EPIDERMIS

The epidermis is a keratinized stratified squamous epithelium derived from ectoderm and is the outermost layer of the skin (Fig. 16-2). In regions with a heavy protective coat of hair, the epidermis is thin; in nonhairy skin, such as that of the mucocutaneous junctions, the epidermis is thicker. Cells of the epidermis undergo an orderly pattern of proliferation, differentiation, and keratinization, the processes of which are not completely understood. During development, the epidermis can become specialized to form various skin appendages such as hair; sweat and sebaceous glands; digital organs (hoof, claw, digital pads); feathers; horn; and specialized glands.

TABLE 16-1 Functions of the Skin

The cells of the epidermis are categorized into two major groups: keratinocytes and nonkeratinocytes. The epidermal layers can be classified from the basement membrane to the outer surface as follows: stratum basale (basal layer), stratum spinosum (spinous or prickle layer), stratum granulosum (granular layer), stratum lucidum (clear layer), and stratum corneum (horny layer).

Epidermal Keratinocytes

Keratinocytes comprise about 85% of the epidermal cells and are classified into layers based on morphology. They vary in size and shape and differentiate as they migrate upward to form keratin.

Epidermal Nonkeratinocytes

Nonkeratinocytes are scattered throughout the epidermis and include melanocytes, tactile epithelioid cells, and intraepidermal macrophages.

Melanocytes

Melanocytes are derivatives of neural crest ectoderm and are located in the basal layer of the epidermis (Fig. 16-1). They also occur in the external epithelial root sheath and hair matrix of hair follicles, in sweat gland ducts, and in sebaceous glands. Melanocytes have several dendritic processes that either extend between adjacent keratinocytes or run parallel to the basement membrane. The melanocyte has a spherical nucleus and contains typical organelles (ribosomes, endoplasmic reticulum, Golgi, etc.). The cytoplasm is clear except for pigment-containing ovoid granules, which are referred to as melanosomes. The melanosomes impart color to skin and hair. Dark brown pigment in skin is called eumelanin, while yellowish-red pigment is called pheomelanin. The enzyme tyrosinase is needed to produce melanin within the melanocytes, and the reaction involves the following series of steps, in short: tyrosine⇒dopa⇒dopaquinone⇒melanin. Albino animals lack tyrosinase; therefore, they cannot produce melanin, even though they have a normal number of melanocytes. After melanogenesis, the melanosomes migrate to the tips of the dendritic processes of the melanocyte; the tips then become pinched off and are phagocytized by the adjacent keratinocytes. They remain as discrete membrane-bounded organelles or become aggregated and surrounded by a membrane to form a melanosome complex. Melano somes are randomly distributed within the cytoplasm of the keratinocytes, although they often become localized over the nucleus, thereby forming a caplike structure that presumably protects the nucleus from ultraviolet radiation (Fig. 16-3). Skin color is determined by several factors, such as the number, size, distribution, and degree of melanization of melanosomes.

Tactile Epithelioid Cells (Merkel Cells)

Tactile epithelioid cells, also known as Merkel cells, are located in the basal region of the epidermis in both hairless and hairy skin. Their long axis is usually parallel to the surface of the skin and, thus, perpendicular to the columnar basal epithelial cells above (Figs. 16-1 and 16-4). The nucleus is lobulated and irregular, and the cytoplasm is clear and lacks tonofilaments. These cells have a characteristic region of vacuolated cytoplasm near the dermis, which has spherical electron-dense granules containing species-specific chemical mediators (e.g., serotonin, serotoninlike substances, vasoactive intestinal polypeptide, peptide histidineisoleucine, and substance P). Tactile epithelioid cells are connected to adjacent keratinocytes by desmosomes. When associated with an axon, a tactile epithelioid cell–neurite complex or nonencapsulated tactile corpuscle is formed, and specialized areas of skin containing these complexes are known as tactile hair discs (Haarscheiben, hair discs, tactile pads, or tylotrich pads). The axon associated with a tactile epithelioid cell is myelinated, but as it approaches the epidermis, the axon loses its myelin sheath and terminates as a flat meniscus on the basal aspect of the cell (Fig. 16-4). Tactile epithelioid cells can release trophic factors that attract nerve endings into the epidermis and can also stimulate keratinocyte growth. In addition, tactile epithelioid cells can function as slow-adapting mechanoreceptors for touch.

