized cells called chondrocytes that produce a large amount of extracellular matrix Osteoblasts are responsible for bone formation. An osteoblast (from the Greek words for " Bone " and "germ" or embryonic is a mononucleate cell that is responsible for bone formation

Extracellular matrix in plants

Plant cells are tesselated to form tissues. The cell wall is the relatively rigid structure surrounding the plant cell. A cell wall is a tough flexible and sometimes fairly rigid layer surrounding a cell, located external to the Cell membrane, which provides the cell with structural The cell wall provides lateral strength to resist osmotic turgor pressure, but 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 such as hemicellulose, pectin, and extensin. Cellulose is an Organic compound with the formula, a Polysaccharide consisting of a linear chain of several hundred to over ten thousand β(1→4 The microfibril is a very fine Fibril, or fiber-like strand consisting of Glycoproteins. A hemicellulose can be any of several Heteropolymers (matrix polysaccharides present in almost all plant cell walls along with Cellulose. Pectin (from Greek πηκτικός - pektikos, "congealed curdled" a white to light brown powder is a Heteropolysaccharide Extensin was discovered by Derek TA Lamport at Cambridge University they are hydroxyproline-rich glycoproteins (HRGPs of the plant cell wall 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. A semipermeable membrane, also termed a selectively-permeable membrane, a partially-permeable membrane or a differentially-permeable membrane, is a membrane 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. ^[8]

Medical Applications

Extracellular Matrix cells have been found to cause regrowth and healing of tissue. 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.

In terms of injury repair and tissue engineering, the extracellular matrix serves two main purposes. Tissue engineering is the use of a combination of cells Engineering and materials methods and suitable biochemical and 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.

For medical applications, the cells required are 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. ^[13]

References

External links

• MeSH Extracellular+matrix
• ANAT3231 Lecture 08 Extracellular Matrix - Lecture about extracellular matrix from UNSW Cell Biology website. Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books
• Extracellular matrix: review of its roles in acute and chronic wounds
• Usage of Extracellular Matrix from pigs to regrow human extremities
• "The Extracellular Matrix of Animals", from Chapter 19 of The Molecular Biology of the Cell, 4th edition, Alberts et al.
• Biology, John W. Kimball. An online Biology textbook.
• [1], The man who grew a finger, By Matthew Price, BBC News