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Epithelium and Glands


Epithelium

Epithelial tissue forms two distinct structural and functional forms: sheets of contiguous cells ( epithelia ), which cover the external and internal surfaces of the body, and clusters of cells ( glands ), which originate from invaginated epithelial cells.

All three germ layers give rise to epithelia. The oral and nasal mucosae, cornea, epidermis of skin, and glands of the skin and mammary glands are derived from ectoderm ; liver, pancreas, and lining of the respiratory and gastrointestinal tract are derived from the endoderm ; and the uriniferous tubules of the kidney, lining of the male and female reproductive systems, endothelial lining of the circulatory system, and mesothelium of the body cavities develop from the mesoderm .

Epithelial tissues have numerous functions:

  • Protection of underlying tissues of the body from abrasion and injury

  • Transcellular transport of molecules across epithelial sheets

  • Secretion of mucinogen (the precursor of mucus), hormones, enzymes, and other molecules from various glands

  • Absorption of material from a lumen (i.e., intestinal tract or certain kidney tubules)

  • Selective permeability , that is, the control of movement of materials between body compartments

  • Detection of sensations via taste buds, retina of the eye, and specialized hair cells in the ear

Epithelium

Tightly bound contiguous cells forming sheets covering or lining the body are known as an epithelium.

The sheets of contiguous cells in the epithelium are tightly bound together by junctional complexes. Epithelia possess little extracellular space and little extracellular matrix. Epithelium is separated from the underlying connective tissue by an extracellular matrix, the basement membrane , composed of the basal lamina and the lamina reticularis (discussed in Chapter 4 ), synthesized by the epithelial cells and cells of the connective tissue. Because epithelium is avascular, the adjacent supporting connective tissue through its capillary beds supplies nourishment and oxygen via diffusion through the basement membrane.

Classification of Epithelial Membranes

Cell arrangement and morphology are the bases of classification of epithelium.

Epithelial membranes are classified according to the number of cell layers between the basal lamina and the free surface and by the morphology of the surface-most epithelial cells ( Table 5.1 ). If the membrane is composed of a single layer of cells , it is called simple epithelium ; if it is composed of more than one cell layer , it is called stratified epithelium ( Fig. 5.1 ). The morphology of the cells may be squamous (flat), cuboidal, or columnar when viewed in sections taken perpendicular to the basement membrane. Stratified epithelia are classified by the morphology of the cells in their superficial layer only . In addition to these two major classes of epithelia, which are further identified by cellular morphology, there are two other distinct types: pseudostratified and transitional (see Fig. 5.1 ).

  • Simple squamous epithelium is composed of a single layer of tightly packed, thin, or low-profile polygonal cells. When viewed from the surface, the epithelial sheet looks much like a tile floor with a centrally placed bulging nucleus in each cell ( Figs. 5.2A, 5.3 ). Viewed in section, however, only some cells display nuclei because the plane of section frequently does not encounter the nucleus. Simple squamous epithelia line pulmonary alveoli, compose the loop of Henle and the parietal layer of Bowman capsule in the kidney, and form the endothelial lining of blood and lymph vessels as well as the mesothelium of the pleural, pericardial, and peritoneal cavities.

    Fig. 5.2, Light micrographs of simple epithelia. (A) Simple squamous epithelium (arrows) . Note the morphology of the cells and their nuclei. Simple cuboidal epithelium (arrowheads) . Note the round, centrally placed nuclei (×270). (B) Simple columnar epithelium. Observe the oblong nuclei (N) and the striated border (arrows) (×540).

    Fig. 5.3, Light micrograph of the kidney cortex displaying simple squamous epithelium (SSE) and simple cuboidal epithelium (SCuE). L, lumen. Note that the nuclei of the simple squamous epithelial cells—when in the plane of the section—bulge into the lumen and that the cytoplasm of the cell is highly attenuated. In three dimensions, it would resemble a fried egg (over medium). The nuclei of cuboidal epithelial cells are round and mostly basally located (away from the lumen). In three dimensions, it would resemble a square glass with a round ice cube at the bottom. (×540)

  • A single layer of polygon-shaped cells constitutes simple cuboidal epithelium (see Figs. 5.2A and 5.3 ). When viewed in a section cut perpendicular to the surface, the cells present a square profile with a centrally placed round nucleus. Simple cuboidal epithelia form the ducts of many glands of the body, the covering of the ovary, and many kidney tubules.

