The extracellular matrix (ECM) is secreted by cells and surrounds them in tissues. It has long been understood to be the structural support for cells since its characteristics set the characteristics of the tissue (i.e. bone compared to cartilage compared to brain)1. However, instead of simply being a passive, mechanical support for cells, it is in fact an extraordinarily complex scaffold composed of a variety of biologically active molecules that are highly regulated and critical for determining the action and fate of the cells that it surrounds4.
The ECM has two basic forms:
The basement membrane (BM) is a thin layer of ECM that forms between the epithelia and endothelia. It surrounds muscle, fat, and nerve cells. It provides mechanical structure, separates different cell types, and signals for cell differentiation, migration, and survival6. A summary of the proteins in the basement membrane and their characterized cell surface receptors are given in Table 16.
The BM structure is thought to be set by laminin and collagen IV. Laminin has been shown to self assemble into polygonal lattices in vitro6. Likewise, collagen IV also self assembles in vitro through interactions between the carboxy-terminal NC1 (non-collagenase) domains and some slight interactions between the collagen triple helices6. The other protein components of the BM are thought to be non-covalently immobilized in the matrix formed by laminin and collagen IV6.
A form of the basement membrane is commercially available. It is derived from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma, a tumor that is rich in ECM proteins. Its major components are laminin, collagen IV, heparan sulfate proteoglycan, and nidogen/entactin. In addition to these proteins, there are a variety of growth factors present including bFGF, EGF, IGF-1, PDGF, NGF and TGF-ß1. This same tumor is the primary source for commercially available mouse laminin.
The ECM is a complex mixture of proteins and glycosaminoglycans (a class of negatively charged polysaccharides). It is composed of three categories of materials:
GAGs were originally primarily known for being “space fillers” in the ECM. More recently they have been shown to be active signaling molecules whose roles in a variety of cellular processes (including cytokine production, leukocyte recruitment and inflammatory response) are important for controlling cell fate7.
Glycosaminoglycans (GAGs) are linear polysaccharides composed of two basic saccharides: an amino sugar and an uronic acid 2,3. The amino sugar is typically either N-acetyl-D-glucosamine (D-GlcNAc) or N-acetyl-D-galactosamine (D-GalNAc). The uronic acid is either D-glucuronic acid (D-GlcA) or L-iduronic acid (L-IdoA)7. These basic components are further varied by epimerization, sulfation, and deacetylation. The order of the carbohydrate chain and the other chemical modifications determine their specificity and functionality7.
Hyaluronan is the simplest GAG since it is non-sulfated, doesn’t undergo epimerization, and is composed of an unmodified disaccharide repeat. It is also not typically covalently linked to any proteins. The other GAGs are chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), and heparan sulfate (HS). These four GAGs are typically covalently attached to proteins to form proteoglycans. Chondroitin and heparan sulfate are extensively modified by sulfation 1,2,3.
A proteoglycan is composed of a core protein with one or more covalently attached GAGs. They are stored in secretory granules, inserted into the plasma membrane or secreted into the ECM8. Table 2 lists several proteoglycans along with their molecular weight, GAG chains, and tissue localization.
Currently there are 15 known heterotrimeric laminins6. Laminin is composed of α, β, and γ chains of which there are 5 α, 4 β, and 6 γ chains2. It has a cross-like structure with 3 short arms and 1 long arm. The α chains possess a large globular domain known as the G domain at the C-termini. This domain is composed of 3 LG domains (LG1-LG3) connected by a linker region to two more LG domains (LG4-LG5). Integrins bind to LG1-3 and dystroglycan to LG4-LG5. Heparan sulfate has been shown to bind to LG4 of the α1 chain6. Laminin is a component of the basement matrix; however, the isoform of laminin present varies with the tissue2. The laminin-1 form is the most prominent in early development and is comprised of α1, β1, and γ1 chains6.
Fibronectin is a dimer with a molecular weight of ~270 kDa. It exists as a soluble form in blood and body fluids and in fibrils in the ECM. It binds collagen, heparin, other fibronectin proteins, and cell surface integrins. Fibronectin binds integrins through the tri-peptide motif of arginine, glycine, and aspartic acid (RGD)2,3.
Collagens are the major structural component of the ECM1. They are the most prevalent protein in the skin and bone, making up 25% of the total protein mass2. Collagens provide scaffolding for the attachment of laminin, proteoglycans and cell surface receptors1. Twenty-eight types of collagens (I–XXVIII) have been identified so far in vertebrates1. Collagens are triple helical proteins that are formed from either homotrimers or heterotrimers of polypeptide chains, referred to as α-chains. α-chains have a three amino acid repeat of Gly-X-Y, where X is typically proline and Y is 4-hydroxyproline (post-translationally modified proline)1,2.
Based on their supramolecular architectures, these types are divided in:
Elastin, as its name suggests, provides elasticity to the ECM. It is produced as tropoelastin, a 72 kDa precursor protein and is secreted from the cell. In the extracellular space, it crosslinks with other elastin molecules to form sheets and fibers. Elastin is the primary ECM protein present in arteries where it composes ~50% of their dry weight2.
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