The extracellular matrix ( extracellular matrix , intercellular substance , EZM ; English extracellular matrix , ECM ) is the tissue (especially in the connective tissue ) that lies between the cells in the so-called intercellular space . The extracellular matrix is made up of various components, which are divided into two large groups: basic substance and fibers. The ratio of the basic substance to the fiber content fluctuates depending on the location, as does the amount of the extracellular matrix in the tissue as a whole, depending on its respective function.
In the case of plants, one does not speak of an extracellular matrix, even if these also have a substance-filled intercellular space.
Initially - in simplified terms - the main components of the extracellular matrix were only assigned a function as “glue” (from which collagen ) or as a tissue-internal water store ( mucopolysaccharides , proteoglycans ). According to today's perspective, the ECM comprises the totality of macromolecules that are located outside the plasma membrane of cells in tissues and organs. Thus, on the surface, the ECM serves primarily as a means of fixing the cells of all tissue animals embedded in it . However, there is always a reciprocal interaction between cells and ECM. The ECM is not static, but has to be understood at the molecular level as being in steady state . The components of the ECM are synthesized and secreted by cells, partly first fixed extracellularly via further bonds and finally degraded extracellularly or intracellularly after endocytosis . In addition, the binding to certain components of the ECM through cell receptors regulates the expression of genes in the cells. Cell adhesion , cell migration , cell proliferation as well as the build-up, remodeling and degradation of tissue result from the mutual influence that happens to the ECM and cells. So z. B. Molecules that are present as structuring proteins represent messenger substances under different conditions. In the framework of the Gordon Conference for Proteoglycans in 1998, an appropriate characterization of these properties of ECM components was coined. They were called demiurg ( after Plato : the world builder acts in and through the logos ).
Macroscopic examples are the mineralized matrix of the bone, the pressure-elastic substance of the cartilage or the tight fibers of the tendons ; microscopically, the ECM is omnipresent throughout the body, almost every tissue is held together by ECM, for example every muscle fiber or every fat cell is wrapped in reticular fibers, the epithelium on every surface of the body sits on a basal lamina , which is also part of the ECM.
The following functions or interactions in various tissues and organs result from the properties of the ECM:
- Shaping of tissues and organs
- Water content of tissues
- Elasticity of tissues
- Tensile strength and stability of bones, tendons and ligaments
- Cytokine reservoir
- Signal transduction in tissues
- Anchoring and polarity specification for cells
- Influence on wound healing processes
- Filter performance of the kidneys due to their special basement membranes
The breakdown and remodeling of the ECM is mainly done by matrix metalloproteinases (MMP) , of which over 20 have been identified so far. These zinc-containing enzymes are either secreted into the ECM by corresponding cells or are located on the cell membranes (MT-MMP, membrane type MMP), with the catalytic center of the enzyme protruding into the extracellular space. These enzymes can initially be inactive precursors , which are converted into the active enzyme by splitting off a peptide ( zymogen activation ). Different MMPs also have different substrate specificities. The MMPs have diverse biological meanings, for example it is known that tumor tissue which secrete MMP-2, MMP-9 and MMP-14 have a particular tendency to metastasize, since the expressed MMPs support the breakdown of basement membranes and the construction of the tumor's own blood vessels.
Corresponding to the MMPs, there are tissue inhibitors of metalloproteinases (TIMP). These proteins sterically inhibit the activity of the MMPs through specific binding to their catalytic centers. This allows the degradation and remodeling of the tissue to be modulated by MMPs. So far, four different TIMPs are known. They are secreted as soluble proteins in the ECM by appropriate cells. TIMP-3 is an exception here. In the ECM, this protein is primarily bound to heparan sulfate proteoglycans and permanently sequestered in the ECM (e.g. in the Bruch's membrane of the eye ).
The ECM consists of fibrous components (fibers) and liquid with the substances dissolved in it (basic substance). In terms of quantity, there are various glycoproteins and polysaccharides in addition to water . There are also nutrients (e.g. amino acids , glucose ), tissue hormones and electrolytes .
The predominant family of proteins is that of collagens , which make up various types of fibers and are present in almost every tissue. Elastic fibers are made from the proteins fibrillin and elastin . There is also a wide variety of adhesion matrix proteins that connect the cells to the ECM.
The second large group are carbohydrates , especially glycosaminoglycans , long-chain polysaccharides of very specific individual components. The glycosaminoglycans associate with proteins and form even larger macromolecules, the proteoglycans . The characteristics of the ECM result from the diversity and interactions of proteins, glycosaminoglycans and proteoglycans.
In the bone in particular, the ECM contains inorganic components, the hydroxylapatite crystals , which give the bone its compressive strength.
27 different proteins from the protein family of collagens are known (collagen I to collagen XXVII). They can be differentiated according to the way in which they associate with one another or with other components. Some of the members of the collagen family are listed below. The collagens I to IV are widespread, the structures formed from them are discussed below.
