EPIDERMIS

The epidermis originates from the ectodermal cells covering the embryo after completion of neurulation (Figs 17-1, 17-2). This is a single-layered epithelium with its apical plasma membrane, facing the amniotic cavity, possessing occasional microvilli. The cells of this single-layered surface ectoderm start to proliferate in the early embryo and form a second protective layer – the periderm or covering layer (Fig. 17-3). The periderm is a temporary covering that is shed once the inner layers differentiate to form a true epidermis. With further proliferation of the cells of the basal layer, a third, intermediate layer is formed. Finally, the epidermis acquires its definitive arrangement and four layers can be distinguished: a) the basal layer or germinative layer (stratum basale); (b) the spinous layer (stratum spinosum); (c) the granular layer (stratum granulosum), and (d) the cornified layer (stratum corneum).

Fig. 17-1: Successive stages in the development of the epidermis and the dermis. A: Ectoderm is composed of a single layer of cells with underlying mesenchyme. B: Development of a second layer, the periderm. C and D: Formation of multi-layered epidermis. E: Fetal epidermis showing the formation of epidermal papillae. F: The epidermis at the late fetal stage displaying the characteristic layers of a stratified sqamous epithelium.

Courtesy Sinowatz and Rüsse (2007).

Fig. 17-2: Epidermis of a cat embryo with a CRL of 17 mm. 1: Epidermis; 2: Amnion; 3: Mesenchyme.

Fig. 17-3: Epidermis of a cat embryo with a CRL of 46 mm. 1: Periderm; 2: Intermediate layer of the epidermis; 3: Basal layer of the epidermis; 4: Epidermal downgrowth; 5: Mesenchyme.

Cells in the basal layer sitting on the basal lamina will become the germinative layer, a zone destined to give rise to the stratified epithelium of the epidermis. The basal layer contains the epidermal stem cells that divide mitotically to continuously replace the upper layers of the epidermis, which cornify and eventually get sloughed off. The stem cells of the epidermis divide asymmetrically: the daughter cell that stays attached to the basal lamina remains a stem cell, whereas the cell that leaves the basal layer and migrates to the surface starts to differentiate. The latter cells produce keratins characteristic of skin and arrange them into dense intermediate filaments. The differentiated epidermal cells are called keratinocytes. They are bound tightly together by desmosomes and produce a water-impermeable seal of lipid and protein that minimizes dehydration of the body (Fig. 17-4).

Fig. 17-4: A: Skin of a fetal cat with a CRL of 8 cm. 1: Epidermis; 2: Dermis; 3: Hair bud; 4: Primordium of a sebaceous gland. B: Skin of a fetal cat with a CRL of 10.5 cm. 1: Epidermis; 2: Dermis; 3: Hair bulb; 4: Hair papilla; 5: Hair root; 6: Epithelial hair sheath; 7: Hair shaft; 8: Sebaceous gland; 9: Sweat gland; 10: Arrector pili muscle.

Continuous cell production in the basal layer generates cells that push older cells to the surface of the epidermis. The movement of epidermal cells from the basal layer is preceded by a loss of adhesiveness to basal membrane molecules, like fibronectin, laminin and collagen types I and IV. These cellular changes can be explained by the loss of several membrane proteins (integrins) from the plasma membrane of basal epidermal cells that mediate the attachment of these cells to basal lamina components. Cells of the spinous layer produce prominent bundles of keratin filaments, which converge on desmosomes, binding the cells to each other. During their migration, synthesis of differentiated products, like keratins, ceases in the cells. Keratohyalin granules begin to appear in the cytoplasm of the outer, postmitotic cells of the spinous layer and become prominent components in the next layer, the granular layer. The cells become flattened and their nuclei are pushed to one edge of the cells as they move into the outermost cornified layer. There, the cells eventually lose their nuclei and resemble more or less flattened sacs packed with keratin filaments and interconnected by the histidine-rich protein filaggrin. The keratinocytes of the cornified layer are continuously shed. The journey from the basal layer to the sloughed cells takes about 2 weeks in mice, 3 weeks in pigs, and 4 weeks in humans.

