The ECM is constantly being remodeled; its synthesis and degradation accompany morphogenesis, tissue regen- eration and repair, chronic fibrosis, and tumor invasion and metastasis. ECM occurs in two basic forms: interstitial matrix and basement membrane (Fig. 1.14 #301 | | |
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Interstitial matrix is present in the spaces between cells in connective tissue, and between the parenchymal epi- thelium and the underlying supportive vascular and smooth muscle structures. The interstitial matrix is synthesized by mesenchymal cells (e.g., fibroblasts), forming an amorphous three-dimensional gel. Its major constituents are fibrillar and nonfibrillar collagens, as well as fibronectin, elastin, proteoglycans, hyaluronate, and other constituents (see later). #303 | | |
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Basement membrane. The seemingly random array of interstitial matrix in connective tissues becomes highly organized around epithelial cells, endothelial cells, and smooth muscle cells, forming the specialized basement membrane. This is synthesized conjointly by the overly- ing epithelium and the underlying mesenchymal cells, forming a flat lamellar “chicken wire” mesh (although labeled as a membrane, it is quite porous). The major constituents are amorphous nonfibrillar type IV colla- gen and laminin.) #305 | | |
Components of the Extracellular Matrix #306 | | |
The components of the ECM fall into three groups of pro- teins (Fig. 1.15): #307 | | |
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Fibrous structural proteins such as collagens and elastins that confer tensile strength and recoil #309 | | |
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Water-hydrated gels such as proteoglycans and hyaluro- nan that permit compressive resistance and lubrication #311 | | |
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Adhesive glycoproteins that connect ECM elements to one another and to cells #313 | | |
Collagens. Collagens are composed of three separate polypeptide chains braided into a ropelike triple helix. About 30 collagen types have been identified, some of which are unique to specific cells and tissues. #314 | | |
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Some collagen types (e.g., types I, II, III, and V colla- gens) form linear fibrils stabilized by interchain hydro- gen bonding; such fibrillar collagens form a major proportion of the connective tissue in structures such as bone, tendon, cartilage, blood vessels, and skin, as well as in healing wounds and scars. The tensile strength of the fibrillar collagens derives from lateral crosslinking of the triple helices by covalent bonds, an unusual post-translational modification that requires hydroxyl- ation of lysine residues in collagen by the enzyme lysyl oxidase. Because lysyl oxidase is a vitamin C-dependent enzyme, children with ascorbate deficiency have skele- tal deformities, and people of any age with vitamin C deficiency heal poorly and bleed easily because of “weak” collagen. Genetic defects in collagens cause dis- eases such as osteogenesis imperfecta and certain forms of Ehlers-Danlos syndrome (Chapter 7). #316 | | |
Nonfibrillar collagens variously contribute to the struc- tures of planar basement membranes (type IV collagen); help regulate collagen fibril diameters or collagen- collagen interactions via so-called “fibril-associated col- lagen with interrupted triple helices” (FACITs, such as type IX collagen in cartilage); and provide anchoring fibrils within basement membrane beneath stratified squamous epithelium (type VII collagen). #317 | | |
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Elastin. The ability of tissues to recoil and recover their shape after physical deformation is conferred by elastin (Fig. 1.15). Elasticity is especially important in cardiac valves and large blood vessels, which must accommodate recurrent pulsatile flow, as well as in the uterus, skin, and ligaments. Morphologically, elastic fibers consist of a central core of elastin with an associated meshlike network composed of fibrillin. The latter relationship partially #319 | | |
explains why fibrillin defects lead to skeletal abnormalities and weakened aortic walls, as in individuals with Marfan syndrome. Fibrillin also controls the availability of TGF-β (Chapter 7). #320 | | |
