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The epidermis (Fig. 7.2, Fig. 7.3) is a compound tissue consisting mainly of a continuously self-renewing, keratinized, stratified squamous epithelium: the principal cells are called keratinocytes. Nonkeratinocytes within the mature epidermis include melanocytes (pigment-forming cells from the embryonic neural crest), Langerhans cells (immature antigen-presenting dendritic cells derived from bone marrow), and lymphocytes. Merkel cells, which may function as sensory mechanoreceptors or possibly as part of the dispersed neuroendocrine system, are associated with nerve endings. Free sensory nerve endings are sparsely present within the epidermis. In routine histological preparations, the non-keratinocytes and Merkel cells are almost indistinguishable, and appear as clear cells surrounded by a clear space produced by shrinkage during processing. Their cytoplasm lacks prominent filament bundles.


Fig. 7.3  The main features of the epidermis, including its cell layers and different cell types. Melanocytes and Merkel cells are derived from the neural crest and Langerhans cells are derived from bone marrow precursor cells.

The population of keratinocytes undergoes continuous renewal throughout life: a mitotic layer of cells at the base replaces those shed at the surface. As they move away from the base of the epidermis, keratinocytes undergo progressive changes in shape and content. They transform from polygonal living cells to non-viable flattened squames full of intermediate filament proteins (keratins) embedded in a dense matrix of cytoplasmic proteins to form mature keratin. The process is known as keratinization or, more properly, cornification.

The epidermis can be divided into a number of layers from deep to superficial as follows: basal layer (stratum basale), spinous or prickle cell layer (stratum spinosum), granular layer (stratum granulosum), clear layer (stratum lucidum) and cornified layer (stratum corneum) (Fig. 7.4). The first three of these layers are metabolically active compartments through which cells pass and change their form as they progressively differentiate. The more superficial layers of cells undergo terminal keratinization, or cornification, which involves not only structural changes in keratinocytes, but also alterations in their relationships with each other and with non-keratinocytes, and molecular changes within the intercellular space.

The epidermal appendages (pilosebaceous units, sweat glands and nails) are formed developmentally by ingrowth of the general epidermis, and the latter is thus referred to as the interfollicular epidermis.


Basal layer

The basal or deepest layer of cells, adjacent to the dermis, is the layer where cell proliferation in the epidermis takes place. This layer contacts a basal lamina (Fig. 7.5, see Fig. 2.7), which is a thin layer of specialized extracellular matrix, not usually visible by light microscopy. By routine electron microscopy the basal lamina appears as a clear lamina lucida (adjacent to the basal cell plasma membrane) and a darker lamina densa. The basal plasma membrane of the basal keratinocytes, together with the extracellular basal lamina (lamina lucida and lamina densa) and anchoring fibrils within the subjacent dermal matrix (the lamina fibroreticularis), which insert into the lamina densa and loop around bundles of collagen, collectively form the basement membrane zone (BMZ) which constitutes the dermo-epidermal junction. This is a highly convoluted interface, particularly in thick, hairless skin, where dermal papillae (rete ridges) project superficially into the epidermal region, interlocking with adjacent downward projections of the epidermis (rete pegs) (Fig. 7.4).


Fig. 7.5  The major features of a hemidesmosome in the basement membrane zone (BMZ) of skin, including some of the important molecular components.

The majority of basal layer cells (Fig. 7.3) are columnar to cuboidal in shape, with large (relative to their cytoplasmic volume) mainly euchromatic nuclei and prominent nucleoli. The cytoplasm contains variable numbers of melanosomes and, characteristically, keratin filament bundles corresponding to the tonofilaments of classic electron microscopy. In the basal keratinocytes these keratins are mostly K5 and K14 proteins. The plasma membranes of apposed cells are connected by desmosomes, and the basal plasma membrane is linked to the basal lamina at intervals by hemidesmosomes (Fig. 7.5, see Fig. 1.5). Melanocytes (see Fig. 7.9), occasional Langerhans cells (see Fig. 7.3) and Merkel cells (see Fig. 3.30) are interspersed among the basal keratinocytes. Merkel cells are connected to keratinocytes by desmosomes, but melanocytes and Langerhans cells lack these specialized contacts. Intraepithelial lymphocytes are present in small numbers.


