The human body is composed of four basic types of tissues, epithelium being one of them. It is present on almost every part of the human body, hence it has several important functions. For example, it has roles in protection, absorption, secretion, and sensation. Its dominant presence also suggests that there are various types of epithelia in order to cater for the varied human body structures.
The main classifications of epithelium are simple and stratified, each one being further divided into several subtypes according to two main factors: cell shape and apical surface specialization. This article will describe stratified (multi-layered) epithelium, focusing on its general characteristics and each major sub-type.
Internal cavities and tubes
Parenchyma of glands
- nonkeratinized (covers the mucosa)
- keratinized (skin)
Cuboidal (lines excretory ducts of glands)
Columnar (conjunctiva of the eyelids)
Transitional (urinary tract)
Stratum lucidum (specific to thick skin)
2-3 layers of cuboidal cells
2-3 layers of columnar cells
This article will discuss the histology of the stratified epithelium.
- Stratified squamous epithelium
- Stratified cuboidal epithelium
- Stratified columnar epithelium
- Transitional epithelium
- Clinical points
Functions and location
Epithelium is one of the four basic types of tissues composing the human body. It is an avascular type of tissue composed of cells with little extracellular matrix, connected by strong intercellular adhesions. They have the appearance of cellular sheets. Epithelium is present almost everywhere in the human body; it covers body surfaces, it lines internal cavities and tubes, forms the parenchyma of glands and can function as sense receptors. The prevalence and location of epithelium reflects its principal functions:
In addition, any substance entering or leaving any tissue or organ must pass through the epithelium. This movement can be either facilitated or inhibited by the epithelium, making it a selective barrier.
The epithelial cells have several characteristics: they contain cell junctions, which allow tight intercellular adhesions. They are polar, having distinct apical, lateral, and basal surface domains. Lastly, their basal surface is attached to a noncellular layer called the basement membrane.
Epithelium is classified descriptively, according to three factors: the number of cell layers forming it, the shape of surface cells, and the specialization of the apical surface domain. The types of epithelium are the following:
Cuboidal (with microvili, without microvili)
Columnar (with microvili, with surface cilia, with stereocilia, with pseudostratification)
Squamous (nonkeratinized, keratinized)
As the epithelium is so predominant and continuously exposed to potentially damaging factors, epithelial cell populations are capable of continuous self-renewal. The rate of cell turnover depends on the type of epithelium. For example, the replacement rate for simple columnar epithelial cells in the small intestine is four to six days, while stratified squamous epithelium of the skin is renewed every 28 days.
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Stratified epithelium consists of two or more cell layers. There is a great amount of variability between the layers due to various cellular shapes and heights. The three types of cellular shapes are squamous, cuboidal, and columnar. Squamous cells have a width greater than the height and contain an ovoid, centered nucleus. The width and height of cuboidal cells are approximately equal and they contain a round, centered nucleus. For columnar cells, the width is smaller than the height, while the nucleus is ovoid and positioned basally.To establish a standard nomenclature, only the shape of the cells within the surface layer is used to sub-classify this tissue type (see above). For example, stratified cuboidal epithelium consists of multiple cellular layers, with the surface layer being made up of cube-shaped cells. The layers situated at a deeper layer can consist of cells of different shapes, but they are generally cuboidal. For squamous stratified epithelium, there is a third sub-classificational feature: the keratinization, or lack thereof, of the apical surface domains of the cells. A typical example of stratified squamous keratinized epithelium is the epidermis.
The function of stratified epithelium is mainly protection. In fact, this specific role is reflected in the direct influence of the type of physical stresses on the degree and nature of the stratification. To perform their main function adequately, stratified epithelium is also quite thick, making it particularly poor for secretion or absorption. However, some stratified surfaces exhibit some degree of permeability for water and small molecules.
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Stratified squamous epithelium
It is important to realize that the difference between “nonkeratinized” and “keratinized” stratified squamous epithelium (SSE) is not the absence or presence of keratin, respectively. Instead, the distinction lies in the amount of keratinized cells present inside the epithelium because both types actually contain this type of fibrous protein.
Nonkeratinized SSE is composed of a variable number of layers. The cells in the deeper, basal layer appear cuboidal with a clear cytoplasm usually, due to their glycogen content. The cells in the surface layer are squamous, or flat. The basal layer is attached to the basement membrane, a sheet of extracellular matrix proteins. It also contains stem cells that are crucial in the self-renewal process. Stem cells continuously divide within the basal layer and migrate towards the apical layer. They replace old cells within this layer, which in turn are subsequently shed as anucleated squamous cells.
