Pathology 104 (Dental Histology) M. Hall

2003

Epithelium

(G & H, Chap. 5, pp 85 - 102)

Note: If you can understand and recognize epithelium in all its forms, your study of histology will be much easier.

Epithelium is comprised of cells which cover not only the exterior surfaces of the body (skin, front of eye) but also line both the internal closed cavities of the body (thoracic [lungs], pericardial [heart] and abdominal [guts]) and those body tubes which communicate with the exterior (the alimentary [GI tract], respiratory [lungs] and genitourinary tracts [kidneys, bladder etc]). Epithelium also forms the secretory portion of glands and their ducts, and the receptors of certain sensory organs (e.g. taste buds; olfactory [smell]cells).

The cells forming the epithelium are in close contact with one another. They may be arranged in multiple layers, as in the covering of the exterior surfaces of the body where protection and impermeability are primary requirements, or in a single layer, as in the lining of most of the internal surfaces of the body.

All epithelia exhibit a free surface at their apex, and on the opposite surface, they adhere to a basement membrane. Thus they are polarized cells. This polarity is maintained by the various intercellular junctions, which bind the cells together and by molecules which bind the epithelial cells to the basement membrane. Thus the apical side of an epithelial cell is generally quite different (structurally and biochemically) from the basal side.

Blood vessels do not normally penetrate the epithelium, so there is no direct contact between the cells and the blood vessels. Capillaries are generally located in the lamina propria, the connective tissue layer which lies under an epithelium. Nutrition of the epithelium thus depends on the diffusion of metabolites through the basal lamina. Since epithelia cover free surfaces of the body, they are often subject to abrasion, thus they are constantly replaced. As cells at the free surface are sloughed off or die, cells sitting on the basement membrane (basal cells) divide and differentiate into the various cells which comprise the epithelium.

A given epithelium may serve one or more functions, depending upon the cell types present. It may be an almost impervious barrier (skin, urinary bladder), it may be secretory (stomach) or it may be both secretory and absorptive (intestines). Covering and lining epithelia form a continuous sheet that separates the underlying connective tissue (lamina propria) from the external environment (e.g. skin), and from the environment of the cavities which communicate with the exterior (e.g. alimentary canal).

Classification of Epithelia.

Classification of the various epithelia of the body is based solely on the arrangement and shape of the cells. The terminology used is thus unrelated to function and serves only for descriptive purposes. Epithelia may be described as:

Simple: one cell thick:

stratified, two or more cells thick.

Epithelia (both simple and stratified) are further described according to the shape of the cells forming the surface layer.

The individual cells comprising the surface layer of the epithelium may be described as:

squamous, where the width and depth of the cell is greater than its height (like a fried egg); cuboidal, where the width, depth and height are approximately the same (like a cube):

columnar, where the height of the cell appreciably exceeds the width or depth.

In a simple epithelium, there is only one layer of cells, but in a stratified epithelium, the shape and height of the cells may vary from layer to layer---but the epithelium is still classified according to the shape of the cells forming the surface layer. Thus in designating an epithelium as simple cuboidal, it would consist of a single layer of cuboidal (i.e. square) cells. Similarly a stratified squamous epithelium (e.g. skin), consists of more than one layer of cells (i.e. stratified), and the surface layer is comprised of squamous (i.e. flat/fried egg) cells.

To complicate this simple classification, two special categories of epithelium are typically included, namely pseudostratified and transitional epithelium. A pseudostratified epithelium has the appearance of being stratified, since the nuclei of the various cells are situated at different levels in the epithelium. However, all of the cells sit on the basement membrane, although some of them do not reach the free surface of the epithelium. Examples of this type of epithelium are found in the respiratory system and the male reproductive system. Transitional epithelium is a name give to the epithelium lining the bladder, ureter and parts of the urethra. It is really a stratified epithelium containing cells of different heights, and which has the ability to stretch (e.g. when the bladder is full) and thus changes its thickness and the shape of the cells at the surface. Unfortunately there is really no easy way to identify these two special epithelia--you just have to remember where they occur.

To complicate matters even further, specific names are also applied to epithelium in certain locations. Endothelium is the name given to the epithelium lining the vascular system. Mesothelium is the epithelium that lines the walls and covers the organs in the closed cavities of the body (i.e. thoracic, pericardial and abdominal cavities). Both endothelium and mesothelium are simple squamous epithelia (so what do they look like?).