Fig. 7.9  Melanocytes in the basal layer of thin skin, including that of the follicular epidermis, in a biopsy of periauricular skin in a Caucasian male. The pigmented melanocytes, visualized immunocytochemically using antibody against a differentiation marker (Melan A/MART-1), extend dendritic processes between keratinocytes of the basal and lower prickle cell layers. Melanocytes are relatively inactive in this specimen, with no melanosomes visible in the surrounding keratinocytes.

At any one time the basal layer of the epidermis contains keratinocytes with different fates. These include multipotent stem cells. On division these may self-renew or produce a daughter cell which is committed to differentiate after undergoing further transit amplifying cell divisions. The activity of stem cells and transit amplifying cells in the basal layer provides a continuous supply of differentiating cells which enter the prickle cell layer. The great majority of these cells are postmitotic, although some cell division may occur in the more basal regions of the prickle cell layer. Stem cells are thought to reside mainly in the troughs of rete pegs, and in the outer root sheath bulge of the hair follicle, but they cannot easily be distinguished morphologically. The distribution of stem cells and the size of their proliferative units (see below) may be quite variable in human skin (Ghazizadeh & Taichman 2005).

The organization of the basal layer and overlying progeny cells is thought to form a series of columns. Several layers of prickle and granular cells overlie a cluster of six to eight basal cells, forming a columnar proliferative unit. Each group of basal cells consists of a central stem cell with an encircling ring of transit amplifying proliferative cells and postmitotic maturing cells. From the periphery of this unit, postmitotic cells transfer into the prickle cell layer. The normal total epidermal turnover time is between 52 and 75 days. In some pathologies of skin, turnover rates and transit times can be exceedingly rapid, e.g. in psoriasis, total epidermal turnover time may be as little as 8 days. The control of keratinocyte proliferation and differentiation is beyond the scope of this publication but is reviewed in Niemann & Watt (2002) and Byrne et al (2003).

Prickle cell layer

The prickle cell layer (Fig. 7.3, Fig. 7.6) consists of several layers of closely packed keratinocytes that interdigitate with each other by means of numerous cell surface projections. The cells are anchored to each other by desmosomes that provide tensile strength and cohesion to the layer. These suprabasal cells are committed to terminal differentiation and gradually move upwards towards the cornified layer as more cells are produced in the basal layer. When skin is processed for routine light microscopy, the cells tend to shrink away from each other except where they are joined by desmosomes, which gives them their characteristic spiny appearance. Prickle cell cytoplasm contains prominent bundles of keratin filaments, (mostly K1 and K10 keratin proteins) arranged concentrically around a euchromatic nucleus, and attached to the dense plaques of desmosomes. The cytoplasm also contains melanosomes, either singly or aggregated within membrane-bound organelles (compound melanosomes). Langerhans cells (see Fig. 7.11) and the occasional associated lymphocyte are the only non-keratinocytes present in the prickle cell layer.


Fig. 7.6  The superficial layers of human thick skin at high magnification, showing the deeply stained keratohyalin granule-containing cells of the granular layer (G) between the prickle cell or spinous layer (S) and the clear (or lucid, L) and cornified (C) layers above. Note that the clear layer is only translucent in unstained preparations and appears eosinophilic, as here, after staining.


Fig. 7.11  Langerhans cells immunolabelled for the marker protein S100, extending dendrites between keratinocytes, mainly in the prickle cell layer of human thin skin. Basal layer melanocytes and scattered dermal cells (possibly of neural origin) are also positive for S100, visualized using a peroxidase method.

Granular layer

Extensive changes in keratinocyte structure occur in the three to four layers of flattened cells in the granular layer. The nuclei become pyknotic and begin to disintegrate; organelles such as ribosomes and membrane-bound mitochondria and Golgi bodies degenerate; and keratin filament bundles become more compact and associated with irregular, densely staining keratohyalin granules (Fig. 7.6). Small round granules (100 × 300 nm) with a lamellar internal structure (lamellar granules, Odland bodies, keratinosomes) also appear in the cytoplasm. Keratohyalin granules contain a histidine-rich, sulphur-poor protein (profilaggrin) which, when the cell reaches the cornified layer, becomes modified to filaggrin. The lamellar granules are concentrated deep to the plasma membrane, with which they fuse, releasing their hydrophobic glycophospholipid contents into the intercellular space within the layer and also between it and the cornified layer. They form an important component of the permeability barrier of the epidermis, rendering it relatively waterproof.