The development of the epidermis and its remarkable proliferative activity is stimulated by several growth factors. Transforming growth factor-α is produced by the basal cells and stimulates them by autocrine mechanisms. Keratinocyte growth factor (KGF, also known as fibroblast growth factor 7, FGF-7), also needed for epidermal development, is made by fibroblasts of the underlying mesenchyme. It is bound by special receptors on the basal cells in the epidermis and probably regulates the differentiation and migration of keratinocytes.

Several other cell types, which are generally termed epidermal non-keratinocytes, can be identified in the developing epidermis. Neural crest cells migrate into the dermis and differentiate into melanoblasts. They also invade the basal layer of the epidermis. Melanoblasts produce melanosomes containing the brown pigment melanin, which is made by oxidation of L-tyrosine in the presence of the enzyme tyrosinase. Melanosomes are transported to neighbouring keratinocytes and commonly make up the different body colour patterns observed in mammals. Merkel cells are intraepidermal mechanoreceptors associated with free nerve terminals. They were once regarded as specialized keratinocytes but new data support the idea that Merkel cells are of neural crest cell origin. Late in prenatal development, the epidermis is invaded by cells of another type, the Langerhans cells, which arise from precursors in the bone marrow. These cells are regarded as peripheral components of the immune system and are involved in the presentation of antigens. They cooperate with T-lymphocytes in the skin to initiate cell-mediated responses to foreign antigens.

DERMIS (CORIUM)

The dermis is derived from several sources. In the trunk, dorsal dermis originates from the dermatomes of the somites, whereas ventral and lateral dermis as well as the dermis of the limbs are derived from the lateral mesoderm. In the head, a considerable part of the cranial skin and anterior neck dermis descends from cranial neural crest ectoderm.

The future dermis initially forms from loosely aggregated mesenchymal cells that are tightly interconnected by focal tight junctions on their cellular processes. These mesenchymal cells secrete an intercellular matrix rich in hyaluronic acid and glycogen. Later they differentiate into fibroblasts, which form increasing amounts of collagen (types I and III) and elastic fibres (Fig. 17-1).

When fully developed, the dermis consists of a highly vascularized, fibroelastic connective tissue that can be subdivided into papillary and reticular layers. Thickenings of the dermis (papillae) project into the basal layers of the epidermis. These alternate with downgrowths of the basal layer, termed epidermal ridges, and are peculiar to the dermoepidermal boundary; they resist shear forces and help maintain the structural integrity of the integument. The papillae contain capillaries and sensory nerve end organs (the Vater-Pacini, Meissner, and Kraus corpuscles).

SUBCUTIS

In most regions of the body mesenchymal cells form a more or less thick layer that gives rise to the loose connective tissue of the subcutis. Besides fibroblasts and different types of free cells, the subcutis contains irregular bundles of collagen fibres interspersed with elastic fibres and a varying number of adipocytes. Bundles of skeletal muscle fibres develop in the subcutis in specific regions of the body, such as the thoracic and cervical regions.

EPIDERMAL APPENDAGES

The skin of the domestic animals displays an astounding degree of functional and morphological variety. This is expressed by the presence of highly specialized cutaneous appendages, including a variety of glands (ranging from apo- and eccrine sweat glands and sebaceous glands to mammary glands), hairs, and terminal phalangeal coverings (claws and hooves). The cutaneous epidermal appendages result from a series of reciprocal interactions between the epidermis and the underlying mesenchyme. A complex cascade of proteins in the Wnt and FGF signalling pathway regulate the epithelio-mesenchymal interactions during the formation of epidermal appendages.

Hair

Hairs are specialized epidermal derivatives that arise from the epidermis as the result of inductive stimuli from the dermis. In the smooth bare skin around the lips, periorbita and lower jaws, focal thickenings of the epidermis are the first microscopic evidence of hair development. Later, the primordia of hairs appear in the general integument and, with the exception of some notable anatomical regions, the entire body surface of domestic mammals is covered by closely spaced hairs. Areas that remain devoid of hair include the rhinarium, hooves, digital pads, and muco-cutaneous junctions. Species and even individuals show a marked variation in hair density, type, distribution pattern and colour.