  • The cells of simple columnar epithelium , when viewed in longitudinal section, are tall, rectangular cells whose ovoid nuclei are usually located essentially at the same level in the basal half of the cell (see Fig. 5.2B ). Simple columnar epithelium may exhibit a striated border composed of microvilli , narrow, finger-like cytoplasmic processes that project from the apical surface of the cells into the lumen. Simple columnar epithelium lines much of the digestive tract, gallbladder, and large ducts of glands; those that line the uterus, oviducts, ductuli efferentes, and small bronchi are ciliated. In these organs, cilia (hair-like structures) project from the apical surface of the columnar cells into the lumen.

  • Stratified squamous (nonkeratinized) epithelium is thick; because it is composed of several layers of cells, only the deepest layer is in contact with the basal lamina ( Fig. 5.4A ). The most basal (deepest) cells of this epithelium are cuboidal in shape, those located in the middle of the epithelium are polymorphous, and the cells composing the free surface of the epithelium are flattened (squamous)—hence, the name stratified squamous. Because the surface cells are nucleated, this epithelium is called nonkeratinized. It is wet and lines the mouth, oral pharynx, esophagus, true vocal folds, and vagina.

    Fig. 5.4, Light micrographs of stratified epithelia. (A) Stratified squamous nonkeratinized epithelium. Observe the many layers of cells and flattened (squamous), nucleated cells in the top layer (arrow) (×509). (B) Stratified squamous keratinized epithelium (×125). (C) Stratified cuboidal epithelium of the duct of a sweat gland (CC) (×509). (D) Transitional epithelium. Observe that the surface cells facing the lumen of the bladder are dome shaped (arrows) , which characterize transitional epithelium (×125).

  • Stratified squamous (keratinized) epithelium is similar to stratified squamous (nonkeratinized) epithelium except that the superficial layers of the epithelium are composed of dead cells whose nuclei and cytoplasm have been replaced with keratin (see Fig. 5.4B ). This epithelium constitutes the epidermis of skin, a tough layer that resists friction and is impermeable to water. There is another category of stratified squamous epithelium—namely, stratified squamous parakeratinized epithelium—which is discussed in Chapter 16 .

  • Stratified cuboidal epithelium , which contains only two layers of cuboidal cells, lines the ducts of sweat glands (see Fig. 5.4C ).

  • Stratified columnar epithelium is composed of a low polyhedral to cuboidal deeper layer in contact with the basal lamina and a superficial layer of columnar cells. This epithelium is found in only a few places in the body: the conjunctiva of the eye, some large excretory ducts, and regions of the male urethra.

  • Transitional epithelium is composed of many layers of cells; those located basally are either low columnar or cuboidal cells. Polyhedral cells compose several layers above the basal cells. This epithelium is located exclusively in the urinary system, where it lines the urinary tract from the renal calyces to the urethra. The most superficial cells of the empty bladder are large, occasionally binucleated, and exhibit rounded dome tops that bulge into the lumen (see Figs. 5.4D and 5.5 ). These dome-shaped cells become flattened, and the epithelium becomes thinner when the bladder is distended with urine.

    Fig. 5.5, This is a photomicrograph of the lining of an empty human urinary bladder. Note that the transitional epithelium (TE) that lines the lumen (L) is composed of several cell layers and that the superficial layer of cells are plump and dome shaped (DSC). The basement membrane (arrow) separates the epithelium from the urinary bladder connective tissue (CT). The epithelial cells between the basement membrane and the dome-shaped cells vary from cuboidal to low columnar in shape. (×540)