FIGURE 16-1 Schematic drawing representing the structure of the integument found in typical skin in various regions of the body. (Adapted from Monteiro-Riviere NA. Comparative anatomy, physiology, and biochemistry of mammalian skin. In: Hobson DW, ed. Dermal and Ocular Toxicology: Fundamentals and Methods. Boca Raton, FL: CRC Press, 1991;1:3).

Intraepidermal Macrophages (Langerhans Cells)

The dendritic cells located in the epidermis are called intraepidermal macrophages (Langerhans cells). They have been reported in adult pigs, cats, and dogs and are well characterized in rodents and humans. However, the specific phenotype (membrane receptors and antigens related to immune function) can vary between species. Intraepidermal macrophages are most commonly found in the upper spinous layer of the epidermis (Figs. 16-1 and 16-5). These cells have also been identified in the stratified squamous epithelium of the upper digestive tract, female genital tract, and sheep rumen. In addition, the cells are present in dermal lymph vessels (referred to here as “veiled cells”), in lymph nodes (interdigitating cells), and in the dermis. Further, they have been reported in the lung in fibrotic disorders, mycosis fungoides, atopic dermatitis, and the nondermatologic disorder eosinophilic granulomatosis.

FIGURE 16-2 Skin (cat). A. Thin skin with one to two viable epidermal cell layers, abdomen. B. Skin with thin epidermis, lumbar region. C. Skin with thick stratum corneum and epidermis, foot pad. Stratum disjunctum (D); stratum corneum (C); stratum lucidum (L); stratum granulosum (G); stratum spinosum (S); stratum basale (B); superficial (papillary) layer of the dermis (P); hair follicle cluster in dermis (HF). Hematoxylin and eosin (×120).

Intraepidermal macrophages usually are not apparent in routine sections but may appear as clear cells in the suprabasal epidermis. They can only be positively identified with special stains. At the ultrastructural level, intraepidermal macrophages have an indented nucleus and the cytoplasm contains typical organelles; they lack tonofilaments and desmosomes. A unique feature of this cell is distinctive rod- or racket-shaped granules in the cytoplasm that are known as intraepidermal macrophage (Birbeck) granules. Depending on the species, these granules can contain Langerin, a Ca⁺⁺-dependent type II lectin. Intraepidermal macrophages have long dendritic processes that traverse the intercellular space up to the granular cell layer. The cells are derived from bone marrow and are part of the mononuclear phagocyte system (monocyte–macrophage system). They are capable of presenting antigen to lymphocytes and are considered to be the initial receptors for cutaneous immune responses (delayed-type hypersensitivity).

Layers of the Epidermis

Stratum Basale

The stratum basale (stratum germinativum) consists of a single layer of columnar or cuboidal cells that rests on the basallamina (Fig. 16-6). The cells are attached laterally to each other and to the overlying stratum spinosum cells by desmosomes and to the underlying basal lamina by hemidesmosomes. The nucleus is large and ovoid and occupies most of the cell. These basal cells are heterogeneous functionally. Some basal cells can act as stem cells, with the ability to divide and produce new cells, whereas others primarily serve to anchor the epidermis.

Stratum Spinosum

The succeeding outer layer is the stratum spinosum, or “prickle cell layer,” which consists of several layers of irregular polyhedral cells (Figs. 16-2C and 16-7). Desmosomes connect these cells to adjacent stratum spinosum cells and to the stratum basale cells below. Tonofilaments are more prominent in this layer than in the stratum basale. The large intercellular space usually seen in this layer is a shrinkage artifact, which occurs in preparing the sample for light microscopic study. The uppermost layers of the stratum spinosum contain small membrane-bounded organelles known as lamellar granules (Odland bodies, lamellated bodies, or membrane-coating granules).

FIGURE 16-3 Melanin granules (arrows) highly concentrated in the stratum basale cell layer and forming apical caps in the upper layers of the horse abdominal skin. Hematoxylin and eosin (×800).

