Extracellular Matrix (ECM)

The extracellular matrix (ECM) is a complex structural entity that surrounds and supports the cells within living systems. In mammalian tissues the ECM is most commonly found in connective tissues such as tendon, cartilage, bone or dermis of the skin. Changes in the amount and organization of the ECM components change the type and form of the ECM. The ECM is produced and maintained by the cells that inhabit it. The proteins within the ECM can be divided into several classes based upon their structure and function within the ECM. The most prominent class is the structural class of ECM proteins. These consist primarily of the collagen and elastin families of proteins.
Collagen fibers strengthen and organize the matrix; elastin fibers provide flexibility and resilience. Proteins such as fibronectin, laminin, and tenascin serve less of a structural role and more of an adhesive or integral role within the ECM matrix; these proteins allow for cell attachment and form crosslinks within the matrix gel. Finally, numerous proteoglycans and heparan sulfate containing proteins form the highly hydrated gel-like mixture that helps stabilize the matrix within its aqueous environment. The Millipore line of ECM proteins, antibodies and kits has grown to be the most complete line available. Millipore's dedication to matrix research is backed by extensive in-house resources and over a decade of experience making ECM products.

Collagen is the main protein component of connective tissues and basement membrane, and occurs in a number of forms (Type I-XVIII) that vary in their tensile strength and tissue localization. Rigid or flexible structure and structural changes in many body tissues are often a result of changes in collagen composition, as is cellular restriction and compartmentalization. One area of intense interest is the basement membrane surrounding the blood vessel endothelium, a thin specialized network of extracellular matrix (ECM) proteins that serves many functions. Composed of proteins and proteoglycans, such as collagen, laminin, entactin, fibronectin, heparin sulfate and perlecan, this membrane acts as a physical barrier between the epithelium and underlying tissues. It provides cell surface anchorage (via integrins, receptor kinases, and cell surface proteoglycans), induces cellular differentiation, gives architectural support, and limits the migration of normal cells. The ability of tumor cells to degrade the ECM components of the basement membrane and surrounding tissues is directly correlated with metastatic potential. By releasing proteolytic enzymes (e.g. MMP collagenases, plasminogen activators, cathepsins), cancer cells are able to breach the membrane and penetrate the blood vessel wall. Collagen, the primary structural element of the basement membrane and tissue scaffolding protein, represents the main deterrent in the migration of tumor cells.

Formalin-fixed paraffin-embedded equine skin containing bovine collagen implant stained with rabbit anti-Collagen Type I (Millipore cat. no. AB758) Bovine collagen = brown staining Native collagen = colorless

Chicken Embryonic Fibroblast cells invading out of tissue into 3D Collagen. Actin is shown in green

Actin cytoskeleton (red) of Cos-7 cells spread in 3D Collagen. The nucleus is shown in purple.

Actin cytoskeleton (red) of apoptotic cells captured in 3D Collagen. The nucleus is shown in purple.

Mouse anti-Procollagen Type I, (Millipore cat. no. MAB1912) staining of normal skin.

Lumina (arrow) and invasive sprouts of HUVEC sandwiched within Fibrin gel (Millipore cat. no. ECM630) and incubated for 72 hours in media supplemented with bFGF, VEGF and PMA (32X magnification).

Fibronectin

Fibronectin is an important high molecular weight glycoprotein that binds integrins as well as components of the extracellular matrix (ECM) including collagen, fibrin, and heparin. Fibronectin can be found in the blood plasma in its soluble form, which is composed of two 250 kDa subunits joined together by disulfide bonds. The insoluble form that was formerly called cold-insoluble globulin is a large complex of cross-linked subunits. There are several main isoforms of fibronectin, all of which are the product of a single gene. The structure of these isoforms are made of three types of repeated internal regions called I, II and III that exhibit different lengths and presence or absence of disulfide bonds. Alternative splicing of the pre-mRNA leads to the combination of these three types of regions but also to a variable region. Fibronectin is involved in the wound healing process and so can be used as a therapeutic agent. It is also one of the few proteins for which production increases with age without any associated pathology. In addition, polymeric forms of fibronectin inhibit tumor growth, angiogenesis and metastasis.

Laminin

Laminin is a large, noncollagenous, basement membrane glycoprotein with diverse biological functions including differentiation, migration, and adhesion of normal and tumor cells. The protein is complex, consisting of three different polypeptide chains (a b g) that are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. The a-2 chain is a subunit of laminin-2 (merosin) and laminin-4 (S-merosin). Its cell binding ability (via membranebound integrin receptors) makes laminin an effective substrate coating for stimulating and enhancing cell migration and neurite outgrowth. In laminin from placenta, the A chain is replaced with merosin, and in laminin found near the neuromuscular junction, the B1 chain is replaced by s-laminin (synapse laminin).

A number of laminin subtypes have now been identified with varied binding properties. For example, laminin-5 is a basement membrane extracellular matrix macromolecule that provides an attachment substrate for both adhesion and migration in a wide variety of cell types, including epithelial cells, fibroblasts, neurons and leukocytes. Laminin-5 is a preferred adhesion substrate for epithelial cells (Koshikawa et al., 2001). Compared to fibronectin, collagen, or vitronectin, cells of epithelial origin will adhere to laminin-5 faster and will spread to a larger extent. Furthermore, laminin-5 protein can be used, in most applications, at coating concentrations in the 1 ìg/mL or lower range, which is approximately 10-fold lower than most other extracellular matrix macromolecules (Koshikawa et al., 2000).

Laminin Protein

Mouse anti-Laminin-5 (Epiligrin) (Millipore cat. no. MAB1947) staining of human colon carcinoma.

Merosin (Laminin-2)

Merosin is a basement membrane-associated ECM protein, similar in size and structure to other laminins. Merosin is found in placenta, peripheral nerve, and is the predominant laminin variant in skeletal muscle basement membranes. Defects in the protein result in a devastating form of congenital muscular dystrophy (MDC1A). The protein structure consists of three laminin chains (a b g) . Merosin forms a link between the peripheral membrane protein a-dystroglycan and the basal lamina. Binding to cells via a high affinity receptor, merosin and other laminins are thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Tenascin

The tenascin family of cell adhesion matrix glycoproteins is involved in diverse substrate-adhesion interactions in developmental, adult and tumor tissues. The best known isoforms are tenascin -C, -X, -R, -Y and -W, with tenascin-C being fairly well characterized. The basic structure includes a linear portion of 14 EGF-like repeats towards the N-terminal end followed by eight or more FnIII domains, depending upon species and splice variant. The diagram below shows a complete monomer and the six-branched “hexabrachion” tenascin N-terminal disulfide-linked dimer of trimers.

Rabbit anti-Tenascin (Millipore cat. no. AB19013) staining of cushion tissue of embryonic mouse heart. Basement membrane between endocardium and myocardium.

Vitronectin

Cell migration is a fundamental function of normal cellular processes, including embryonic development, angiogenesis, wound healing, immune response, and inflammation. Cell migration is governed by a variety of factors, including cell surface adhesion receptor binding to extracellular matrix (ECM) proteins. One such matrix protein is vitronectin (VN). VN is a widely distributed high molecular weight glycoprotein found in most extracellular matrices and blood plasma that is known to promote cell adhesion and affect cell morphology, migration, differentiation, and cytoskeletal organization. Millipore has a number of antibodies, purified proteins and migration assays for vitronectin related research.

SDS-PAGE and Coomassie stain using 3 mg of recombinant Vitronectin (Millipore cat. no. 08-126). Arrow indicates human Vitronectin at a MW of 78kDa.)

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