  • Pseudostratified columnar epithelium appears to be stratified, but it is actually composed of a single layer of cells. All of the cells in pseudostratified columnar epithelium are in contact with the basal lamina, but only some cells reach the surface of the epithelium ( Fig. 5.6 ). Cells not extending to the surface usually have a broad base and become narrow at their apical end. Taller cells reach the surface and possess a narrow base in contact with the basal lamina and a broadened apical surface. Because the cells of this epithelium are of different heights, their nuclei are located at different levels, giving the impression of a stratified epithelium, even though it is composed of a single layer of cells. Pseudostratified columnar epithelium is found in the male urethra, epididymis, and larger excretory ducts of glands. The most widespread type of pseudostratified columnar epithelium is ciliated , having cilia on the apical surface of the cells that reach the epithelial surface. Pseudostratified ciliated columnar epithelium is found lining most of the trachea and primary bronchi, the auditory tube, part of the tympanic cavity, the nasal cavity, and the lacrimal sac.

    Fig. 5.6, Light micrograph of pseudostratified epithelia. This type of epithelium appears to be stratified; however, all of the epithelial cells in this figure stand on the basal lamina (BL) (×540).

TABLE 5.1
Classification of Epithelia
Type Shape of Surface Cells Sample Locations Functions
Simple
Simple squamous Flattened Lining: Pulmonary alveoli, loop of Henle, parietal layer of Bowman capsule, inner and middle ear, blood and lymphatic vessels, pleural and peritoneal cavities Limiting membrane, fluid transport, gaseous exchange, lubrication, reducing friction (thus aiding movement of viscera), lining membrane
Simple cuboidal Cuboidal Ducts of many glands, covering of ovary, form kidney tubules Secretion, absorption, protection
Simple columnar Columnar Lining: Oviducts, ductuli efferentes of testis, uterus, small bronchi, much of digestive tract, gallbladder, and large ducts of some glands Transportation, absorption, secretion, protection
Pseudostratified All cells rest on basal lamina but not all reach epithelial surface; surface cells are columnar. Lining: Most of trachea, primary bronchi, epididymis and ductus deferens, auditory tube, part of tympanic cavity, nasal cavity, lacrimal sac, male urethra, large excretory ducts Secretion, absorption lubrication, protection, transportation
Stratified
Stratified squamous (nonkeratinized) Flattened (with nuclei) Lining: Mouth, epiglottis, esophagus, vocal folds, vagina Protection, secretion
Stratified squamous (keratinized) Flattened (without nuclei) Epidermis of skin Protection
Stratified cuboidal Cuboidal Lining: Ducts of sweat glands Absorption, secretion
Stratified columnar Columnar Conjunctiva of eye, some large excretory ducts, portions of male urethra Secretion, absorption, protection
Transitional Dome shaped (relaxed), flattened (distended) Lining: Urinary tract from renal calyces to urethra Protection, distensible

Fig. 5.1, Types of epithelia.

Polarity and Cell-Surface Specializations

Epithelial cell polarity and cell-surface specializations are related to cellular morphology and function.

Epithelial cells have distinct morphological, biochemical, and functional domains and, thus, commonly display a polarity support these various regions. Consequently, many epithelial cells possess an apical domain that faces a lumen and a basolateral domain whose basal component is in contact with the basal lamina. The functional distinctions of these regions are responsible for the presence of surface modifications and specializations of these domains in that the apical surfaces of many epithelial cells may possess microvilli or cilia, whereas their basolateral regions may exhibit various junctional specializations and intercellular interdigitations. The apical and basolateral domains are isolated from each other by tight junctions that encircle the apical aspect of the cell.

Apical Domain

The apical domain represents the free surface of the epithelial cells.

The apical domain is that region of the epithelial cell that abuts the lumen; it is rich in ion channels, carrier proteins, ATPase (adenosine triphosphatase, transmembrane ATPase), glycoproteins, and hydrolytic enzymes as well as aquaporins , proteins that form channels that regulate the water balance of the cell. Regulated secretory products are released from the epithelial cells at the apical domains. Modifications of the apical surface that facilitate many of the functions of epithelial cells include microvilli (and associated glycocalyx) as well as stereocilia, cilia, and flagella.

