Introduction and Goals
This tutorial describes some aspects of how cells are organized in multicellular organisms. You will learn about the mechanisms by which cells adhere to an extracellular network and to each other, and how they become organized into functional units. You will explore the molecules that mediate this organization and that confer the distinct properties of structure and function. Plant cells have a unique feature that contributes to their overall morphology, and this will be described. Finally, you will learn about the properties of stem cells, a unique cell type that has promoted exciting and currently, controversial research.
By the end of this tutorial you should know:
- The function and properties of connective tissue
- The composition of connective tissue, including structural proteins, adhesive glycoproteins, proteoglycans and glycosaminoglycans
- The unique properties and composition of the plant extracellular matrix
- The polarized nature of epithelial cells
- The cell junctions of epithelial cells, including tight junctions, gap junctions and adhesive junctions
- The several different types of cell adhesion molecules
- The properties of stem cells
Animals Have Four Primary Tissues
Cells with similar properties can be categorized as part of the same tissue. Organsare formed by the interaction of one or more tissues that form a structural and functional unit (e.g. the heart). There are four primary tissues in animals: connective, epithelial, muscle and nervous. In this tutorial, some of the unique cellular and molecular properties of connective and epithelial tissues will be described. Connective tissueis distinct from the other primary tissues because it consists of cells that are surrounded by a large amount of extracellular material. Epithelial tissueconsists of cells that form membranes that cover and line the body surface and cavities, and cells that form glands that secrete hormones and other substances. Muscle tissue consists of cells specialized for contraction. Nervous tissue consists of neurons, cells specialized for the conductance and transmission of electrochemical impulses, as well as support cells (review Tutorial on Membrane Potential, Ion Transport and Nerve Impulse).
Functions of Connective Tissue
Connective tissue can range from flexible tissue (e.g. tendons) to much firmer tissue (e.g. bones). Some connective tissue (e.g. bone) provides structural support for the organism, whereas other connective tissue (e.g. the dermis layer of skin) is more flexible but also provides support and attachment for the epidermis. Connective tissue, as the name suggests, also functions to connect and attach (e.g. tendons, which attach muscle to bone). Some connective tissue (e.g. cartilage in the joints) is fairly elastic and resistant to a great deal of compression. Finally, the many types of cells found in blood are also considered connective tissue surrounded by plasma. All of these tissues have large amounts of extracellular matrix (ECM), composed of both proteins and carbohydrates. Most ECM is made and secreted by cells called fibroblasts, which are dispersed throughout the matrix. The material comprising the ECM is secreted by the fibroblasts via the exocytosis pathways described in previous tutorials. Once outside the cells, these macromolecules form large complex aggregates organized into a macromolecular network. The precise nature of the macromolecules and their organization determines the type of connective tissue formed. In addition, the ECM is often a molecular surface that other types of cells adhere to, and it can regulate their growth, shape and motility. This is particularly important during embryonic development, when specific groups of cells need to move in a regulated fashion from one region of the embryo to another.
Composition of the animal ECM
Collagen, a structural protein of the ECM
The most abundant protein found in animals is collagen. It is the predominant structural component of the ECM of bones, cartilage, tendons and skin. In vertebrates there are many different types of collagens, encoded for by over 20 different genes. Collagen types in the ECM are tissue specific. However, there are two distinguishing features of all collagens: their unusual amino acid composition and their organization into rigid fibers. Collagens consist of large amounts of the amino acids glycine and proline, as well as two unusual amino acids, hydroxylysine and hydroxyproline. All collagens in the ECM are thick, rigid fibers composed of many molecules of collagen packed together by hydrogen bonding. In fibroblasts, three collagen polypeptides are wound together in a triple helix, referred to as procollagen, and then secreted. The presence of glycine at every third residue in the collagen polypeptides facilitates the formation of this triple helix because of all the amino acids, glycine has the smallest side chain; thus, glycine allows the collagen polypeptides to be held together tightly. Outside the cell, the ends of procollagen are cleaved to allow it to assemble into a collagen fibril, which, in turn, assembles into collagen fibers. The organization of collagen fibers is tissue specific and is regulated by the fibroblasts that secrete the collagen polypeptides. For example, in skin the collagen fibers are crisscrossed so that tension is provided in any direction, whereas in tendons the collagen fibers lie parallel to each other, between the muscle and bone, to provide strength in one axis.