Proteoglycans and hyaluronan (Fig. 1.15). Proteogly- cans form highly hydrated gels that confer resistance to compressive forces; in joint cartilage, proteoglycans also provide a layer of lubrication between adjacent bony sur- faces. Proteoglycans consist of long polysaccharides called glycosaminoglycans (examples are keratan sulfate and chondroitin sulfate) attached to a core protein; these are then linked to a long hyaluronic acid polymer called hyal- uronan in a manner reminiscent of the bristles on a test-tube brush. The highly negatively charged, densely packed sul- fated sugars attract cations (mostly sodium) and abundant water molecules, producing a viscous, gelatin-like matrix. Besides providing compressibility to tissues, proteogly- cans also serve as reservoirs for secreted growth factors (e.g., FGF and HGF). Some proteoglycans are integral cell membrane proteins that have roles in cell proliferation, migration, and adhesion, for example, by binding and con- centrating growth factors and chemokines (Fig. 1.15). #321 | | |
Adhesive glycoproteins and adhesion receptors. These are structurally diverse molecules variously involved in cell-cell, cell-ECM, and ECM-ECM interactions (Fig. 1.16). Prototypical adhesive glycoproteins include fibronectin (a major component of the interstitial ECM) and laminin (a major constituent of basement membrane). Integrins are representative of the adhesion receptors, also known as cell adhesion molecules (CAMs); the CAMs also include immu- noglobulins family members, cadherins, and selectins. #322 | | |
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Fibronectin is a large (450 kD) disulfide-linked heterodi- mer that exists in tissue and plasma forms; it is synthe- sized by a variety of cells, including fibroblasts, monocytes, and endothelium. Fibronectin has specific domains that bind to distinct ECM components (e.g., col- lagen, fibrin, heparin, and proteoglycans), as well as inte- grins (Fig. 1.16). In healing wounds, tissue and plasma fibronectin provide a scaffold for subsequent ECM depo- sition, angiogenesis, and reepithelialization. #324 | | |
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Laminin is the most abundant glycoprotein in the base- ment membrane. It is an 820-kD cross-shaped heterotri- mer that connects cells to underlying ECM components such as type IV collagen and heparan sulfate (Fig. 1.16). Besides mediating the attachment to the basement membrane, laminin can also modulate cell proliferation, differentiation, and motility. #326 | | |
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Integrins are a large family of transmembrane heterodi- meric glycoproteins composed of α- and β-subunits that allow cells to attach to ECM constituents such as laminin and fibronectin, thus functionally and structurally linking the intracellular cytoskeleton with the outside world. Integrins also mediate cell-cell adhesive interac- tions. For instance, integrins on the surface of leukocytes are essential in mediating firm adhesion to and transmi- gration across the endothelium at sites of inflammation (Chapter 3), and they play a critical role in platelet aggregation (Chapter 4). Integrins attach to ECM com- ponents via a tripeptide arginine-glycine-aspartic acid motif (abbreviated RGD). In addition to providing focal attachment to underlying substrates, binding through the integrin receptors can also trigger signaling cascades that influence cell locomotion, proliferation, shape, and differentiation (Fig. 1.16). #328 | | |
MAINTAINING CELL POPULATIONS #329 | | |
Proliferation and the Cell Cycle #330 | | |
Cell proliferation is fundamental to development, main- tenance of steady-state tissue homeostasis, and replace- ment of dead or damaged cells. The key elements of cellular proliferation are accurate DNA replication accom- panied by the coordinated synthesis of all other cellular constituents, followed by equal apportionment of DNA and other cellular constituents (e.g., organelles) to daugh- ter cells through mitosis and cytokinesis. #331 | | |
The sequence of events that results in cell division is called the cell cycle. The cell cycle consists of G1 (pre- synthetic growth), S (DNA synthesis), G2 (premitotic growth), and M (mitotic) phases; quiescent cells that are not actively cycling are in the G0 state. (Fig. 1.17). Cells can enter G1 either from the G0 quiescent cell pool or after completing a round of mitosis. Each stage requires completion of the previous step, as well as activation of necessary factors (see later); nonfidelity of DNA replica- tion or cofactor deficiency results in arrest at the various transition points. #332 | | |