Microvilli

Microvilli are small, finger-like cytoplasmic projections emanating from the free surface of the cell into the lumen.

Microvilli represent the striated border of the intestinal absorptive cells and the brush border of the kidney proximal tubule cells observed by light microscopy. Electron microscopy demonstrated these closely packed microvilli to be 1 to 2 μm long cylindrical, membrane-bound projections that greatly increase the surface areas of these cells ( Fig. 5.7 ). In other, less active cells, microvilli may be sparse and short. Each microvillus contains a core bundle of 25 to 30 actin filaments , whose members are cross-linked to each other by a number of actin-binding proteins, such as espin , fascin , villin , and fimbrin . The plus ends of the actin filaments are embedded in an amorphous region composed mostly of villin, at the tip of the microvillus. The minus ends of the actin filaments are embedded in and attached to the terminal web , which is a complex of actin and spectrin molecules, as well as intermediate filaments located at the cortex of the epithelial cells ( Figs. 5.8, 5.9, and 5.10 ). Myosin-I and calmodulin provide structural support by connecting the actin filaments at the periphery of the bundle to the plasma membrane of the microvillus. Tropomyosin and myosin II , located in the terminal web, act on the actin filaments , causing contraction of the apical aspect of the cell, thereby spreading the microvilli apart, increasing the space available for molecular transport at the cell apex. Epithelia not functioning in absorption or transport may exhibit microvilli without cores of actin filaments.

Fig. 5.7, Electron micrograph of microvilli of epithelial cells from the small intestine (×2800).

Fig. 5.8, High-magnification electron micrograph of microvilli (×60800).

Fig. 5.9, Electron micrograph of the terminal web and microvillus. Observe that the actin filaments of the microvilli are attached to the terminal web (A, ×83060; B, inset, ×66,400).

Fig. 5.10, Schematic diagram of the structure of a microvillus.

An amorphous, fuzzy coating over the tips of the microvilli, the glycocalyx is composed of carbohydrate residues attached to the transmembrane proteins of the plasmalemma. These glycoproteins function in the realms of protection and cell recognition (see Chapter 2 ).

Stereocilia (not to be confused with cilia) are long, rigid, nonmotile microvilli present only in the epididymis and on the sensory hair cells of the cochlea (inner ear). The core actin filaments of stereocilia are held together by fimbrin . The peripheral-most members of the actin filament bundle are bound to the stereocilia’s membrane by ezrin and villin-2 ; there is no villin at the tip of the stereocilia where the plus ends of the actin filaments terminate. The minus ends of the actin filaments terminate in the terminal web. In the epididymis, stereocilia probably function in increasing the surface area; in the hair cells of the ear, they function in signal generation.

Cilia

Cilia are of two types: long, motile, hair-like structures emanating from the apical cell surface (whose core is composed of a complex arrangement of microtubules known as the axoneme) and primary cilia, which are similar but are nonmotile.

Motile cilia (called cilia in this textbook) are hair-like projections that emanate from the surface of certain epithelial cells. Usually, they are 7 to 10 μm long and 0.2 μm in diameter. Cilia of the respiratory tree, for example, move mucus and debris toward the oropharynx via rapid, rhythmic oscillations, where they may be swallowed or expectorated. Cilia of the oviduct move the fertilized ovum toward the uterus.

The internal structure of cilia, as demonstrated by electron microscopy, reveals that the core of the cilium contains complex microtubules called the axoneme , which is composed of a constant number of longitudinal microtubules arranged in a specific 9 + 2 organization ( Figs. 5.11 and 5.12 ) . Two centrally placed microtubules ( singlets ) are surrounded by nine doublets of microtubules. The singlets are separated from one another, both display a circular profile in cross-section, and each is composed of 13 protofilaments. The nine doublets are each composed of two subunits. In cross-section, subunit A is a microtubule composed of 13 protofilaments, exhibiting a circular profile. Subunit B possesses 10 protofilaments, exhibits an incomplete circular profile in cross-section, and shares three protofilaments of subunit A.

Fig. 5.11, Schematic diagram of the microtubular arrangement of the axoneme in the cilium.