Stratum Granulosum

The third layer is the stratum granulosum, which consists of several layers of flattened cells lying parallel to the epidermal–dermal junction (Figs. 16-2C and 16-8). This layer contains irregularly shaped, nonmembrane-bounded, electron-dense keratohyalin granules. These granules contain profilaggrin, a structural protein and a precursor of filaggrin, and are believed to play a role in keratinization and barrier function. The stratum granulosum is not present in all stratified squamous epithelia such as in the mucous membranes of the mouth (buccal mucosa). Another characteristic feature of the stratum granulosum is the presence of the lamellar granules. These granules are smaller than mitochondria and occur near the Golgi complex and smooth endoplasmic reticulum (sER). Higher in the epidermis, these granules increase in number and size, move toward the cell membrane, and release their lipid contents by exocytosis into the intercellular space between the stratum granulosum and stratum corneum, thereby coating the cell membrane of the stratum corneum cells (Fig. 16-8). As one can now appreciate, the term “membrane-coating granule” is appropriate. The major components of lamellar granules are lipids (ceramides, cholesterol, fatty acids, and small amounts of cholesteryl esters) and hydrolytic enzymes (acid phosphates, proteases, lipases, and glycosidases). The content and mixture of lipids can vary between species.

Stratum Lucidum

The stratum lucidum (clear layer) is only found in specific areas of exceptionally thick skin and in hairless regions (e.g., plantar and palmar surfaces, planum nasale) (Fig. 16-2C). It is a thin, translucent, homogeneous line between the stratum granulosum and stratum corneum. This stratum consists of several layers of fully keratinized, closely compacted, dense cells devoid of nuclei and cytoplasmic organelles. The cell cytoplasm contains protein-bound phospholipids and eleidin, which is a protein that is similar to keratin but has a different staining affinity.

FIGURE 16-4 Schematic drawing of a tactile epithelioid cell–neurite complex from a foot pad of a cat. Irregular nucleus (N); Golgi (GO); desmosomes (D) glycogen (GY); cytoplasmic process (P); basement membrane (BM); Merkel cell dense core granules (G); axon (A); nerve plate or disc (NP).

FIGURE 16-5 Schematic of an intraepidermal macrophage (L). Heavy black areas represent the intercellular space. The racket shape granules (arrow) can be found in the dendritic processes. Note the indented nucleus and electron-lucent cytoplasm. (From Monteiro-Riviere NA. Ultrastructural evaluation of the porcine integument. In: Tumbleson ME, ed. Swine in Biomedical Research. New York: Plenum Press, 1986;1:641.)

Stratum Corneum

The stratum corneum is the outermost layer of the epidermis and consists of several layers of completely keratinized dead cells, which are constantly being shed. This layer appears clear and contains no nuclei or cytoplasmic organelles (Figs. 16-2 and 16-8). The most superficial layers of the stratum corneum that undergo constant desquamation are referred to as the stratum disjunctum. The stratum corneum varies in thickness in different areas (i.e., abdomen versus back) of the body and between species. On the palmar and plantar surfaces, where considerable abrasive action occurs, the stratum corneum is thickest (Fig. 16-2C). The stratum corneum cells are highly organized and stacked one upon another to form vertical interlocking columns with a flattened tetrakaidecahedron shape. This 14-sided polygonal structure provides a minimum surface: volume ratio, which allows for space to be filled by packing without interstices. This spatial arrangement, typical of hairy skin, helps one to understand that transepidermal water loss is a function of the integrity and permeability of this layer. The intercellular substance derived from the lamellar granules is present between the stratum corneum cells and forms the intercellular lipid component of a complex stratum corneum barrier, which prevents both the penetration of substances from the environment and the loss of body fluids. The keratinized cells are surrounded by a plasma membrane and a thick submembranous layer that contains a protein, involucrin. This protein is synthesized in the stratum spinosum and cross-linked in the stratum granulosum by an enzyme that makes it highly stable. Therefore, involucrin provides structural support to the cell, thereby allowing the cell to resist invasion by microorganisms and destruction by environmental agents, but it does not seem to regulate permeability.

