Basal Lamina and Extracellular Matrix

The extracellular matrix is composed of a variety of proteins and polysaccharides that are secreted locally and assembled into an organized meshwork in close association with the surface of the cells that produce it. In most connective tissues, the matrix macromolecules are secreted largely by cells called fibroblasts such as the chondroblasts in cartilage and osteoblasts in bone. At the interface between an epithelium and connective tissue, the matrix forms a basal lamina which are flexible, thin mats of specialized EM that underlie all epithelia cell sheets and tubes. Although the precise composition varies from tissue to tissue, most basal aminae contain (1) Type IV collagen, (2) the large heparan sulfate proteoglycan perlecan, (3) the glycoproteins laminin and (4) nidogen.

The EM was once thought to serve mainly as as just a scaffold but it is now recognized to have an active role in a cell's development, migration, proliferation, shape and function. Two main classes of extracellular macromolecules that make up the matrix can be classified as either:

  • soluble which include the polysaccharide chains of the glycosaminoglycans (GAGs) which are usually found covalently linked to protein in the form of proteoglycans.

GAGs are unbranched chains of repeating disaccharide units. They are called GAGs because one of the 2 sugars in the repeating disaccharide is always an amino sugar which in most cases is sulfunated making GAGs highly negatively charged (anionic). This property means that such GAGs can be easily purified with ion exchange chromotography and then eluted with a Na+ gradient. 4 main groups of GAGs distinguished according to their sugars are the following: (1) hyaluronans (which differs from the other GAGs in that it contains no sulfated sugars, chain length is enormous , is generally not linked covalently to any core protein, and is spun out directly from the cell surface by an enzyme complex embedded in the Plasma membrane whereas the other GAGs are synthesized inside the cell and released by exocytosis. Hylauronans are important as a space filler during embryonic development where it can be used to force a change in the shape of a structure as it expands with water to occupy a large volume (2) chondrotin sulfate and dermatan sulfate (3) heparan sulfate and (4) keratan sulfate

Except for hyaluronan, all GAGs are found covalently attached to protein in the form of proteoglycans. The GAGs are linked to a tetrasaccharide which is linked to a serine side chain on the core protein. Proteoglycans are easily distinguished from other glycoproteins by their large weight due to their long, unbranched GAG chains. Some proteoglycans include (1) aggrecan which is huge with over 100 GAG  chains (like chondroitin sulfate) is a major component of cartilage. Aggrecan can even assemble with hyaluronan in the extracellular space to form aggregates that are as big as a bacterium. (2) decorin which is much smaller with 1 GAG chain (chondroitin sulfate or dermatan sulfate) and can bind to TGFbeta and inhibit its activity. (3) syndecans (GAG chains are chondroitin sulfate & heparan sulfate) which are located on the surface of many types of cells where they serve as receptors for matrix proteins. Syndecans can be found in focal adhesions where they modulate integrin function.

  • insoluble which include fibrous proteins like

(1) collagen, which are the most abundant proteins in mammals constituting 25% of their total protein mass. In contrast to GAGs which resist compressive forces, collagen fibrils form structures that resist tensile forces. The fibrils are organized in different ways in different tissues. The connective tissue cells themselves determine the arrangement of the collagen fibrils as for example by exerting tension on the matrix. The primary feature of a collagen molecule is its long, stiff triple stranded helical structure in which 3 collagen polypeptide alpha chains are wound around one another. Proline (which because of its ring structure stabilizes the helical conformation in each alpha chain) and glycine (which is regularly spaced at every 3rd residue and due to being the smallest amino acid (having only a H atom as a side chain)  can fit into the helix are abundant in collagen. Individual collagen polypeptide chains are synthesized on membrane bound ribosomes and injected into the ER as precursors called pro-α chains. In the lumen of the ER, selected prolines and lysines are hydroxylated which are thought to help stabilize the triple stranded helix. Conditions that prevent proline hydroxylation such as a deficiency of ascorbic acid (vitamin C) causes scurvy which loosens the matrix in blood vessels and teeth. After secretion from the cell, the propeptides found at both the collagen N and C terminal ends are removed by specific proteolytic enzymes. The collagen molecules then assemble in the extracellular space to form much larger collagen fibrils. The fibrils are then strengthed by the formation of covalent cross-links between lysine residues. The main types of collagen found in connective tissues are Type I or fibrillar collagens which is the principal collagen of skin and bone, Type IX or fibril associated collagen which link fibrils with one another to form fiber, and Type IV or network forming collagens that constitutes a major part of the basal lamina.

(2) elastin, which like collagen is unusually rich in proline and glycine but unlike collagen is not glycosylated and contains some hydroxyproline but no hydroxylysine. Elastin is the dominant matrix protein of arteries comprising 50% of the dry weight of the aorta. Elastin resists not only tensile forces but also has the ability to recoil like a rubber band.

(3) fibronectin, a large glycoprotein, is a dimer composed of two very large subunits joined by disulfide bonds near the C-termini. Each chain is folded into domains specialized for binding to a particular molecule (i.e., collagen or heparin) or to a cell. Transcription produces a single large RNA molecule that can be alternatively spliced to produce various isoforms of fibronectin. The main isoform, the type III fibronectin repeat is the most common. A specific RGD (Arg-Gly-Asp) sequence is found in the cell binding domain of one of the type III repeats. Even very short peptides contain this RGD sequence can compete with fibronectin for the binding site on cells, thereby inhibiting the attachment of the cells to a fibronectin matrix. Fibronectin is important not only for cell adhesion to the matrix but also for guiding cell migrations in vertebrate embryos. Large amounts of fibronectin, for example, are found along the pathway followed by migrating prospective mesodermal cells during gastrulation.

(4) laminin is one of the proteins that makes up the basal lamina.

The regulated turnover of extracellular matrix macromolecules is important in various processes like when cells migrate through a basal lamina. For example, white blood cells migrate across the BL of a blood vessel into tissues in response to infection. In this process, matrix components such as collagen, laminin and fibronectin are degraded by extracellular proteolytic enzymes (proteases) that are secreted locally by cells. These proteins belong to 1 of two of the following classes:

  • matrix metalloproteases depend on bound Ca2+ or Zn2+ for activity

  • serine proteases have a highly reactive serine in their active site. Many proteases are secreted as inactive precursors that can be activated locally when needed. For example, plasminogen is an inactive protease precursor in the blood that is cleaved locally by other proteases called plasminogen activators to yield the active serine protease plasmin which helps break up blood clotes. Tissue type plasminogen activator (tPA) is often given to patients who have had thrombotic stroke to help dissolve the arterial clot.

 

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