Adhesive Glycoproteins of the ECM
Adhesive glycoproteins, both in the ECM and on cell surfaces, allow the adhesion of cells to the ECM (see Figure 1). Fibronectinis one of the most common adhesive glycoproteins. It is a modular protein that has binding sites for collagen, as well as other components of the ECM, and binding sites for the cell surface; thus, fibronectin provides a link between the ECM and the cells that adhere to it. There are two major types of fibronectins, both encoded for by the same gene: tissue fibronectin is found in the ECM of connective tissue, and soluble plasma fibronectin is found in blood, where it promotes blood clotting. Laminin, another adhesive glycoprotein found in the specialized ECM, is associated with epithelial cells (Figure 1).
Integrins are located on the surfaces of many of the cells that grow and adhere to the ECM. This class of transmembrane receptor proteins can bind fibronectin and laminin in the ECM (Figure 1). In addition, integrins can bind cell surface proteins. The extracellular domain of an integrin receptor binds to adhesive glycoproteins in the ECM, whereas the intracellular domain binds to the cytoskeleton, thereby ensuring that the cell is securely anchored to the ECM. Furthermore, integrins play roles in cell signaling and can trigger intracellular signal transduction cascades, thereby linking adhesion to the ECM with changes in the growth and fate of a cell.
Proteoglycans and GAGs in the ECM
The ECM provides mechanical strength (via collagens), a surface for cell adhesion (via fibronectins and laminins), and the ability to resist compression. This last characteristic is conferred by proteins and carbohydrates present in the matrix. Proteoglycans are extracellular proteins covalently bound to a special class of long-chain polysaccharides called glycosaminoglycans (GAGs). This is illustrated in Figure 2. This class of proteins is highly diverse and is often heavily decorated with GAGs. Proteoglycans form huge aggregates with each other, as well as with free GAGs in the ECM. These large complexes occupy a large volume and trap a great deal of water. This serves to fill space within the tissue, as well as making the tissue resistant to compression. Recent evidence has suggested that proteoglycans play more active roles than just space-filling. Some growth factors actually bind to and require specific proteoglycans for delivery and/or binding to their respective receptors.
The plant cell wall
Plant cells are surrounded by a tough cell wall, which is the predominant ECM in plants. The cell wall provides strength in plant tissues. The primary component of the plant cell wall is the polysaccharide cellulose. Cellulose is synthesized extracellularly by enzyme complexes embedded in the plasma membrane of the cell, and is deposited in oriented rigid fibers. Initially, a cell will synthesize a thin primary cell wall that is capable of expanding as the cell grows. Once the tissue has stopped growing, a more rigid secondary cell wall is deposited. In addition to cellulose, there are other polysaccharides and some structural glycoproteins that interact to form a strong and solid ECM. In the case of woody tissue there is another type of molecule in the ECM, lignin, which forms a large crosslinked network that is very strong and can support the weight of a large tree.
Epithelial Cells: Polarized Cells
Epithelial tissue is widespread and varied, however, all cells of epithelial tissues organize into multicellular sheets that line or cover many surfaces and cavities. This cellular organization is achieved through a variety of mechanisms that allow cell adhesion and coordination. Cells within an epithelial sheet are polarized with two distinct sides: the apical surface, which is exposed to air or fluid; and the basal surface, which is attached to a distinct thin layer of ECM referred to as the basal lamina. The attachment of the epithelial sheet to the basal lamina is mediated by a distinct junction called the hemidesmosome. The extracellular domain of integrin on the epithelial cells recognizes and binds the adhesive glycoprotein laminin in the ECM. The intracellular domain of integrin is anchored to the cytoskeleton by binding to intermediate filaments.
The two surfaces of the epithelial cells have very different properties and functions. Consider the epithelial cells lining the small intestine. The apical surface faces the lumen of the small intestine, and is primarily responsible for absorption of nutrients. The basal surface adheres to the underlying basal lamina, and is primarily responsible for exporting nutrients into the bloodstream. The apical and basal membranes have distinct protein compositions that mediate these different activities; the apical surface contains sodium/glucose symporters to import glucose against its concentration gradient, whereas the basolateral surface contains glucose transporters to export glucose down its concentration gradient (see Tutorial on Passive and Active Transport).