FIGURE 16-6 Transmission electron micrograph of pig skin. Area depicting the epidermis (E); dermis (D); epidermal–dermal junction (J); stratum basale cell (SB); tonofilaments (T); and desmosome attachments (arrow) (×10,700).

FIGURE 16-7 Transmission electron micrograph of the stratum spinosum of pig skin. Area shows the nuclei of two stratum spinosum (SS) cells attached by desmosomes (arrows) (×23,500).

Keratinization

Keratinization is the process by which epidermal cells (keratinocytes) differentiate. After the basal epithelial cells undergo mitosis, they migrate upward. The volume of the cytoplasm increases and the differentiation products (tonofilaments, keratohyalin granules, and lamellar granules) are formed in large amounts. The tonofilaments and the amorphous material, keratohyalin, form a meshwork. As the cellular contents increase, the nuclei disintegrate and the lamellar granules discharge their contents into the intercellular space, coating the cells. The remaining organelles such as mitochondria and ribosomes disintegrate, and the flattened cells become filled by filaments and keratohyalin, which then form bundles. The final product of this epidermal differentiation and keratinization process is the stratum corneum, which consists of protein-rich cells containing fibrous keratin and keratohyalin surrounded by a thicker plasma membrane coated by the exterior lipid matrix. This forms the commonly known “brick and mortar” structure in which the lipid matrix acts as the mortar between the cells, which are the bricks.

Epidermal–Dermal Junction

The epidermal–dermal junction (or skin basement membrane zone) is a complex and highly specialized structure recognized with the light microscope (periodic acid-Schiff stain) as a thin, homogeneous band. When viewed with the transmission electron microscope, however, the epidermal–dermal junction consists of four components: (a) the cell membrane of the basal epithelial cell, which includes the hemidesmosomes; (b) the lamina lucida (lamina rara); (c) the lamina densa (basal lamina); and (d) the subbasal lamina (sublamina densa or reticular lamina) with a variety of fibrous structures (anchoring fibrils, dermal microfibril bundles, microthreadlike filaments) (Fig. 16-9). The basement membrane has a complex molecular architecture with numerous components that play a key role in adhesion of the epidermis to the dermis. The macromolecules that are ubiquitous components of all basement membranes include type IV collagen, laminin, entactin/nidogen, and heparan sulfate proteoglycans. Other basement membrane components such as bullous pemphigoid antigen (BPA), epidermolysis bullosa acquisita (EBA), fibronectin, GB3, L3d, and 19DEJ-1 are limited in their distribution to the epithelial basement membrane of skin. The basal cell membrane of the epidermal–dermal junction is not always smooth. It may be irregular, forming fingerlike projections into the dermis. The basement membrane (a) plays a role in maintenance of epidermal–dermal adhesion, (b) acts as a selective barrier between the epidermis and dermis by restricting some molecules and permitting the passage of others, (c) influences cell behavior and wound healing, and (d) serves as a target for both immunologic (bullous diseases) and nonimmunologic injury (friction- or chemical-induced blisters).

FIGURE 16-8 Transmission electron micrograph of the upper stratum granulosum (SG) and stratum corneum (SC) of pig skin. Membrane-coating granules or lamellar bodies (arrows) are present in the stratum granulosum, with some fusing to the plasma membrane to release their contents. Keratohyalin granules (K) and numerous desmosomes (D) are present (×14,900).

FIGURE 16-9 Schematic of the basement membrane of skin depicting the precise location of the macromolecular components. (From Monteiro-Riviere NA, Inman AO. Indirect immunohistochemistry and immunoelectron microscopy distribution of eight epidermal-dermal junction epitopes in the pig and in isolated perfused skin treated with bis (2-chloroethyl) sulfide. Toxicol Pathol 1995;23:313–325.)

DERMIS

The dermis can be divided into a superficial papillary layer that blends into a deep reticular layer without a clear line of demarcation (Fig. 16-10). The papillary layer is the thinnest layer, consists of loose connective tissue, is in contact with the epidermis, and conforms to the contour of the stratum basale. The papillary layer can protrude into the epidermis, thereby giving rise to the dermal papilla. When the epidermis invaginates into the dermis, epidermal pegs are formed. The reticular layer is thicker and consists of dense irregular connective tissue. Connective tissue cells are fewer in the deeper layers of the dermis.