Clear layer

The clear layer is only found in thick palmar or plantar skin. It represents a poorly understood stage in keratinocyte differentiation. It stains more strongly than the cornified layer with acidic dyes (Fig. 7.6), is more refractile optically, and often contains nuclear debris. Ultrastructurally, its cells contain compacted keratin filaments and resemble the incompletely keratinized cells which are occasionally seen in the innermost part of the cornified layer of thin skin.

Cornified layer

The cornified layer (Fig. 7.3, Fig. 7.6) is the final product of epidermal differentiation, or cornification. It consists of closely packed layers of flattened polyhedral squames (Fig. 7.7), ranging in surface area from 800 to 1100 μm2. These cells overlap at their lateral margins and interlock with cells of apposed layers by ridges, grooves and microvilli. In thin skin this layer may be only a few cells deep, but in thick skin it may be more than 50 cells deep. The plasma membrane of the squame appears thicker than that of other keratinocytes, partly due to the cross-linking of a soluble precursor, involucrin, at the cytoplasmic face of the plasma membrane, in the complex insoluble cornified envelope. The outer surface is also covered by a monolayer of bound lipid. The intercellular region contains extensive lamellar sheets of glycolipid derived from the lamellar granules of the granular layer. The cells lack a nucleus and membranous organelles, and consist solely of a dense array of keratin filaments embedded in a cytoplasmic matrix which is partly composed of filaggrin derived from keratohyalin granules.


Fig. 7.7  The epidermal surface surrounding the aperture of a sweat duct. Several polygonal, scale-like keratinocytes (squames) of the superficial cornified layer are visible in this scanning electron micrograph.

Under normal conditions the production of epidermal keratinocytes in the basal layer is matched by loss of cells from the cornified layer. Desquamation of these outer cells is normally imperceptible. When excessive, it appears in hairy regions as dandruff, and more extensively in certain diseases and, to a lesser extent, after sunburn, as peeling, scaling and exfoliation. The thickness of the cornified layer can be influenced by local environmental factors, particularly abrasion, which can lead to a considerable thickening of the whole epidermis including the cornified layer. The soles of the feet become much thickened if an individual habitually walks barefoot, and cornified pads develop in areas of frequent pressure, e.g. corns from tight shoes, palmar calluses in manual workers, and digital calluses in guitar players.


Epidermal keratinization has historically been the term applied to the final stages of keratinocyte differentiation and maturation, during which cells are converted into tough cornified squames. However, this is now regarded as ambiguous because the term keratin is assumed to refer to the protein of epithelial intermediate filaments, rather than (as previously) to the whole complement of proteins in the terminally differentiated cell of the stratum corneum.

Keratins are the intermediate filament proteins found in all epithelial cells. There are two types, type I (acidic) and type II (neutral/basic); they form heteropolymers, are coexpressed in specific pairs and are assembled into 10 nm intermediate filaments. Fifty-four different keratin genes have been recognized and their protein products are numbered. The nomenclature for human keratins and keratin genes has recently been revised and is given in Schweizer et al (2006). Different keratin pairs are expressed according to epithelial cell differentiation; antibodies to individual keratins are useful analytical tools (Fig. 7.8). Keratins K5 and K14 are expressed by basal keratinocytes. New keratins, K1 and K10, are synthesized suprabasally. In the granular layer the filaments become associated with keratohyalin granules containing profilaggrin, a histidine-rich phosphorylated protein. As the cells pass into the cornified layer, profilaggrin is cleaved by phosphatases into filaggrin which causes aggregation of the filaments and forms the matrix in which they are embedded. Other types of keratin expression occur elsewhere, particularly in hair and nails, where highly specialized hard, or trichocyte, keratin is expressed. This becomes chemically modified and is much tougher than in the general epidermis. For a recent review of keratin function see Gu & Coulombe 2007.


Fig. 7.8  Thin skin in the region of a human hair follicle, immunolabelled to detect keratins (including K5) in the basal and suprabasal interfollicular epidermis (between arrowheads), the hair follicle (HF) and associated sebaceous glands (S). The presence of keratins was visualized using a peroxidase technique.