Cells in an epithelium function as a single continuous sheet of cells, closely juxtaposed, firmly attached and coordinately regulated. Epithelial cells have a variety of cell junctions that allow this type of tissue organization (illustrated in Figure 3). There is a distinct junction right below the apical surface of epithelial cells, termed thetight junction, which seals the gap between two epithelial cells in a sheet. The plasma membranes of adjacent cells are closely juxtaposed through the binding of transmembrane proteins on adjacent cells, which fills the extracellular space and serves to prevent the diffusion of solutes into the space between adjacent cells. This allows the tissue to act as an effective barrier; diffusion between cells is restricted, so only regulated transport through the cells can occur. Furthermore, the tight junction serves to maintain the polarity of epithelial cells because it inhibits the lateral movement of membrane proteins, thereby restricting proteins to either the apical or basolateral domains.
A gap junction is a second type of cell junction in epithelial cells as well as other tissues (including muscle). The gap junction is a channel between two adjacent cells that allows the diffusion of small hydrophilic solutes and ions between the two cells. Gap junctions are composed of transmembrane proteins called connexins. Six subunits of connexin form a cylindrical channel through the plasma membrane of one cell, and are linked to a similar channel in the adjacent cell. Gap junctions allow diffusion of ions, second messengers involved in signaling pathways (e.g. cAMP), and metabolites (e.g. ATP) between cells. This allows electrochemical continuity, rapid communication and uniform activity in cells organized into a tissue.
An adhesive junction is a third type of cell junction in epithelial cells. It allows cells to bind tightly to their neighbors and to be integrated into a tissue. Characteristically, the adhesive junction is mediated by the extracellular binding of a class of transmembrane proteins called cadherins. Cadherin molecules mediate cell recognition because the extracellular domains bind to the same cadherin on an adjacent cell (see Figure 4). They anchor the two cells together because the intracellular domain binds to the cytoskeleton. There are two distinct types of adhesive junctions: the adherens junction and the desmosome. In epithelial cells the adherens junction is a band encircling the apical surface of the cell. In other cell types it is a small point of attachment. Cadherins that participate in this type of junction are linked to actin in the cytoskeleton via their intracellular domains. The desmosomeis a small disc of adhesion between two cells. It is mediated by a distinct type of cadherin that is linked to the intermediate filaments in the cytoskeleton. The hemidesmosome, described earlier, is similar to the desmosome, however, it anchors the cell to the basal lamina as opposed to another cell.
Plant cells do not have any of these types of cell junctions. Instead, they are separated by cell walls. They do, however, have a structure (plasmodesma) analogous to the gap junction, which allows the movement of small molecules and ions between adjacent cells. The plasmodesmata are channels through the cell walls, composed of plasma membranes, which connect two adjacent plant cells.
Cell Recognition and Adhesion
In addition to the rather specialized adhesive junctions described above, there are a variety of proteins on a cell's surface that function in cell recognition and adhesion during tissue formation. There are several different classes of such proteins, and multiple members in each class, with distinct distributions in different cell types. The diversity is great and somewhat bewildering, however, in this tutorial you will learn about three classes of proteins and some general principles of cell adhesion (see Figure 4). In general, adhesion proteins are transmembrane proteins that bind to either themselves or to other transmembrane proteins on adjacent cells. In some cases the adhesion proteins are linked to the cytoskeleton, anchoring cells to each other. In some cells the interaction of the extracellular domains of adhesion proteins will trigger activation of the intracellular signal transduction pathways that regulate cell growth and migration.
Perhaps one of the largest classes of proteins involved in cell recognition and adhesion are the cell adhesion molecules (CAMs), which all share an immunoglobulin domain. The distribution of different CAMs is tissue specific (e.g. N-CAM is found on neural cells), and the interaction between one tissue type of CAM with itself (homophilic binding) on adjacent cells contributes to the aggregation and adhesion of cells into organs during embryonic development. CAMs are also abundant in lymphocytes and other cells of the immune system, regulating cell adhesion as well as cell signaling through both homophilic and heterophilic binding(binding with a different type of CAM). Another class of cell adhesion protein is the cadherin family, which participates in adhesive junctions (discussed above). Like CAMs, there are several cadherins and their distribution is often tissue specific. Cadherins tend to exhibit homophilic binding and require calcium ions (calcium-dependent adhesion), hence their name. Integrins are another class of adhesion protein; although we have already described integrins as transmembrane proteins that bind to the ECM, some integrins can also bind to cell surface proteins on adjacent cells. There are many other adhesion proteins that have more selective distributions and roles, but they will not be described here.
