The cells of a multicellular organism need to be held together. In vertebrates and other complex organisms, cells are assembled to make tissues—collections of interconnected cells that perform a similar function—and organs. Various levels of interaction contribute to this process:
• As they move and assemble into tissues and organs, cells must be able to recognize and bind to each other, a process known as cell adhesion;
• Cells in animal tissues frequently form cell junctions with their neighbors that can have different functions;
• The cells of tissues are also bound by the extracellular matrix (ECM), the complex network of secreted macromolecules occupying the space between cells. Most human tissues contain ECM, but the proportion can vary widely.
Even where cells do not form tissues, as in the case of blood cells, cell adhesion is vitally important, permitting transient cell–cell interactions that are required for various cell functions.
During embryonic development, groups of similar cells are formed into tissues. For even simple tissues such as epithelium, the descendants of the progenitor cells must not be allowed to simply wander off. The requirement becomes more critical when the tissue is formed after some of the progenitor cells arrive from long and complicated cell migration routes in the developing embryo. Cells are kept in place by cell adhesion, and the architecture of the tissue is developed and maintained by the specificity of cell adhesion interactions.
Cell adhesion molecules work by having a receptor and a complementary ligand attached to the surfaces of adjacent cells. There may be hundreds of thousands of such molecules per cell and so binding is very strong. Cells may stick together directly and/or they may form associations with the ECM. During development, changes in the expression of adhesion molecules allow cells to make and break connections with each other, facilitating cell migration. In the mature organism, adhesion interactions between cells are generally strengthened by the formation of cell junctions.
Cell adhesion molecules (CAMs) are typically transmembrane receptors with three domains: an intracellular domain that interacts with the cytoskeleton; a transmembrane domain; and an extracellular domain that interacts either with identical CAMs on the surface of other cells (homophilic binding) or with different CAMs (heterophilic binding), or the ECM. There are four major classes of cell adhesion molecule:
• Cadherins are the only class to participate in homophilic binding;
• Integrins are adhesion heterodimers. They usually mediate cell–ECM interactions but some leukocyte integrins are involved in cell–cell adhesion;
• Selectins mediate transient cell–cell interactions in the bloodstream. They are important in binding leukocytes to the endothelial cells lining blood vessels so that blood cells can migrate out of the bloodstream into a tissue (extravasation).
• Ig-CAMs (immunoglobulin superfamily cell adhesion molecules) possess immunoglobulin-like domains.
Different types of cell junction can regulate the contact between cells
As listed below, different types of cell junction can regulate contact between adjacent cells in vertebrate organisms, and between cells and the ECM. They can have different functions: helping to anchor cells, acting as barriers, or permitting direct intercellular passage of small molecules.
Anchoring cell junctions
Some cell junctions mechanically attach cells (and their cytoskeletons) to their neighbors or to the ECM using dedicated proteins, notably cadherins (cell–cell joining) and integrins (principally for cell–ECM joining). In each case, actin filaments or intermediate filaments are tethered to the cell junction: cell–cell adhesion also involves linking of cytoskeletons of the neighboring cells, and cell–matrix adhesion also involves the cytoskeleton of the anchored cell. The four major types of anchoring cell junction are listed below and illustrated in Figure 3.11A.
• Adherens junctions. Cadherins on one cell bind to cadherins on another. The cadherins are linked to actin filaments using anchor proteins such as catenins, vinculin, and α-actinin.
• Desmosomes. Desmocollins and desmogleins on one cell bind to the same molecule types on another. They are linked to intermediate filaments using anchor proteins such as desmoplakins and plakoglobin.
• Actin-linked focal adhesions. Integrins on a cell surface bind to ECM proteins. The integrins are connected internally to actin filaments using anchor proteins such as talin, vinculin, α-actinin, and filamin.
• Hemidesmosomes. Integrins on epithelial cell surfaces bind to a protein component, laminin, of the basal lamina. The integrins are connected internally to inter mediate filaments using anchor proteins such as plectin.