Epidermal lipids

The epidermis serves as an important barrier to the loss of water and other substances through the body surface (apart from in sweating and sebaceous secretion). A variety of lipids are present and synthesized in the epidermis, including triglycerides and fatty acids, phospholipids, cholesterol, cholesterol esters, glycosphingolipids and ceramides. An intermediate in the synthesis of cholesterol, 7-dehydrocholesterol, is the precursor of vitamin D, which is also synthesized in the skin. The content and composition of epidermal lipids change with differentiation. Phospholipids and glycolipids at first accumulate within keratinocytes above the basal layer, but higher up they are broken down and are practically absent from the cornified layer. Cholesterol and its esters, fatty acids and ceramides accumulate towards the surface, and are abundant in the cornified layer. The lamellar arrangement of the extracellular lipids is a major factor in their barrier function.


Melanocytes are melanin pigment-forming cells derived from the neural crest (Fig. 7.9, Fig. 7.10). They are present in the epidermis and its appendages, in oral epithelium, some mucous membranes, the uveal tract (choroid coat) of the eyeball, parts of the middle and internal ear and in the pial and arachnoid meninges at the base of the brain. The cells of the retinal pigment epithelium, developed from the outer wall of the optic cup, also produce melanin, and neurones in different locations within the brainstem (e.g. the locus coeruleus and substantia nigra) synthesize a variety of melanin called neuromelanin. True melanins are high molecular weight heteropolymers attached to structural protein. In humans there are two classes, the brown-black eumelanin, and the red-yellow phaeomelanin, both derived from the substrate tyrosine. Most natural melanins are mixtures of eumelanin and phaeomelanin, and phaeomelanic pigments, trichochromes, occur in red hair.


Fig. 7.10  Electron micrograph of a basal epidermal melanocyte, showing its nucleus and cytoplasm containing melanosomes (short arrows). There are no desmosomes connecting it with apposed keratinocytes. The cytoplasm of the keratinocytes is full of dense keratin filaments (absent from the melanocyte), as well as transferred melanosomes. The dermo-epidermal junction is indicated (long arrows). Human tissue.

Melanocytes are dendritic cells, and lack desmosomal contacts with apposed keratinocytes, though hemidesmosomal contacts with the basal lamina are present. In routine tissue preparations, melanocytes appear as clear cells in the basal layer of the epidermis; numbers per unit area of epidermis range from 2300 per mm2 in cheek skin to 800 per mm2 in abdominal skin. It is estimated that a single melanocyte may be in functional contact via its dendritic processes with up to 30 keratinocytes. The nucleus is large, round, and euchromatic, and the cytoplasm contains intermediate filaments, a prominent Golgi complex and vesicles and associated rough endoplasmic reticulum, mitochondria, and coated vesicles, together with a characteristic organelle, the melanosome.

The melanosome is a membrane-bound structure which undergoes a sequence of developmental stages during which melanin is synthesized and deposited within it by a tyrosine–tyrosinase reaction. Mature melanosomes move into the dendrites along the surfaces of microtubules and are transferred to keratinocytes through their phagocytic activity. Keratinocytes engulf and internalize the tip of the dendrite with the subsequent pinching off of melanosomes into the keratinocyte cytoplasm. Here, they may exist as individual granules in heavily pigmented skin, or be packaged within secondary lysosomes as melanosome complexes in lightly pigmented skin. In basal keratinocytes they can be seen to accumulate in a crescent-shaped cap over the distal part of the nucleus. As the keratinocytes progress towards the surface of the epidermis, melanosomes undergo degradation, and melanin remnants in the cornified layer form dust-like particles. Melanosomes are degraded more rapidly in Caucasian skin than in dark-skinned races, where melanosomes persist in cells of the more superficial layers.