Fibrillary collagens: Type I, II, III, V and XI collagens
Network-forming collagens: Type IV (basement membrane!), VIII and X collagens
Fibril-associated collagens (FACIT): Type IX, XII and XIV collagens
String of pearls collagens: Type VI collagen
Anchoring fibrils : Type VII collagen
Collagens with transmembrane domains: collagens of type XIII and XVII
The nomenclature is misleading on one point: Only the fibers made from collagen I are called collagen fibers ; other structures, e.g. B. reticular fibers are made up of a protein from the collagen family (in this example collagen III), but are not referred to as collagen fibers . Collagen IV, together with the laminins , entactin and the proteoglycan Perlecan, form basement membranes .
Collagen fibers give the tissue tensile strength. The 2–20 µm thick fibers consist of collagen fibrils (diameter up to 130 nm), which in turn are made up of collagen I molecules .
The collagen fibers are tensile in their longitudinal direction, they can hardly be stretched. Each connective tissue that is subjected to tensile stress contains collagen fibers that are aligned in the direction of the stress. If a tissue is stressed in every direction, the fibers are braided ( dermis , sclera , cornea , muscle fascia , dura mater , stratum fibrosum of the joint capsules ), if stress in only one direction, the fibers are aligned in parallel (especially tendons , ligaments ), and collagen fibers also ensure tensile strength in bones and dentin (dentin) ( glass bone disease !).
Reticular fibers consist of thin bundles (1 µm) of fibrils of a collagen that forms thinner fibrils than collagen I, namely collagen III. These bundles form microscopic networks or grids. Reticular fibers are widespread; they form networks under many basal laminae, around all capillaries, muscle fibers, peripheral nerve fibers, fat cells and every cell of the smooth muscle. They are the determining components of the ECM in the reticular connective tissue .
Elastic fibers have an extraordinary property, namely reversible stretchability. They are made up of thin fibrils of the protein fibrillin and - aligned with them - an amorphous substance made from the protein elastin . A fiber is approximately 2 µm in diameter. Elastic fibers are always associated with collagen fibers in order not to be overstretched themselves and vice versa to bring the collagen fibers back into their original position. In particular, elastic fibers occur in elastic connective tissue and in elastic cartilage, but also, depending on the degree of elasticity required, in many other tissues.
The basic substance is the unformed part of the extracellular matrix. It fills the space between the fibers that appears empty in the histological sectional image. It is composed very heterogeneously.
Glycosaminoglycans and proteoglycans
Glycosaminoglycans (GAGs), long-chain polysaccharides made from disaccharide units of certain sugars, are found in large quantities in the ECM. The following should be mentioned here: hyaluronic acid , heparan sulfate , dermatan sulfate , chondroitin sulfate and keratan sulfate . Except for hyaluronic acid, all GAGs are bound to proteins and thus form proteoglycans . The role of proteoglycans and GAGs for the capabilities of the ECM becomes particularly clear in cartilage. They can bind a lot of water and are therefore important for the properties of the respective ECM. Proteoglycans have a decisive influence on the self-assembly of collagens (fibrillogenesis). In addition, proteoglycans often mediate the interactions between other matrix proteins. Ultimately, it should be noted that the proteoglycans can also bind messenger substances and other proteins of different functionality (e.g. TGF- beta, TIMP-3 etc.) in the ECM and the pericellular matrix. They thus exert a great influence on the behavior of cells and are involved in the formation, breakdown and remodeling of tissues (e.g. wound healing , angiogenesis , arteriosclerosis , fibrosis , dissemination of tumor cells in the event of metastasis, etc.).
Almost all cells have receptors with which they come into contact with the ECM. Different adhesion proteins, adapter proteins or other adhesive proteins are often used, which are themselves part of the ECM and on the one hand interact with other components of the matrix and on the other hand with the cell receptors. There is a large variety of glycoproteins , as an example the protein family of the laminins , as further well-known examples the glycoproteins vitronectin and fibronectin .
Frequently used receptors, which are of great importance for cell adhesion, are the integrins . In most integrins, alpha- and beta-subunits of the integrin jointly recognize a corresponding amino acid binding sequence in the protein portion of the ECM components. Probably the best known recognition sequence that is used on matrix proteins by the integrins for cell binding is the RGD sequence (arginine-glycine-aspartate). In addition, a large number of cell binding sequences have been identified in the ECM. Various alpha and beta integrins, which mediate further specific cell bonds to ECM components, could also be described.
- Shirley Ayad, Ray Boot-Handford, Martin J. Humphries, Karl E. Kadler, C. Adrian Shuttleworth: The Extracellular Matrix. FactsBook. 2nd edition. Academic Press, London et al. 1998, ISBN 0-12-068911-1 , p. 3 ff.