In a broad sense, the extracellular matrix is the non-cellular component that appears in all tissues and organs of multicellular organisms. It is usually defined as a three-dimensional network of macromoleculesthat offers mechanical and biochemical support to the cells around it.
The processes that occur in the extracellular matrix regulate diverse cellular functions and are involved in numerous physiological and pathological processes. Its role is fundamental in the functioning of the organism.
Although the composition and structure is very different between different living beings, and even between different tissues, the extracellular matrix maintains common functions such as cell adhesion , cell-cell communication and the regulation of cell differentiation, migration and maturation .
Components and structure of the extracellular matrix
The extracellular matrix of the human body includes:
- Interstitial matrix : is the intercellular space, the space that remains between some cells and others within a tissue. It is occupied by a kind of aqueous gel of polysaccharides and fibrous proteins , together with other molecules dispersed in it, such as electrolytes, enzymes and chemical transmitters.
- Basal membrane : this membrane, generally considered part of the epithelial tissue , is formed by extracellular matrix depositions , especially proteins, and epithelial cells rest on it.
The extracellular matrix of each tissue has its own characteristics. They can be as different as the extracellular matrix of the bone tissue, which is hard and highly mineralized, or the blood plasma, which has a fluid matrix (blood can be considered a type of tissue, specifically a type of connective tissue ).
In some tissues, such as muscle tissue and nerve tissue, the extracellular matrix acquires a high degree of functional specialization.
The substances and components of the extracellular matrix are produced by the so-called resident cells , which are usually differentiated and specialized cells in each type of tissue, for example fibroblasts .
Among the main molecules that we can in the extracellular matrix, include glycosaminoglycans and proteoglycans , and fibrous proteins such as collagen or elastin .
In the extracellular matrix there are highly glycosylated proteins that are known as proteoglycans . The glucidic part of these molecules are glycosaminoglycans , a type of structural function polysaccharides.
Glycosaminoglycans, also known as glycosaminoglucuronans (IUPAC) or mucopolysaccharides , are long sugarchains formed by the repetition of two units of an amino sugar .
With the exception of hyaluronic acid, most glycosaminoglycans in the extracellular matrix are bound to proteins in the form of proteoglycans.
The proteoglycan molecules have a negative net electric charge , which causes sodium ions (Na + ) to adhere . These ions increase the osmotic pressure helping to retain waterand keep the extracellular matrix hydrated.
Among the most prominent glycosaminoglycans, we have heparan sulfate, chondroitin sulfate and keratin sulfate , present as proteoglycans, and hyaluronic acid , present in free form.
Heparan sulfate is a GAC ??that appears in high proportion as a proteoglycan. The main proteoglicans of heparan sulfate are perlecan , a specific proteoglycan of the basement membrane, agrin and collagen XVIII .
Heparan sulfate proteoglycans regulate processes involved in cell development and migration, such as angiogenesis, embryogenesis or even tumor metastasis.
Chondroitin sulfate proteoglycans contribute to the resistance of cartilage, tendons, ligaments and walls of blood vessels , especially the aorta and other large vessels. He also seems to be involved in neuroplasticity .
The proteoglycans of keratan sulfate, unlike other glycosaminoglycans, do not contain uronic acid . Kerathan sulfates are present especially in tissues such as the cornea and bones .
Hyaluronic acid is a glycosaminoglycan in the extracellular matrix that does not form proteoglycans . It consists of a polysaccharide in which D-glucuronic acid and N-acetylglucosamine alternate.
Hyaluronic acid absorbs and retains significant amounts of water , providing the tissues with the necessary turgor to resist compression and keep them hydrated.
Hyaluronic acid is found in large amounts in the extracellular matrix of tissues such as the skin or in the joints that support load.
It is also part of the gel that occupies the interstitial space and can also be found adhered to the cell surface, where it is able to interact with the transmembrane receptor CD44.
2. Fibers and proteins
The collagen is the most abundant protein in the extracellular matrix , in fact, is the most abundant protein in the entire human body, especially present in the hard tissue . In bone, for example, collagen accounts for up to 90% of the proteins in the extracellular matrix.
The collagen adopts a fibrillar structure that serves as support for the resident cells. Some diseases are due specifically to genetic alterations of collagen, for example osteogenesis imperfecta and epidermolysis bullosa.
If collagen provides resistance, elastin provides elasticity and allows the extracellular matrix to stretch if necessary and then return to the original state.