Cell junctions acting as barriers
Tight junctions are primarily designed to act as barriers, and are especially prevalent in the epithelial cell sheets lining the free surfaces and all cavities of the body. Here they serve as selective permeability barriers by separating fluids with different chemical compositions on either side. By creating such tight seals between cells, they can prevent even small molecules from leaking from one side of the epithelial sheet to the other (Figure 1).
Fig1. The six principal classes of cell junctions found in vertebrate epithelial cells. (A) This example shows intestinal epithelial cells that are arranged in a sheet overlying a thin layer of extracellular matrix (ECM), known as the basal lamina. Individual cells are symmetrical along the axes that are parallel to the ECM layer but show polarity along the axis from the top (apical) end of the cell that faces the lumen to the bottom (basal) part of the cell. Actin filaments (red lines) and intermediate filaments (blue lines) are each important in two types of cell junctions. Thus, cells are anchored to the ECM via actin filaments (actin-linked cell matrix adhesion) or intermediate filaments (at hemidesomosomes), and are bound to their neighbors via actin filaments (at adherens junctions) or intermediate filaments (at desmosomes, located below the adherens junctions). Two additional cell junctions are used in cell-cell adhesion. Tight junctions act as barriers. They occupy the most apical position and divide the cell surface into an apical region (which is rich in intestinal microvilli) and the remaining basolateral cell surface. Gap junctions are communicating junctions and are located in more basal regions. (B) Three dimensional structure of neighboring epithelial cells showing the apical sealing bands that encircle the cells at tight junctions (top) with an exploded view of the connecting plasma membranes at bottom. Sealing strands are shown in red; ICS, intercellular spaces. (A, adapted from Alberts B et al. [2014] Molecular Biology of the Cell, 6th edn. Garland Science. With permission from WW Norton.)
Tight junctions are made up of a network of sealing strands formed by direct joining of the extracellular domains of transmembrane proteins embedded in the two plasma membranes. The sealing strands completely encircle the apical (outward-facing) ends of each epithelial cell (Figure 1B).
Communicating cell junctions
Gap junctions permit inorganic ions and other small, hydrophilic molecules (<1 kDa) to pass directly from a cell to its neighbors (Figure 1A). The plasma membranes of participating cells come into close contact, establishing a uniform gap of about 2–4 nm. The gap is bridged by contact between a radial assembly of six connexin molecules on each plasma membrane; when oriented in the correct register, they form an intercellular channel. Gap junctions allow electrical coupling of nerve cells and co-ordinate cell functions in a variety of other tissues.
The extracellular matrix regulates cell behavior as well as acting as a scaffold to support tissues
The ECM is a supportive matrix that occupies the space between cells of different types of tissue and accounts for a substantial amount of tissue volume, especially in connective tissues (which are the major component of cartilage and bone and provide the frame work of the body). Its hallmark is a three-dimensional array of secreted protein fibers embedded in a gel of complex carbohydrates; these molecular components are mostly made locally by some cells embedded within the ECM.
The molecular composition of the ECM is variable and dictates the physical properties of connective tissue. It can be calcified to form very hard structures (bones, teeth), it can be transparent (cornea), and it can form strong ropelike structures (tendons). The ECM is not just a scaffold for supporting the physical structure of tissues, however. It also regulates the behavior of cells that come into contact with it. It can influence their shape and function, and affect their development and their capacity for proliferation, migration, and survival. Neighboring cells can, in turn, modify ECM structure by secreting enzymes, such as proteases.
In accordance with its diverse functions, the ECM contains a complex mixture of mac romolecules (Figure 2). In connective tissue, for example, the matrix macromolecules are largely secreted by fibroblast-type cells (see also Figures 3 and 4, when we give the example of the structure of intestinal tissue). In addition to proteins, the ECM mac romolecules include two other types of complex polymers, as listed below.
• Glycosaminoglycans are extremely long polysaccharide chains assembled from tandem repeats of particular disaccharides. Hyaluronic acid is the only example of a free glycosaminoglycan in the ECM, one that is not covalently attached to a protein. Its structure is based on repeats of the disaccharide N-acetyl-d glucosamine–d-glucuronic acid; there can be as many as 25,000 repeats.