The cell cycle is regulated by numerous activators and inhibitors. Cell-cycle progression is driven by proteins called cyclins—named for the cyclic nature of their pro- duction and degradation—and cyclin-associated enzymes called cyclin-dependent kinases (CDKs) (Fig. 1.18). CDKs acquire the ability to phosphorylate protein substrates (i.e., kinase activity) by forming complexes with the relevant cyclins. Transiently increased synthesis of a particular cyclin leads to increased kinase activity of the appropriate CDK binding partner; as the CDK completes its round of phosphorylation, the associated cyclin is degraded and the CDK activity abates. Thus, as cyclin levels rise and fall, the activity of associated CDKs likewise waxes and wanes. #333 | | |
More than 15 cyclins have been identified; cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDKs. The cell cycle thus resembles a relay race in which each leg is regulated by a distinct set of cyclins: as one collection of cyclins leaves the track, the next set takes over. #334 | | |
Embedded in the cell cycle are surveillance mechanisms primed to sense DNA or chromosomal damage. These quality-control checkpoints ensure that cells with genetic imperfections do not complete replication. Thus, the G1-S checkpoint monitors the integrity of DNA before irrevers- ibly committing cellular resources to DNA replication. Later in the cell cycle, the G2-M check point ensures that there has been accurate DNA replication before the cell actually divides. When cells do detect DNA irregularities, checkpoint activation delays cell-cycle progression and triggers DNA repair mechanisms. If the genetic derange- ment is too severe to be repaired, the cells either undergo #335 | | |
apoptosis or enter a nonreplicative state called senescence— primarily through p53-dependent mechanisms (see later). #336 | | |
Enforcing the cell-cycle checkpoints is the job of CDK inhibitors (CDKIs); they accomplish this by modulating CDK-cyclin complex activity. There are several different CDKIs: #337 | | |
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One family of CDKIs—composed of three proteins called p21 (CDKN1A), p27 (CDKN1B), and p57 (CDKN1C)— broadly inhibits multiple CDKs #339 | | |
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Another family of CDKIs has selective effects on cyclin CDK4 and cyclin CDK6; these proteins are called p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D) #341 | | |
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Defective CDKI checkpoint proteins allow cells with damaged DNA to divide, resulting in mutated daughter cells at risk for malignant transformation #343 | | |
An equally important aspect of cell growth and division is the biosynthesis of other cellular components needed to make two daughter cells, such as membranes and organ- elles. Thus when growth factor receptor signaling stimu- lates cell-cycle progression, it also activates events that promote changes in cellular metabolism that support growth. Chief among these is the Warburg effect, men- tioned earlier, marked by increased cellular uptake of glucose and glutamine, increased glycolysis, and (counter- intuitively) decreased oxidative phosphorylation. These changes are major elements of cancer-cell growth and are discussed in greater detail in Chapter 6. #344 | | |
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Not all stem cells are created equal. During develop- ment, totipotent stem cells can give rise to all types of differentiated tissues; in the mature organism, adult stem cells in various tissues only have the capacity to replace damaged cells and maintain cell populations within the tissues where they reside. There also are populations of stem cells between these extremes with varying capacities to differentiate into multiple cell lineages. Thus, depend- ing on the source and stage of development, there may be limits on the cell types that a stem cell population can generate. #346 | | |
In normal tissues (without neoplasia, degeneration, or healing), there is a homeostatic equilibrium between the replication, self-renewal, and differentiation of stem cells and the death of the mature, fully differenti- ated cells (Fig. 1.19). The dynamic relationship between stem cells and terminally differentiated parenchyma is nicely exemplified by the continuously dividing epithe- lium of the skin. Thus, stem cells at the basal layer of the epithelium progressively differentiate as they migrate to the upper layers of the epithelium before dying and being shed. #347 | | |
Under conditions of homeostasis, stem cells are char- acterized by two important properties: #348 | | |
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Self-renewal, which permits stem cells to maintain their numbers. Self-renewal may follow asymmetric or sym- metric division. #350 | | |
