Chondroitin sulfates contribute to the tensile strength of cartilage, tendons , ligaments , and walls of the aorta. They have also been known to affect neuroplasticity. 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. 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. 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, CD Collagens are the most abundant protein in the ECM. 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. 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. In , Huleihel et al.
Similar to ECM bioscaffolds, MBVs can modify the activation state of macrophages and alter different cellular properties such as; proliferation, migration and cell cycle. Fibronectins are glycoproteins that connect cells with collagen fibers in the ECM, allowing cells to move through the ECM.
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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.
Laminins are proteins found in the basal laminae of virtually all animals.
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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. 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. 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. 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 concentration,  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.
Differing mechanical properties in ECM exert effects on both cell behaviour and gene expression. 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.
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 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. 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  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. 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. This allows the rapid and local growth factor-mediated activation of cellular functions without de novo synthesis. 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.
The stiffness and elasticity of the ECM has important implications in cell migration , gene expression,  and differentiation. 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. 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 signalling pathways as well as association with the cellular cytoskeleton via a set of adaptor molecules such as actin. 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. 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. First, it prevents the immune system from triggering from the injury and responding with inflammation and scar tissue.
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Next, it facilitates the surrounding cells to repair the tissue instead of forming scar tissue. For medical applications, the ECM required 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.
Government for wounded soldier applications. As of early , 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. 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. 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. A class of biomaterials derived from processing human or animal tissues to retain portions of the extracellular matrix are called ECM Biomaterial. 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 major enzymes responsible for the ECM breakdown under physiological conditions are matrix metalloproteinases MMPs, or matrixins , which belong to a family of zinc-dependent and calcium-activated neutral endopeptidases, comprising secreted and membrane-associated members. MMPs are involved in degradation of the ECM and basement membrane; however, they also cleave a variety of other ECM-related proteins, including cytokines, chemokines, and growth factors [ 6 ]. A good example is TIMP-2, which regulates beta1 integrin expression and the size of myotubes formed during myoblast differentiation [ 7 ].
MMPs play an important role in skeletal muscle cell growth and differentiation, as they are engaged in release and activation of cytokines and growth factors. The main contributors to ECM assembly in skeletal muscle are resident fibroblasts; however, muscle cells also synthesize and secrete numerous ECM components and ECM-related molecules, suggesting their active and direct participation in ECM remodeling.
Thus, the composition of the ECM exerts mechanical, metabolic, hemodynamic, and angiogenic effects in skeletal muscle tissue. The extracellular matrix and its receptors also provide an appropriate and permissive environment for muscle development and some ECM components, in addition to muscle-specific factors, can serve as good indicators of skeletal muscle functioning. This chapter summarizes current knowledge on the role of ECM components related to skeletal muscle development and regeneration, which is of great importance for potential therapeutic interventions.
It also focuses on the contribution of ECM in motor and metabolic functions of skeletal muscle tissue. Finally, the attention is paid on potential implications of changes in ECM assembly and function in health and disease. Fetal stage is crucial for skeletal muscle development, when muscle fibers are formed by fusion of mesodermal progenitor cells, myoblasts. During postnatal period, the number of myofibers remains constant; however, the size of each myofiber can increase by fusion with muscle stem cells, called satellite cells.
Skeletal muscle is one of the most adaptive tissues in the body, and the adult regenerative myogenesis after muscle injury depends on satellite cells. These cells are normally quiescent, but in response to overloading or muscle damage, they become activated; that is, they begin to proliferate, and their progeny myoblasts terminally differentiate and fuse with one another or with existing myofibers to restore the contractile muscle apparatus and normal tissue architecture [ 8 ].
Proper muscle regeneration depends on the cross-talk between the satellite cells and their microenvironment cell niche.