• Proteoglycans are a type of glycoprotein that has a protein core with sugar side chains, at least one of which is a glycosaminoglycan. They exist in various different forms in the ECM.
Fig2. Molecular structure of the extracellular matrix (ECM). The principal molecular components of the ECM, glycoproteins and proteoglycans, are made within the cell and exported by exocytosis. The most prominent glycoproteins are long collagens that have a triple-helical structure (which gives the resulting fibers a high tensile strength and great elasticity) and fibronectins that help attach cells to the ECM via integrin receptor proteins in the plasma membrane. Not shown are additional glycoproteins such as elastin (which confers flexibility on the ECM) and laminin (which forms webs that help hold neighboring cells together). The proteoglycans are small glycoproteins bound to long polysaccharides; they regulate the movement of molecules through the matrix and also the binding of cations and water. (The consistency of the matrix as a whole depends on how much water can be trapped; the more interlinks, the more water can be trapped, making the consistency soft, such as that of cartilage.) Note that multiple cell types can be surrounded by a common ECM, as in the example of connective tissue shown in Figure 3.14. (Modified from Urry LA et al. [2016] Biology, 11th edn.)
Fig3. The gut as an example of the relationships between cells, tissues, and organs. The gut is a long, tube-shaped organ largely constructed from three tissues. Epithelial tissues form the inner and outer surfaces of the tube and are separated from internal layers of muscle tissue by connective tissue. The latter is mostly composed of extracellular matrix (extracellular fluid containing a complex network of secreted macromolecules; see Figure 2). The inner epithelial layer (top) is a semi-permeable barrier, keeping the gut contents within the gut cavity (the lumen) while transporting selected nutrients from the lumen through into the extracellular fluid of the adjacent connective tissue layer. (Adapted from Alberts B et al. [2014] Molecular Biology of the Cell, 6th edn. Garland Science.)
Fig4. Connective tissue: cells and structure. The figure shows the example of connective tissue underlying epithelium. The epithelial tissue consists of a cellular layer plus an underlying thin layer (the basal lamina) consisting of extracellular matrix secreted by the cells above. Connective tissue is dominated by an extracellular matrix (ECM), a three-dimensional array of protein fibers embedded in a gel of complex carbohydrates (glycosaminoglycans), with cells sparsely distributed within the ECM. Some of the cells are indigenous, including fibroblasts (cells that synthesize and secrete most of the ECM macromolecules), fat cells, and mast cells that secrete histamine containing granules in response to insect bites or exposure to allergens. In addition, there are various immigrant blood and immune system cells (such as monocytes, macrophages, T cells, plasma cells, and leukocytes). (Adapted from Alberts B et al. [2014] Molecular Biology of the Cell, 6th edn. Garland Science. With permission from WW Norton.)
Being extremely large and highly hydrophilic, glycosaminoglycans readily form hydrated gels that generally act as cushions to protect tissues against compression. Tissues such as cartilage, where the proteoglycan content of the ECM is particularly high, are highly resistant to compression. Proteoglycans can form complex superstructures in which individual proteoglycan molecules are arranged around a hyaluronic acid backbone. Such complexes can act as biological reservoirs by storing active molecules such as growth factors, and proteoglycans may be essential for the diffusion of certain signaling molecules.
The ECM macromolecules have different functional roles. The glycoproteins pre dominantly have structural roles (notably collagens; elastin also allows tissues to regain their shape after being deformed), or have roles in adhesion (fibronectin and vitrinectin in cell–matrix adhesion; laminins in adhesion of cells to the basal lamina of epithelial tissue (see below). Proteoglycans can bind growth factors and other bioactive molecules, and are important in regulating adhesion and some other processes. For example, hyaluronic acid is involved in regulating cell migration, particularly during development and tissue repair).
Specialized cell types are organized into tissues
There are many different types of cells in adult humans, but they are organized into just a few major types of tissue. Organs are typically composed of a small number of different tissue types; for example, the gut comprises a layer of epithelium, connective tissue, and smooth muscle (Figure 3). Of the common tissues, epithelial, muscle, nervous, and connective tissues are outlined below; lymphoid tissue is described in Section 3.4 when we consider immune system cells.
