Key Concepts Of Section

The Extracellular Matrix of Nonepithelial Tissues

■ Connective tissue, such as tendon and cartilage, differs from other solid tissues in that most of its volume is made up of extracellular matrix (ECM) rather than cells.

■ The synthesis of fibrillar collagen (e.g., types I, II, and III) begins inside the cell with the chemical modification of newly made a chains and their assembly into triple-helical procollagen within the endoplasmic reticulum. After secretion, procollagen molecules are cleaved, associate laterally, and are covalently cross-linked into bundles called fibrils, which can form larger assemblies called fibers (see Figure 6-20).

■ The various collagens are distinguished by the ability of their helical and nonhelical regions to associate into fibrils, to form sheets, or to cross-link other collagen types (see Table 6-1).

■ Hyaluronan, a highly hydrated GAG, is a major component of the ECM of migrating and proliferating cells. Certain cell-surface adhesion receptors bind hyaluronan to cells.

■ Large proteoglycan aggregates containing a central hyaluronan molecule noncovalently bound to the core protein of multiple proteoglycan molecules (e.g., aggrecan) contribute to the distinctive mechanical properties of the matrix (see Figure 6-22).

■ Fibronectins are abundant multiadhesive matrix proteins that play a key role in migration and cellular differentiation. They contain binding sites for integrins and ECM components (collagens, proteoglycans) and can thus attach cells to the matrix (see Figure 6-23).

■ The tripeptide RGD sequence (Arg-Gly-Asp), found in fibronectins and some other matrix proteins, is recognized by several integrins.

6.5| Adhesive Interactions and Nonepithelial Cells

After adhesive interactions in epithelia form during differentiation, they often are very stable and can last throughout the life span of epithelial cells or until the cells undergo differentiation into loosely associated nonpolarized mesenchymal cells, the epithelial-mesenchymal transition. Although such long-lasting (nonmotile) adhesion also exists in nonepithelial tissues, some nonepithelial cells must be able to crawl across or through a layer of extracellular matrix or other cells. In this section, we describe various cell-surface structures in nonepithelial cells that mediate long-lasting adhesion and transient adhesive interactions that are especially adapted for the movement of cells. The detailed intracellular mechanisms used to generate the mechanical forces that propel cells and modify their shapes are covered in Chapter 19.

Integrin-Containing Adhesive Structures Physically and Functionally Connect the ECM and Cytoskeleton in Nonepithelial Cells

As already discussed in regard to epithelia, integrin-containing hemidesmosomes connect epithelial cells to the basal lamina and, through adapter proteins, to intermediate filaments of the cytoskeleton (see Figure 6-1). In nonepithelial cells, integrins in the plasma membrane also are clustered with other molecules in various adhesive structures called focal adhesions, focal contacts, focal complexes, 3D adhesions, and fibrillar adhesions and in circular adhesions called podosomes (Chapter 14). These structures are readily observed by fluorescence microscopy with the use of antibodies that recognize integrins or other coclustered molecules (Figure 6-27). Like cell-matrix anchoring junctions in epithelial cells, the various adhesive structures attach nonepithelial cells to the extracellular matrix;

► EXPERIMENTAL FIGURE 6-27

Integrins cluster into adhesive structures with various morphologies in nonepithelial cells. Immunofluorescence methods were used to detect adhesive structures (green) on cultured cells. Shown here are focal adhesions (a) and 3D adhesions (b) on the surfaces of human fibroblasts. Cells were grown directly on the flat surface of a culture dish (a) or on a three-dimensional matrix of ECM components (b). The shape, distribution, and composition of the integrin-based adhesions formed by cells vary, depending on culture conditions. [Part (a) from B. Geiger et al., 2001, Nature Rev.. Mol. Cell Biol. 2:793. Part (b) courtesy of K. Yamada and E. Cukierman; see E. Cukierman et al., 2001, Science 294:1708-12.]

they also contain dozens of intracellular adapter and associated proteins that mediate attachment to cytoskeletal actin filaments and activate adhesion-dependent signals for cell growth and cell motility.

Although found in many nonepithelial cells, integrin-containing adhesive structures have been studied most frequently in fibroblasts grown in cell culture on flat glass or plastic surfaces (substrata). These conditions only poorly approximate the three-dimensional ECM environment that normally surrounds such cells in vivo. When fibroblasts are cultured in three-dimensional ECM matrices derived from cells or tissues, they form adhesions to the three-dimensional ECM substratum, called 3D adhesions. These structures dif-

(b) 3D adhesion

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