Melanin has biophysical and biochemical properties related to its functions in skin. It protects against the damaging effects of UV radiation on DNA and is also an efficient scavenger of damaging free radicals. However a high concentration of melanin may adversely affect synthesis of vitamin D in darker-skinned individuals living in northern latitudes. Melanin pigmentation is both constitutive and facultative. Constitutive pigmentation is the intrinsic level of pigmentation and is genetically determined, whereas facultative pigmentation represents reversible changes induced by environmental agents, e.g. UV and X-radiation, chemicals, and hormones. Racial variations in pigmentation are due to differences in melanocyte morphology and activity rather than to differences in frequency or distribution. In naturally heavily pigmented skins the cells tend to be larger, more dendritic, and to contain more large, late-stage melanosomes than melanocytes of paler skins. The keratinocytes in turn contain more melanosomes, individually dispersed, whereas in light skins, the majority are contained within secondary lysosomes to form melanosome complexes.

Response to UV light includes immediate tanning, pigment darkening, which can occur within a matter of minutes, probably due to photo-oxidation of pre-existing melanin. Delayed tanning occurs after about 48 hours, and involves stimulation of melanogenesis within the melanocytes, and transfer of additional melanosomes to keratinocytes. There may also be some increase in size of active melanocytes, and in their apparent numbers, mainly through activation of dormant cells. Freckles in the skin of red-haired individuals are usually thought to be induced by UV, though they do not appear until several years after birth, despite exposure. Paradoxically, melanocytes are significantly fewer in freckles than in adjacent paler epidermis, but they are larger and more active. What determines the onset of freckles, or their individual location, is not known.

Adrenocorticotrophin (ACTH) is thought to affect melanocyte activity, and is probably responsible for the hyperpigmentation associated with pituitary and adrenal disorders. In pregnancy, higher levels of circulating oestrogens and progesterone are responsible for the increased melanization of the face, abdominal and genital skin, and the nipple and areola, much of which may remain permanently.

In albinism, the tyrosinase required for melanin synthesis is either absent or inactive, and melanocytes, though present, are relatively quiescent cells in an otherwise normal epidermis. Melanocytes decrease significantly in numbers in old age, and are absent from grey-white hair. For further reading on melanocyte function in health and disease, see Goding (2007).

Langerhans cells

Langerhans cells (Fig. 7.11) are immature dendritic antigen-presenting cells (see p. 79) regularly distributed throughout the basal and prickle cell layers of the epidermis and its appendages, apart from the sweat gland. They are also present in other stratified squamous epithelia, including the buccal, tonsillar and oesophageal epithelia, as well as the cervical and vaginal mucosae and the transitional epithelium of the bladder. They are found in the conjunctiva, but not in the cornea. In routine preparations they appear as clear cells, relatively high in the stratified layer. They enter the epidermis from the bone marrow during development to establish the postnatal population (460–1000/mm2, 2–3% of all epidermal cells, with regional variations), and this is maintained by continual replacement from the marrow.

The nucleus is euchromatic and markedly indented and the cytoplasm contains a well-developed Golgi complex, lysosomes (which often contain ingested melanosomes), and a characteristic organelle, the Birbeck granule. The latter are discoid, cup-shaped, or have a distended vesicle resembling the head of a tennis racket; in section they often appear as a cross-striated rod 0.5 μm long and 30 nm wide. When stimulated by antigen, Langerhans cells migrate out of the epidermis to lymphoid tissues (see Fig. 4.14). Their numbers are increased in chronic skin inflammatory disorders, particularly of an immune aetiology, such as some forms of dermatitis.

Merkel cells

Merkel cells are present as clear oval cells, singly or in groups, in the basal layer of the epidermis, especially of thick skin. They are also present in the outer root sheath of some large hair follicles. Merkel cells are derived embryologically from the neural crest and are not related developmentally to keratinocytes, as was once thought. They can be distinguished histologically from other clear cells (melanocytes and Langerhans cells) only by immunohistochemical and ultrastructural criteria.

Short, stiff processes of their plasma membrane interdigitate with adjacent basal keratinocytes, to which the Merkel cell is attached by small desmosomes. The cytoplasm contains numerous closely-packed intermediate filaments (simple epithelial keratins, mostly K8 and K18 but also K19 and K20), and characteristic 80–110 μm dense-core granules. The basal plasma membrane is closely apposed to the membrane of an axonal terminal. Merkel cells are thought to function as neuroendocrine sensory receptors, and are slowly adapting mechanoreceptors which respond to directional deformations of the epidermis and direction of hair movement by releasing a transmitter from their dense-core cytoplasmic granules.

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