Epithelial tissue
Epithelial tissue has little ECM and is characterized by tight cell binding between adjacent cells, forming cell sheets on the surface of the tissue. The cells are bound to their neighbors by strong adhesive forces that permit the cells to bear most of the mechanical stress that the tissue is subjected to. Here, the ECM mostly consists of a thin layer, the basal lamina, that is secreted by the cells in the overlying epithelium layer (Figure 4).
The individual cells within a layer of epithelium show consistent internal asymmetry (cell polarity) in a plane that is at right angles to the cell sheet. The apex of an epithelial cell, the end facing the exterior (or the lumen of a cylindrical tube), is the one part of the cell not attached to its cell neighbors or to the basal lamina. On the apical sur face are microvilli. These small, hairlike projections are composed of complex plasma membrane folds surrounding an actin microfilament core, and are not found at the basal end of the cell (the part attached to the basal lamina) or on the lateral regions, the sides attached to neighboring cells (see Figure 4).
Connective tissue
Connective tissue is largely composed of ECM that is rich in fibrous polymers, notably collagen. Sparsely distributed within this tissue is a remarkable variety of specialized cells. The indigenous cells—mesenchymal stem cells and the differentiated cells that they give rise to, notably fibroblasts—synthesize and secrete most of the ECM macromolecules (see Figure 4). There are also some immigrant cells, notably immune system and blood cells. Because cells are sparsely distributed in the supporting ECM, it is the ECM rather than the cells within it that bears most of the mechanical stress falling on connective tissue. Two types of connective tissue are recognized, as listed below.
• Loose connective tissue. This has fibroblasts surrounded by a flexible collagen fiber matrix, and is found beneath the epithelium in skin and many internal organs. It also forms a protective layer over muscle, nerves, and blood vessels.
• Fibrous connective tissue. Here, the collagen fibers are densely packed, providing strength to tendons and ligaments. Cartilage and bone are rigid forms of connective tissue.
Muscle tissue
Muscle tissue is composed of contractile cells that have the special ability to shorten or contract in order to produce movement of the body parts. Skeletal muscle fibers are cylindrical, striated, under voluntary control, and multinucleated because they arise by fusion of precursor cells called myoblasts. Smooth muscle cells are spindle-shaped, have a single, centrally located nucleus, lack striations, and are under involuntary control (see Figure 3). Cardiac muscle has branching fibers, striations, and intercalated disks; the component cells, cardiomyocytes, each have a single nucleus and contraction is not under voluntary control.
Nervous tissue
Nervous tissue is limited to the brain, spinal cord, and nerves. Neurons are electrically excitable cells that process and transmit information via electrical signals (impulses) and secreted neurotransmitters. They have three principal parts: the cell body (the main part of the cell, performing general functions); a network of dendrites (extensions of the cytoplasm that carry incoming impulses to the cell body); and a single, long axon that carries impulses away from the cell body to the end of the axon (Figure 5).
Fig5. Neurons and myelination. (A) Neuron structure. Each neuron has a single, long axon with multiple axon termini (dendrites) that are connected to other neurons or to an effector cell such as a muscle cell. Neurons are insulated by certain glial cells such as Schwann cells that form a myelin sheath. (B) Myelination of an axon from a peripheral nerve. Each Schwann cell wraps its plasma membrane concentrically around the axon, forming a myelin sheath covering 1 mm of the axon. (Adapted from Alberts B et al. [2014] Molecular Biology of the Cell, 6th edn. Garland Science. With permission from WW Norton.)
Neurons account for less than 10% of cells in the nervous system; the other 90% are glial cells. Glial cells do not transmit impulses, but instead support the activities of the neurons in a variety of ways. The axons of neurons have an insulating sheath of a phospholipid, myelin, that is produced by certain glial cells: oligodendrocytes (in the central nervous system) and Schwann cells (in the peripheral nervous system). Astrocytes are small, star-shaped glial cells that ensheath synapses and regulate neuronal function. Microglial cells are phagocytic and protect against bacterial invasion. Other glial cells provide nutrients by binding blood vessels to the neurons.