Hairs appear as solid proliferations from the basal layer of the epidermis that penetrates the underlying dermis. The basal epidermal cells divide, elongate and penetrate the dermis at an oblique angle. At their terminal ends, these hair buds (hair germs, hair pegs) invaginate. The invaginations are rapidly filled with mesenchymal cells and form the dermal papillae which contain blood vessels and nerve endings. Under the continuing influence of the dermal papilla, the cells of the epidermal downgrowth continue to divide and form an early hair bud. Soon the cells in the centre of the hair bud become spindle-shaped and keratinized. They form the hair shaft, while the peripheral cells remain more cuboidal, giving rise to the epithelial hair sheath that later develops into the internal and external root sheath. Around the epidermal hair sheath, the surrounding mesenchyme forms a dermal root sheath (Fig. 17-5).

Fig. 17-5: Skin of a bovine fetus with a CRL of 62 cm. 1: Epidermis; 2: Basal layer of epidermis; 3: Epithelial root sheath; 4: Hair papilla; 5: Dermis.

In the following weeks the epidermal bud overgrows the dermal papilla, resulting in the shaping of an early hair follicle. At this stage the epithelial wall of the hair follicle shows two bulges penetrating the surrounding mesoderm. The cells of the upper swelling form the sebaceous glands, which produce sebum, an oily skin lubricant. During prenatal development the products of the fetal sebaceous glands accumulate on the surface of the skin as vernix caseosa. This substance serves as a protective coating for the epidermis while it is continuously bathed in amniotic fluid.

The second bulge is the attachment site for a tiny muscle, the arrector pili muscle. This bulge induces the adjacent mesenchyme cells to form the smooth muscle cells of the muscle. Its mesodermally-derived smooth muscle fibres can lift the hair to a nearly vertical position in a cold environment. New data show that this lower bulge houses at least two remarkable types of stem cell: the multipotent hair follicle stem cells and the melanocyte stem cells. Melanocyte stem cells are derivatives of the neural crest, produce the pigment melanin, and probably give rise to all pigmented cells of the skin.

Hair follicles can be classified as either primary or secondary. The bulbs of primary hair follicles are located deep in the dermis. A single hair (guard hair), which is usually associated both with sebaceous and sweat glands, emerges from a primary follicle. Primary hair follicles are at first evenly spaced; later, new primary follicles develop between those already established. This leads to a species-specific formation of groups of two, three or four follicles in close proximity to each other (see later).

The spacing of the primary hair follicles involves the influence of several growth and transcription factors. FGF-5, produced by the surrounding mesenchyme, has a stimulatory effect on the epidermal downgrowth of the hair buds. Counteracting this is an inhibitory influence of BMP-2 and BMP-4, which may regulate the spacing between adjacent hair buds. Soon after its formation, the hair bud begins to express Sonic hedgehog (Shh), which stimulates cell proliferation and growth of the hair follicles.

Secondary hair follicles have a relatively small diameter and are located more superficially in the dermis. While the hairs emerging from secondary follicles (secondary or under hairs) are usually associated with sebaceous glands, they lack sweat glands and arrector pili muscles.

There is wide variation in the type and surface distribution of hair follicles in domestic animals. In horses and cattle only primary follicles are present, distributed evenly in rows over the body surface. In sheep, wool hair follicles form clusters, each cluster usually consisting of three primary follicles interspersed among secondary follicles. The number of secondary follicles can be up to six times higher than the number of primary follicles, depending on the breed. In the pig, primary hair follicles are arranged in clusters of three or four primary follicles per cluster. The skin of dogs and cats possesses compound follicles (where two or more hairs project through a common pore) that develop postnatally. In cats, single primary follicles are surrounded by several (2–5) compound follicles, which have up to three coarse primary hairs and six to twelve secondary hairs. In dogs, compound follicles occur in clusters of three, with a slightly larger centre follicle.