Non-keratinized epithelium usually bears a mucous membrane, which serves as an additional protective and lubricating layer of the epithelium. It may be seen in the some parts of the oral cavity, pharynx, esophagus, distal ureters, vagina and external female genitalia. Nonkeratinized epithelium does contain some keratinized cells, however the amount of keratin deposition will vary depending on the level of dessication and abrasion it may be exposed to. For example, in instances of individuals with a history of chronic smoking or alcohol use, the epithelia of the oropharynx and upper digestive tract can become atypically keratinized. Furthermore, clenching or grinding of teeth against the non-keratinized epithelium of the buccal mucosa may result in the formation of calloused tissue.
As the amount of keratin is quite low in this sub-class of stratified epithelium, the flat shaped cells retain their normal, characteristic nuclei and metabolic functions.
Keratinzed stratified squamous epithelium is important in tissues exposed to regular physical abrasion, as well as the possibility of desiccation (drying out) and water loss. Keratinized epithelium, is composed of numerous layers of dead squamous cells, which are specially structured to be waterproof and reduce evaporation from underlying tissues. Therefore they constitute an important part of the epidermis or external skin. They are also found in certain regions of the oral cavity (e.g. hard palate, dorsum of the tongue) where eating, speaking and breathing could result to significant loss of water. Keratinized cells are most commonly identified by their anuclear appearance.
While nonkeratinized SSE contains a relatively small amount of keratin, the keratinized sub-class is full of it. The best example of keratinized SSE is the epidermis of the skin. It consists of either four distinct layers in thin skin or five in thick skin. They are called, starting from the deepest:
- stratum basale
- stratum spinosum
- stratum granulosum
- stratum lucidum (specific to thick skin)
- stratum corneum
The stratum basale (basal layer) consists of stem cells that continuously divide by mitosis to give rise to keratinocytes. These basal keratinocytes have a small amount of basophilic cytoplasm, closely packed nuclei, and a cuboidal or low columnar shapes. They are arranged in a single layer and contain highly irregular and folded basal surfaces with a high number of hemidesmosomes, which are responsible for the attachment of the stratum basale to the lamina lucida of the basement membrane.
The basal layer also contains scattered melanocytes. These cells contain specific granules called melanosomes, which are responsible for the production of the precursor to pigment melanin. This pigment gives the skin its characteristic colour and protects against ultraviolet radiation. In routine H&E stains, melanocytes appear rounded with a clear cytoplasm. However, in more detailed examinations, it is clear that melanocytes contain some specific cytoplasmic processes which extend between keratinocytes within the stratum spinosum. These processes are used for transferring melanosomes to keratinocytes, which ultimately situate like a cap over their nuclei.
The stratum spinosum (spinous layer) consists of keratinocytes that have migrated from the stratum basale, located below. The stratum spinosum is in fact multilayered, rather than one discrete and single layer. Keratinocytes also synthesize cytokeratins (intermediate filaments) that subsequently aggregated into tonofibrils. The surface of these cells contains desmosomes, which form intercellular junctions. In this layer, the keratinocytes are shaped like a polyhedron, have round-oval nuclei, prominent nucleoli and cytoplasms. They also synthesize cytokeratins (intermediate filaments) that subsequently aggregated into tonofibrils.
As the keratinocytes continue their migration, they enter the stratum granulosum (granular layer). As the cells mature, they synthesize irregularly shaped keratohyalin granules (densely basophilic) that contain various proteins, such as involucrin, loricrin and filaggrin. These protein types interact with the previously produced tonofibrils, to result in cross-linked intermediate filaments called keratin.
The keratinocytes also produce lamellar bodies, which are tubular or ovoid shaped granules that are assembled by the Golgi complex. In fact, these bodies are heterogenous mixtures, or assemblies of probarrier lipids, lipid processing enzymes, proteins, and proteases. They can be membrane bound and hence coat the cell’s membrane or secreted within the extracellular space. Their contents allow the lamellar bodies to form an epidermal water barrier, which is hydrophobic. This overall process is called keratinisation (cornification). This is considered a special type of apoptosis because the typical cellular fragmentation is replaced by keratin accumulation. In the epidermis, keratinisation happens continuously. However, its rate can be induced by excessive abrasion. Some examples include incorrectly fitted teeth within the oral cavity (nonkeratinized SSE) or high frictional levels of the skin (keratinized SSE), leading to calluses. Overall, the high amount of keratin makes the epidermis extremely resilient to the constant mechanical abrasion it is exposed to.
The stratum lucidum is apparent only in thick skin, providing protection against increased friction This layer contains visible eosinophilic cells, but as a whole, this layer is highly refractile and stains quite poorly. The cells contain a high amount of keratin, hence the nucleus and other organelles have disrupted morphologies.
The stratum corneum is the topmost, non-living, cellular layer of the epidermis composed of terminally differentiated keratinocytes. They are filled with keratin intermediate filaments, giving them quite an irregular and flatter shape than normal. In addition, they are quite thin, anucleated, and have no cytoplasmic organelles, hence they are metabolically inactive.