FIGURE 16-10 Pig skin from the abdomen. Epidermis (E); stratum corneum (C); superficial papillary dermis (PD); epidermal peg (EP); dermal papilla (DP); deep reticular dermis (RD). Hematoxylin and eosin (×250).

In the dermis, smooth muscle fibers are located near hair follicles and are referred to as arrector pili muscles. In addition, dermal smooth muscle fibers are present in specialized areas such as the scrotum, penis, and teat. Skeletal muscle fibers of the cutaneous trunci penetrate the dermis and allow voluntary movement of the skin. Also, skeletal muscle fibers are associated with the large sinus hairs of the facial region.

HYPODERMIS

Beneath the dermis is a layer of loose connective tissue, the hypodermis (subcutis), which is not part of the skin but rather the superficial fascia seen in gross anatomic dissections. The hypodermis anchors the dermis to the underlying muscle or bone. The loose arrangement of collagen and elastic fibers allows the skin flexibility and free movement over the underlying structures. Adipose tissue is present in this layer and may form small clusters of cells or large masses that create a cushion or pad of fat called the panniculus adiposus (Fig. 16-11). Pork bacon and fatback are derived from the panniculus adiposus. Large fat deposits (structural fat) in the hypodermis are characteristic of the carpal, metacarpal/metatarsal, and digital pads, where they act as shock absorbers.

SKIN APPENDAGES

The hair shaft is composed of three layers: an outermost cuticle, a cortex of densely packed keratinized cells, and a medulla of loose cuboidal or flattened cells (Fig. 16-12). The cuticle is formed by a single layer of flat keratinized cells in which the free edges, which overlap like shingles on a roof, are directed toward the distal end of the shaft. The cortex consists of a layer of dense, compact, keratinized cells with their long axes parallel to the hair shaft. Nuclear remnants and pigment granules are present within the cells. Desmosomes hold the cells firmly together. Near the bulb, the cells are shorter and more oval and contain spherical nuclei. The medulla forms the center of the hair and is loosely filled with cuboidal or flattened cells (Fig. 16-12). In the root, the medulla is solid, whereas in the shaft, it contains air-filled spaces. The pattern of the surface of the cuticular cells, together with the cellular arrangement of the medulla, is characteristic for each species.

FIGURE 16-11 Hypodermis with three large primary hair follicles (H) extending into the subcutaneous fat (F) (dog). Note the sebaceous glands (arrows) and apocrine gland ducts (A). Hematoxylin and eosin (×35).

The hair or fleece of sheep is referred to as fibers. The three types of fibers are (a) wool fibers, tightly crimped fibers of small diameter lacking a medulla; (b) kemp fibers, coarse and with a characteristic medulla; and (c) coarse fibers of intermediate size relative to wool and kemp fibers. The various breeds of sheep produce wools with different characteristics, and these various kinds of fleece are used for different purposes.

HairFollicles

Structure

The hair follicle is formed by growth of the ectoderm into the underlying mesoderm of the embryo. The epithelial downgrowth becomes canalized, and the surrounding cells differentiate into several layers or sheaths that surround the hair root. The follicle is embedded in the dermis, usually at an angle, and the bulb may extend as deep as the hypodermis (Figs. 16-11 and 16-13). The hair follicle consists of four major components: (a) internal epithelial root sheath, (b) external epithelial root sheath, (c) dermal papilla, and (d) hair matrix.

FIGURE 16-12 Schematic of a cross section of a hair follicle.