The elastin content varies considerably according to the tissue, being more abundant where more elasticity is needed, for example in blood vessels, lungs or skin.
Elastin is synthesized mainly by fibroblasts and muscle cells. The lack of elastin is involved in diseases such as cutis laxa or Williams syndrome.
Fibronectin is a group of glycoproteins that in the cellular matrix have a fundamentally mechanical function . They connect the cells with the collagen fibers allowing the movement of the cells through the extracellular matrix.
Other known functions of fibronectin is the retention of platelets to promote blood coagulation in the face of tissue damage that involves hemorrhage.
Laminin and its various types can be found in the basal lamina in virtually all animals. Laminin adopts a network structure, unlike collagen that adopts a fibrillar structure.
Laminin is involved in cell adhesion and adhesion of other components of the extracellular matrix, for example in the union of collagen and nidogens , other proteins of the basal lamina.
3. Extracellular nanovesicles
In the extracellular matrix can be found nanovesicles previously described as exosomes, whose content is very diverse: proteins, lipids or fragments of DNA and RNA .
Nanovesicles are currently considered as key components of the extracellular matrix. Among its functions, they regulate the activation state of macrophages and regulate cell proliferation and migration, although its mechanism of action is not completely known.
The nature and composition of the extracellular matrix gives it many functions that can be described in general:
- Tissue segregation
- Regulation of intercellular communication
Growth factors may be retained in the extracellular matrix. Before certain physiological changes, the cells of the zone release proteases that break the structure of the extracellular matrix, releasing those growth factors.
This allows a rapid and local activation of processes mediated by growth factors without the need for a new synthesis of these chemical mediators. Thus, the extracellular matrix intervenes in the regulation of the entire cell cycle .
The formation of extracellular matrix is ??in itself an essential process in the growth, development and repair of tissues , including wound healing, and is also involved in fibrosis and cancer invasion and metastasis.
These processes are not known exactly, but it is known that the cells are attached to the extracellular matrix and can move through it in a process known as durotaxis . The rigidity and elasticity of the extracellular matrix is ??fundamental in the durotaxis.
The rigidity and elasticity of the extracellular matrix also affects genetic expression , which has its impact on the processes of cell differentiation and proliferation, not only in normal processes, but also in neoplastic and carcinogenic processes.
Cell adhesion to the extracellular matrix
The adhesion of the cells to the extracellular matrix occurs through the so-called adhesion complexes , which can be of two forms:
- Focal adhesion : the cells are connected to the extracellular matrix through actin filaments.
- Hemidesmosomes : the cells are connected to the extracellular matrix through intermediate filaments of keratin. They are especially numerous in the union of cells to the basement membrane, and are very similar to the desmosomes that occur in the cell-cell junction.
Cell-matrix adhesion is regulated by the expression of integrins in the cell membrane. Integrins can bind to matrix proteins, such as fibronectins and laminins, but also to the surface integrins of other cells.
The union of the cells to the matrix is ??an elementary process in any multicellular organism. Integrins are not simple mechanical anchors to the matrix, but are capable of transmitting signals to the cellular interior, for example of growth factors and cytokines.
The role of rigidity and elasticity
The extracellular matrix can have an extremely variable stiffness and elasticity, from the soft tissue of the brain to the hard tissue of the bone, and it can also change within the same tissue according to the physiological state.
The degree of rigidity is closely related to the concentration of collagen and elastin , and is a property that regulates numerous cellular functions involved in migration, differentiation, proliferation and cell death.
- Effect on gene expression : it is not known how it is produced, but the mechanical properties of the extracellular matrix affect gene expression and behavior. Changes in stiffness and elasticity of the extracellular matrix is ??perceived through adhesion complexes. Through the integrins, the contractile forces are transmitted to the actin-myosin fibers of the cytoskeleton. This field of cell biology is still very unknown.
- Effect on cell differentiation : celldifferentiation, a process in which one type of cell is transformed into another type, is a very complex process regulated by numerous factors. In some circumstances it has been seen that tissue stiffness and elasticity is a fundamental factor; for example, in the differentiation of mesenchymal stem cells .
- Durotaxis : the durotaxis is a cell migration process guided by a gradient in the rigidity and elasticity of the extracellular matrix. Each individual cell of a tissue tends to move towards areas of greater rigidity. In the molecular mechanism involved the adhesion complexes, including integrins and signaling proteins, such as PTK2, talin, vinculin or various GTPases, which cause changes in the actomyosin contractility of the cytoskeleton.