Fig. 5.12, Electron micrographs of cilia. (A) Longitudinal section of cilia (×36000). (B) Cross-sectional view demonstrating microtubular arrangement in cilia (×88000).

Several elastic protein complexes are associated with the axoneme. Radial spokes project from subunit A of each doublet inward toward the central sheath surrounding the two singlets. Neighboring doublets are connected by nexin , another elastic protein, extending from subunit A of one doublet to subunit B of the adjacent doublet (see Fig. 5.11 ).

The microtubule-associated protein dynein has ATPase activity and is known as the ciliary dynein arm . Two dynein arms, an inner and an outer , radiate from subunit A of one doublet toward subunit B of the neighboring doublet. These dynein arms are arranged at 24-nm intervals along the length of subunit A so that subunit A resembles a millipede and its numerous bilaterally symmetrical legs. Dynein ATPase, by hydrolyzing ATP, provides the energy for the ciliary bending. Movement of the cilia is initiated by the dynein arms transiently attaching to specific sites on the protofilaments of the adjacent doublets, sliding them toward the tip of the cilium. However, nexin , an elastic protein extending between adjacent doublets, restrains this action to some degree, thus translating the sliding movement into a bending motion. As the cilium bends, an energy-requiring process , the elastic protein complex is stretched. When the dynein arms release their hold on the B subunit, the stretched elastic protein complex returns to its original length, thereby snapping the cilium back to its straight position ( requiring no energy ). This snapping movement of the cilium back to its original position causes the movement of the material at the tip of the cilium. An additional protein, tektin , which resembles a rod and is approximately 2 to 3 nm in diameter, assembles head to tail to form a “rod” along the entire doublet microtubule. This tektin rod is located at the junction of microtubules A and B, close to the outer dynein arm, acting as a support for the doublet and preventing the cilium from bending too far.

Clinical Correlations

Kartagener syndrome results from hereditary defects in the ciliary dynein that would normally provide the energy for ciliary bending. Thus, ciliated cells without functional dynein are prohibited from functioning. Persons having this syndrome are susceptible to lung infections because their ciliated respiratory cells fail to clear the tact of debris and bacteria. Additionally, males with this syndrome are sterile because their sperm are immotile.

The 9 + 2 microtubule arrangement within the axoneme continues throughout most of the length of the cilium except at its base, where it is attached to the basal body (see Fig. 5.11 ). The morphology of the basal body is similar to that of a centriole in that, instead of nine doublets and a pair of singlets, it is composed only of nine triplets and no singlets. The basal body and its associated components are responsible for the adherence of the cilium to the cell and for the ability of all of the cilia of the cell to beat in a uniform fashion and in the identical direction.

Basal bodies develop from procentriole organizers . As the procentriole lengthens, a third microtubule, microtubule C , is added to microtubule B. The new microtubule is also composed of 10 protofilaments and shares 3 of microtubule B’s protofilaments. Once formed, the basal body migrates to the apical plasmalemma and gives rise to a cilium. At this junction of the basal body and the axoneme, known as the transition zone , nine doublet microtubules develop from the nine triplets of the basal body, and a pair of central microtubules, the two singlets , forms to give the cilium’s axoneme its characteristic 9 + 2 microtubule arrangement. Arising from this transition zone and attached to microtubule C is the alar sheath , a fibrous semipermeable membrane that forms an upside-down, tent-like cover whose tip encloses microtubule C and whose base attaches to the cell membrane around the region where the cilium emerges from the cell, effectively separating the cytoplasm of the cilium from that of the cell. Two additional structures are associated with the basal body: the basal foot , which is responsible for orienting the cilia so that all cilia face and beat in the same direction, and the striated rootlet , which is believed to anchor the basal body into the apical cytoplasm.