Basement membrane

All epithelial cells have at their basal surfaces a sheetlike extracellular structure called the basement membrane, which is secreted by the epithelial cells. This structure is generally visible only with the electron microscope. The basement membrane is composed mainly of type IV collagen, a glycoprotein called laminin and two proteoglycans, heparan sulfate and chondroitin sulfate, although a number of other very important components are also present. A basement membrane is present where epithelial cells come into contact with connective tissue. These basement membranes provide a selective barrier limiting or regulating exchanges of macromolecules between connective tissue and other tissues. You will generally not be able to see the basement membrane unless the tissue is stained with a special stain called PAS. Attachment of the epithelium to the basement membrane is essential for the development and function of the epithelium

All epithelia have a layer of connective tissue underneath the basement membrane. This layer of connective tissue may have different names, depending on where it is found. In most cases it is called the lamina propria. The lamina propria not only serves to support the epithelium, but also binds it to neighboring structures.

Cell adhesion and intercellular contacts

Epithelial cells are extremely cohesive. This quality of intercellular adhesion is especially marked in epithelial tissues subjected to traction and pressure (e.g. skin). This is due to interactions of integral membrane proteins on adjacent cells, calcium ions and to a variety of specialized intercellular junctions. These junctions, which are on the lateral surfaces of adjacent cells, serve as 1) sites of adhesion, 2) as seals to prevent the flow of materials between the cells, and 3) as sites for intercellular communication. Under the light microscope, it is sometimes possible to see dense spots between adjacent epithelial cells, towards the apical surface. This specialization is called the terminal bar or junctional complex. Electron microscopy has shown this complex to be comprised of a number of specialized structural components, which are present in a definite order, from the apex towards the base of the cell. The junctional complex is composed of (1) the zonula occludens, (2) the zonula adherens and (3) the macula adherens. (Note: zonula means a continuous belt-like structure which completely surrounds the cell, while macula refers to discrete spot-like contacts between cells).

The zonula occludens, or tight junction, is located most apically in the epithelial cell and represents a continuous belt of plasma membrane union between neighboring cells. This junction forms a barrier to diffusion of large and small molecules (even ions) between adjacent cells.

The next junction is the zonula adherens, which also completely encircles each cell, but the adjacent plasma membranes are separated by a gap of about 20 nm. This junction probably provides rigidity and stability to the cell.

The macula adherens (also called a desmosome) is an additional adhesion device, generally situated just below the level of the zonula adherens and provides particularly strong attachment between cells. It is found in epithelia which are subject to abrasion (e.g. skin) and in tissues which are subject to physical stress (e.g. heart muscle). This junction is a disc shaped structure occurring as a row of spots (like spot welding) around the circumference of the cell. The intercellular space is about 30 nm.

A final junction, which is found in epithelia, but is not limited to this tissue, is the gap junction. This junction is characterized by a close (2 nm) apposition of adjacent cell membranes. Gap junctions have a little hole in the center and are sites of communication between cells, allowing the interchange of ions and other molecules with molecular weights less than 1,500 daltons. When sheets of cells, or tissues, are joined by gap junctions in each cell, they can respond to stimuli as a unit, rather than individually.

In summary, there is a requirement for attachments between certain populations of cells. In epithelial cells, the junctional complex is particularly significant, since it serves to create a barrier allowing the cells to restrict the free passage of substances across its surfaces. While it is the zonula occludens of the junctional complex that principally affects this function, it is the adhesive properties of the zonula and macula adherens which guard against physical disruption of the barrier.

Cell adhesion molecules.

Cell-cell and cell-extracellular matrix (ECM) adhesive interactions are clearly important in maintaining the integrity of epithelial sheets, and in some disease states--most noticeably inflammation, tumor invasion and metastasis (the spread of cancer cells from one site to another). The molecules which mediate the adhesion of eukaryotic cells to ECM components and to other cells, fall into 4 major classes: integrins, cadherins, selectins and the immunoglobulin superfamily.

Integrins are a family of molecules which are responsible for the adhesion of cells to the ECM which they synthesize. They are non-covalently associated heterodimer receptors. Integrins play a crucial role in the assembly of the ECM and thus have a profound effect on cell motility and growth. ECM components that serve as ligands for integrins include fibronectin, laminin, collagens, tenascin, vitronectin and fibrinogen. Integrins also coordinate signals from outside of the cell with intracellular events.