Their plasma membrane is also thickened and their pH ranges between 4.5 to 6. At this stage, they are known as keratin squames. Together they form a pattern called orthokeratosis, which is the normal presentation of squamous cells in the stratum corneum, that when together, create a basket-weave pattern. The squames are also coated with an extracellular layer of lipids, allowing them to repel water and make the epidermis and efficient water barrier. In this layer, the process of desquamation happens regularly. It involves the exfoliation and loss of the squames through the degradation of their intercellular desmosomes.
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Stratified cuboidal epithelium
Stratified cuboidal epithelium is quite thin, consisting of two or three layers of cuboidal cells. This type is relatively rare, occurring specifically in the lining of excretory ducts, such as salivary and sweat glands. Its main function is structural reinforcement, since it is not significantly involved in absorption or secretion.
Stratified columnar epithelium
Similarly to the cuboidal sub-type, stratified columnar epithelium is quite rare. It is located in the conjunctiva inside the eyelids and areas of tissue transition. It is mostly responsible for protection and mucous secretion.
Location and characteristics
Transitional epithelium (TE), also called urothelium, is a special type of stratified epithelium. It lines the urinary tract, specifically the major and minor calyces in the kidney, renal pelvis, ureters, bladder, the proximal part of the urethra, and the prostate gland in males. As it travels through the excretory passages, TE increases from two cell layers (minor calyces) to four or five (in the ureter) and ends up consisting of at least six (in the empty bladder).
It is called transitional because it contains mixed features from both stratified cuboidal and stratified squamous epithelia. The features that make this epithelium special are:
- its distention capability
- resistance to the toxicity of urine
- impermeability to water and salts
When a respective structure of the urinary tract fills up with urine, the pressure inside increases, subsequently increasing the surface area. To accommodate this phenomenon, the individual cells unfold and flatten. This ability is the reason for the high variation in the number of cell layers observed in nondistended components of the urinary tract, mentioned above. In fact, this number is consistent throughout, being two or three layers.
Following hematoxylin and eosin staining (H&E), surface cells from empty excretory components are termed umbrella (dome shaped) cells. They have a cuboidal shape and a curved apical surface that bulges into the lumen, giving them a large and rounded appearance. They can also contain two nuclei. However, their appearance is influenced by the extent of distention, so it can vary. Upon examination with the transmission electron microscope (TEM), the cells’ apical surfaces contain regions of modified plasma membrane called plaques. These plaques are especially rigid and thick. They are also attachment points for actin filaments, extending from their inner surfaces into the cytoplasm of the cells. These filaments prevent excessive stretching during distension. Plaques are separated by interplaque regions, which consist of normal plasma membrane. In relaxed states, the plaques are invaginated, forming distinctive fusiform vesicles. However, they are only apparent rather than completely closed vesicles because their lumens are continuous with the cells’ exterior. These vesicles unfold and disappear during distention, as the plaques become part of the cell surface. Umbrella cells also display small vesicles and mitochondria.
As urothelium is classified as stratified epithelium, it is multi-layered. Underneath the umbrella cells, which are located at the surface, a layer of intermediate cells can be found. They have a pyriform shape and contain long, thin cytoplasmic processes (tails) that anchor the urothelium layers to the basement membrane via special anchoring proteins. Both of those layers originate from basal cells, which form the deepest layer of TE. This single cell layer directly contacts the connective tissue and capillary bed.
Psoriasis is an autoimmune condition that affects the skin. This condition is called parakeratosis, where nuclei are retained in the stratum corneum, which indicates a hyperproliferative disorder. These modified squames form an opaque, flakey and white layer, which is commonly observed in psoriatic plaques. Epidermal hyperplasia is a common manifestation, which is due to an excessively fast maturation of keratinocytes. Normally, their maturation and keratinisation are very regulated and slow processes that last approximately 50 to 60 days. In psoriasis, this entire process takes up to 7 days. This extremely short timeframe results in the improper development of tonofibrils, keratohyalin granules, and nuclear degeneration in the keratinocytes of the stratum granulosum. This ultimately results in an abnormal basal layer and keratin squames that are nucleated in the stratum corneum (normally they should be anucleated).
Epithelial metaplasia involves a change from one mature type of epithelium into another. It is an adaptive process propelled by the cells’ adaptive response to stressful stimuli, such as chronic inflammation. Hence, the new cell type is more suited to deal with these new conditions. One type is squamous to columnar epithelial metaplasia. This happens in Barrett’s syndrome, where stratified squamous nonkeratinized epithelium in the lower portion of the esophagus transforms into simple columnar epithelium in response to frequent gastroesophageal reflux.
Metaplasia is reversible, meaning that once the stress is removed, the cells revert back to their original type. However, if the stimuli persist for a long time, the epithelium can transform into a carcinoma. This is usually the case in cancers affecting the lungs, cervix and the bladder.
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