Cilia (as well as flagella) require the constant transport of various substances in and out of their cytoplasm. Generally, this movement is known as axonemal transport ; however, within cilia, it is referred to as intraciliary transport ( intraflagellar transport in flagella). If it occurs from the basal body toward the tip of the cilium, it is known as anterograde intraciliary transport ; in the opposite direction, it is known as retrograde intraciliary transport . The material to be transported (e.g., tubulin molecules) is referred to as cargo . The transport of cargo is performed by carrier proteins known as raft proteins , which are ferried in the anterograde direction by kinesin-2 and in the retrograde direction by dynein-2 along the outer aspect (facing the plasmalemma of the cilia) of the axoneme microtubules. The change of direction from anterograde to retrograde intraciliary transport occurs at the distal tip of the cilia and depends on the presence of the enzyme intestinal cell kinase (ICK) , which phosphorylates a subunit of kinesin-2, a motor-protein that functions not only in intraciliary transport but also in ciliogenesis, the formation of cilia. In the absence of ICK, intraciliary transport ceases, and ciliogenesis does not occur in the proper fashion.

Clinical Correlations

Individuals with Majewski polydactyly syndrome , a recessive autosomal defect, have been shown to have abnormally developed chondrocyte cilia. These individuals display abnormal chondrogenesis, as well as abnormal osteogenesis, resulting in shortened limbs, narrowed thoracic cage, fused fingers and toes, genital malformations, cardiovascular problems, and respiratory insufficiency, among numerous other congenital defects. It appears that the chondrocyte cilia of these individuals are foreshortened and display a bulbous expansion, and their intraciliary retrograde transport was disrupted.

Primary Cilia

Primary cilia are nonmotile and are noted to be present on most mammalian cells that are not participating in the cell cycle, that is, they are in the G o state. Each cell possesses a single primary cilium that functions in surveying its immediate environment and in eliciting the cell to respond to changes in that milieu. The axoneme of primary cilia has no central singlets, dynein arms, central sheath, or radial spokes. Their nine doublets resemble those of the motile cilia’s axoneme. Primary cilia display the presence of a protein complex, known as the BBSome complex (Bardet-Biedl syndrome protein complex) at the junction of the basal body with the basal foot. The BBSome complex, in a fashion similar to COP I, COP II, and clathrin, forms a membrane coat that sorts, binds to, and ferries membrane proteins (e.g., membrane-bound receptors), into the cytoplasm of primary cilia to be inserted into their plasmalemma.

The basal foot serves a similar role in primary cilia as it does in motile cilia; it ensures that primary cilia of all cells in the region are aligned in the same direction, thus, they are exposed to the same conditions.

Clinical Correlations

A number of genetic disorders that involve primary and motile cilia are known as ciliopathies . These involve various mutations that result in disturbances in the intraciliary transport and may be lethal during fetal life or early in postnatal development.

Some of these mutations involve the MKS1 gene ( Meckel syndrome, type 1 ) that codes for MKS1 protein . This protein, in conjunction with another protein known as meckelin , is associated with the basal body and is essential for ciliogenesis, and its mutant form is responsible for the lethal genetic ciliopathy known as Meckel syndrome . The symptoms of this condition include aberrant formation of the central nervous system, defects in hepatogenesis, polydactyly, and the formation of renal cysts that cause an enormous enlargement of the kidneys.

Other mutations involve genes coding for melanocortin-4 receptor ( MC4R ), a protein that associates with the enzyme adenylate cyclase 3 ( ADCY3 ) on the primary cilia of certain neurons of the paraventricular nucleus of the hypothalamus. These neurons regulate body weight by monitoring the energy storage of the body and adjusting energy outflow and ingestion of food. Mutated MC4R cannot join with ADCY3; as a consequence, adenylyl-cyclase signaling is inhibited, resulting in severe obesity in the affected individuals.

Flagella

The only cells in the human body that possess flagella are the spermatozoa. The structure of flagella is discussed in Chapter 21 , which covers the male reproductive system.

Basolateral Domain

The basolateral domain includes the basal and lateral aspects of the cell membrane.

The basolateral domain may be subdivided into two regions: the lateral plasma membrane and the basal plasma membrane. Each region possesses its own junctional specializations and receptors for hormones and neurotransmitters. In addition, these regions are rich in Na + -K + ATPase and ion channels and are sites for constitutive secretion.

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