Tissue Renewal and Stem Cells
The cells of the primary tissues, described earlier, are all differentiatedcells (cells that have undergone a series of changes during development to become specialized, such as a motor neuron or an intestinal epithelial cell). Most differentiated cells do not divide, so when they die they need to be replaced in the tissue. The renewal rates within different tissues vary greatly. For example, neurons will generally survive the lifetime of an organism and are rarely replaced. Conversely, the epithelial cells lining the intestine survive only a few days and are rapidly replaced. The new cells are derived from a population of stem cells, which can divide continuously. Stem cells have two unique properties: self-renewal and the ability to give rise to differentiated cells. That is, the new differentiated cells "stem" from the precursor stem cell population. When a stem cell divides, one of the two daughter cells retains the stem cell properties and the other daughter cell becomes a precursor that will continue to divide and give rise to differentiated cells (Figure 5). Adult stem cells are generally limited to one type of tissue, and often, to a narrow range of cell types. For instance, a small population of stem cells in the lining of the epithelial of the intestine gives rise to precursors of the differentiated intestinal epithelial cells. Bone marrow contains another type of stem cell that gives rise to the precursors for red blood cells (replaced every 4 months) and other blood cell types.
Unfortunately when there is extensive damage to tissue due to disease or injury, cells are not readily replaced by adult stem cells in the body. The one exception is bone marrow, which can be transplanted from one individual to another to repopulate the blood cells. Bone marrow transplants have been used successfully to treat a variety of blood diseases such as leukemia and certain types of anemia. In recent years there have been efforts to grow and manipulate another type of stem cell, embryonic stem cells. Embryonic stem cells have the potential to give rise to a greater diversity of cell types, and to be a source of cells for every differentiated cell type. Research is focused on developing embryonic stem and adult stem cell lines that can be transplanted into patients, with the hope that these cells will acclimate themselves in their new environment and repopulate the missing or damaged tissue. In the future, therapies could be developed to replace lost nerve cells in patients suffering from neurodegenerative diseases (e.g. Parkinson's disease), or to repopulate the insulin-secreting cells of the pancreas in diabetic patients. The controversy surrounding human embryonic stem cell research arises because human embryos must be used, and they are generated by in vitro fertilization. If you are interested in the biology and potential uses of stem cells, visit this useful site sponsored by the National Institute of Health (Stem Cells at NIH).
This tutorial defined connective tissue and epithelial tissue, and addressed their unique cellular and molecular properties. Connective tissue is surrounded by large amounts of extracellular material, and can be flexible or rigid. The extracellular matrix (ECM) of animals is mostly collagen. Cells adhere to the ECM via adhesive glycoproteins (e.g., fibronectin and laminin). Integrins are transmembrane receptor proteins that further ensure cell anchoring, as well as play a role in cell signaling. Proteoglycans and glycosaminoglycans (GAGs) confer the ECM with the ability to resist compression. The ECM of plants is predominantly the cell wall, composed primarily of cellulose. Lignin is also part of the plant ECM.
Epithelial tissue forms membranes that cover and line body surfaces and cavities, and forms glands. Epithelial sheets have an apical and basal surface, both of which have different properties and functions. Cell junctions allow tissue organization in the epithelium. These include: tight junctions, which separate epithelial cells within a sheet; gap junctions, which via a channel, allow diffusion of certain solutes and ions between cells within a sheet; and adhesive junctions, which allow the tight bonding of cells and their integration into tissues. None of these cell junctions are found in plants. Plant cells are separated by cell walls that contain plasmodesma (functionally analogous to the gap junction).
Three types of adhesion proteins were discussed: cell adhesion molecules (CAMs), cadherins, and integrins. These transmembrane proteins function in cell recognition and adhesion during tissue formation.
Finally, stem cells were discussed. Stem cells can self-renew and give rise to differentiated cells; that is, the new differentiated cells "stem" from the precursor stem cell population. Adult stem cells are generally limited to one type of tissue, with usually a narrow range of cell types. Conversely, embryonic stem cells can potentially give rise to a greater diversity of cell types, and hence, might be a source for every differentiated cell type.