The innermost layer, next to the hair root, is the internal epithelial root sheath, which is composed of three layers: (a) internal root sheath cuticle, (b) middle granular epithelial layer (Huxley’s layer), and (c) outer pale epithelial layer (Henle’s layer) (Fig. 16-12). The cuticle of the internal epithelial root sheath is formed by overlapping keratinized cells similar to those of the cuticle of the hair, except that the free edges are oriented in the opposite direction or toward the hair bulb. This arrangement results in a solid implantation of the hair root in the hair follicle. The granular epithelial layer is composed of one to three layers of cells rich in trichohyalin (keratohyalin in hair) granules. The pale epithelial layer is the outermost layer of the internal epithelial root sheath and is composed of a single layer of keratinized cells. Immediately below the opening of the sebaceous glands, the internal epithelial root sheath of the large follicles becomes corrugated, forming several circular or follicular folds. The sheath then becomes thinner, and the cells fuse, disintegrate, and become part of the sebum.

The external epithelial root sheath is composed of several layers of cells similar to the epidermis with which it is continuous in the upper portion of the follicle. External to this layer is a homogeneous glassy membrane corresponding to the basal lamina of the epidermis (Fig. 16-12). The entire epithelial root sheath (internal and external) is enclosed by a dermal root sheath composed of collagen and elastic fibers richly supplied by blood vessels and nerves, especially in the dermal papilla.

The dermal papilla of the hair follicle is the region of connective tissue directly underneath the hair matrix. The cells covering the dermal papilla and composing most of the hair bulb are the hair matrix cells. These are comparable to stratum basale cells of regular epidermis and give rise to the cells that keratinize to form the hair (Fig. 16-13). They differ from the keratinocytes of the surface epidermis with respect to the type of keratin produced. The surface keratinocytes produce a “soft” form of keratin that passes through a keratohyalin phase. The cells containing “soft” keratin have a high lipid content and a low sulfur content and desquamate when they reach the surface of the epidermis. In contrast, the matrix cells of the hair follicle produce a “hard” keratin, which is also characteristic of horn and feather. The keratinocytes of the follicle do not go through a keratohyalin phase, do not desquamate, and have a low lipid and high sulfur content.

FIGURE 16-13 Schematic of a longitudinal section of a hair follicle.

Hair pigment is derived from the epidermal melanocytes located over the dermal papilla. Gray hair results from the inability of melanocytes in the hair bulb to produce tyrosinase. Hair color is determined by the amount and distribution of pigment and by the presence of air, which appears white in reflected light. Silvery white hair is the result when the pigment has faded and the medulla becomes filled with air.

Associated with most hair follicles are bundles of smooth muscle called the arrector pili muscle. This muscle attaches to the dermal root sheath of the hair follicle and extends toward the epidermis, where it connects to the papillary layer of the dermis (Fig. 16-14). These muscles are anchored by elastic fibers at their attachments and are innervated by autonomic nerve fibers. The arrector pili muscles are especially well developed along the back of dogs, where they cause the hair to “bristle” when they contract. The contraction of the arrector pili muscles during cold weather elevates the hairs, thus allowing minute air pockets to form in the coat. This dead-air space provides significant insulation that helps to maintain internal body temperature. The contraction of this muscle not only erects the hairs but also may play a role in emptying the sebaceous glands. In addition to the arrector pili muscle, the interfollicular muscle, which spans the triad of hair follicles, has been described in pigs (Figs. 16-15 and 16-16). It is located midway between the level of the sebaceous gland and the apocrine sweat gland. Upon contraction, the interfollicular muscle draws the three follicles close together and rotates the outer follicles of the triad into a new relationship. Adjustment of the hair follicle and hair may play a part in thermoregulation, sensory function, emptying of the skin glands, or self defense.

Types of Hair Follicles

Hair follicles are classified into several types. A primary hair follicle has a large diameter, is rooted deep in the dermis, and is usually associated with sebaceous and sweat glands and an arrector pili muscle (Fig. 16-11). The hair that emerges from such a follicle is called a primary hair (guard hair). A secondary follicle is smaller in diameter than a primary follicle, and the root is nearer the surface. It may have a sebaceous gland but lacks a sweat gland and an arrector pili muscle. Hairs from these follicles are secondary hair, or underhairs. Secondary hairs lack a medulla.

FIGURE 16-14 Longitudinal section of a hair follicle (HF) showing an attached arrector pili muscle (P), cross section of the interfollicular muscle (M), epidermis (E), hair (H), and hypodermis (D) (pig). Hematoxylin and eosin (×50).

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