Cadherins are a family of Ca²⁺ -dependent mediators of cell-cell adhesion which are important in the formation and maintenance of intercellular junctions. Cadherins bind homotypically (i.e. binding to another molecule of the same cadherin on a neighboring cell). In general, cadherins function in maintaining tissue structural integrity. E-(epithelial) cadherin is expressed by nearly all adult epithelial tissues, while N-(neural) cadherin is expressed in neural and muscle cells.

Selectins also mediate cell-cell adhesion, but they do so through interaction of their extracellular carbohydrate-binding domains with heterotypic (i.e. binding to a different molecule) ligands. L-(leukocyte) selectin is expressed on lymphocytes and neutrophils, while E- and P- selectins are expressed on endothelial cells and platelets respectively. All three selectins have been implicated in the recruitment of lymphocytes into inflammatory tissue sites.

The immunoglobulin-like cell adhesion molecules (CAMs) mediate cell-cell adhesion via homotypic and heterotypic interactions. Cell-cell adhesion mediated by these CAMs is generally Ca²⁺ -dependent. These molecules have particularly important functions in neural development and in leukocyte trafficking.

Cell surface modifications.

The apical surface of epithelial cells may contain microvilli, cilia or stereocilia, while the basal and lateral surfaces often contain surface folds. These modifications are related to the function of the particular epithelium.

Microvilli are cytoplasmic fingerlike protrusions from the cell surface. They vary in appearance from small, irregular, bleblike projections to tall, closely packed, uniform projections which provide an enormous increase in the free surface area of the cell. In general, the number and shape of the microvilli in a given cell type correlate with its absorptive capacity. Cells whose principal function is the transport of fluid (e.g. kidney tubules), or nutrients (e.g. small intestine) contain many tall, closely packed microvilli. Each microvillus is an extension of the cytoplasm of the cell, and is covered by the plasma membrane. They also contain a core of 20-30 actin filaments which are anchored to the plasma membrane at the tip and sides of the microvillus, and extend down into the apical cytoplasm where they interact with a horizontal network of filaments, the terminal web. The actin filaments are responsible for movement of the microvilli, which probably aids in the absorption process.

Cilia appear as short, fine hairlike structures on the apical surface of the cell. The number of cilia per cell may vary from one to several hundred (as in the respiratory tract). Each cilium is associated with a single basal body, from which the cilium develops. When viewed in cross section, each cilium contains nine pairs of peripherally arranged microtubules surrounding two central microtubules. Cilia undergo a regular and synchronous undulating movement, creating a wave that sweeps across the epithelium (like the wind blowing across a field of wheat). This rhythmic movement is capable of moving fluid or particles across the surface of epithelia, or through tubular organs or ducts (e.g. removing saliva from the respiratory system).

Stereocilia are not cilia at all, they are just very long, nonmotile microvilli, which lack notable internal structural features. They are found in the epididymis of the male reproductive system, and in the sensory epithelium of the ear (hair cells), and are probably involved with the resorption of fluids. These stereocilia frequently aggregate to give the appearance of the hairs of a paint brush.

Lateral and basal folds

The lateral and basal surfaces of certain epithelial cells show numerous infoldings, or interdigitations of each cell with its neighbor. The infoldings increase the surface area of the cell, and are particularly prominent in cells which transport fluid rapidly, as in the intestinal epithelium. Mitochondria are typically located in the infoldings at the basal transporting surface to provide the energy requirements for active transport. The orientation of the mitochondria results in a striated appearance along the basal aspect of the cell when observed with the light microscope. You will clearly see this in some of the ducts of the salivary gland later on in this course.

Important definitions

In two general locations within the body, the epithelium and its underlying connective tissue form a functional unit called a "membrane."

A mucous membrane, also called the mucosa, lines the open cavities of the body, i.e. those cavities which connect with the outside of the body, (the alimentary canal, the respiratory tract and the genitourinary tract). It consists of a surface epithelium; a basement membrane and an underlying layer of connective tissue called the lamina propria, and sometimes a layer of smooth muscle, called the muscularis mucosa as the deepest layer. The basement membrane separates the epithelium from the lamina propria.

A serous membrane, also called the serosa, lines the closed cavities of the body, namely the abdominal, pleural and pericardial cavities. Structurally the serosa consists of a lining epithelium called mesothelium, a supporting connective tissue, and a basement membrane between the two.

The epithelial layers which are part of a mucosa or serosa are typically "wet" epithelia, i.e. they are in contact with fluid of some kind. Thus we do not call the skin a mucosa or a serosa.