A class of fibrous proteins or scleroproteins that represents the principal constituent of EPIDERMIS; HAIR; NAILS; horny tissues, and the organic matrix of tooth ENAMEL. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms a coiled-coil alpha helical structure consisting of TYPE I KERATIN and a TYPE II KERATIN, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. alpha-Keratins have been classified into at least 20 subtypes. In addition multiple isoforms of subtypes have been found which may be due to GENE DUPLICATION.

Genes in the KRT group provide instructions for making proteins called keratins. Keratins are a group of tough, fibrous proteins that form the structural framework of epithelial cells, which are cells that line the surfaces and cavities of the body. Epithelial cells make up tissues such as the hair, skin, and nails. These cells also line the internal organs and are an important part of many glands.

Keratins are best known for providing strength and resilience to cells that form the hair, skin, and nails. These proteins allow tissues to resist damage from friction and minor trauma, such as rubbing and scratching. Keratins are also involved in several other critical cell functions, including cell movement (migration), regulation of cell size, cell growth and division (proliferation), wound healing, and transport of materials within cells.

Humans have at least 54 functional keratin genes, which are divided into type I and type II keratins. Most of the type I keratin genes, designated KRT9 through KRT20, are located in a cluster on chromosome 17. The type II keratin genes, designated KRT1 through KRT8, are found in another cluster on chromosome 12.

Different combinations of keratin proteins are found in different tissues. In each tissue, a type I keratin pairs with a type II keratin to form a structure called a heterodimer. Heterodimers interact with one another to form strong, flexible fibers called keratin intermediate filaments. These filaments assemble into a dense network, which forms the structural framework of cells.

Mutations in at least 20 KRT genes have been found to cause human diseases affecting the skin, hair, nails, and related tissues. The most well-studied of these diseases include epidermolysis bullosa simplex (EBS) and pachyonychia congenita. Mutations in KRT genes alter the structure of keratins, which prevent them from forming an effective network of keratin intermediate filaments. Without this network, cells become fragile and are easily damaged, making tissues less resistant to friction and minor trauma. Even normal activities such as walking can cause skin cells to break down, resulting in the formation of painful blisters and calluses.

Examples of genes in this gene group: KRT1, KRT3, KRT4, KRT5, KRT6A, KRT6B, KRT6C, KRT10, KRT12, KRT13, KRT14, KRT16, KRT17, KRT81, KRT83, KRT86

Keratinocyte is the cell that produces keratin and is the most predominant type of cell found in the epidermis.

Medulla is in hair, the innermost layer of keratinocytes originating from the hair matrix.

Melanosome is a intercellular vesicle that transfers melanin from melanocytes into keratinocytes of the epidermis.

Basal cell is a type of stem cell found in the stratum basale and in the hair matrix that continually undergoes cell division, producing the keratinocytes of the epidermis.

Cortex is in hair, the second or middle layer of keratinocytes originating from the hair matrix, as seen in a cross-section of the hair bulb.

Cuticle is in hair, the outermost layer of keratinocytes originating from the hair matrix, as seen in a cross-section of the hair bulb.

Hair is a keratinous filament growing out of the epidermis.

Internal root sheath is an innermost layer of keratinocytes in the hair follicle that surround the hair root up to the hair shaft.

Keratin is a type of structural protein that gives skin, hair, and nails its hard, water-resistant properties.

Medulla is in hair, the innermost layer of keratinocytes originating from the hair matrix

Melanosome is a intercellular vesicle that transfers melanin from melanocytes into keratinocytes of the epidermis.

Nail body is a main keratinous plate that forms the nail.

Although you may not typically think of the skin as an organ, it is in fact made of tissues that work together as a single structure to perform unique and critical functions. The skin and its accessory structures make up the integumentary system, which provides the body with overall protection. The skin is made of multiple layers of cells and tissues, which are held to underlying structures by connective tissue (Figure 5.2). The deeper layer of skin is well vascularized (has numerous blood vessels). It also has numerous sensory, and autonomic and sympathetic nerve fibers ensuring communication to and from the brain.

Figure 5.2 Layers of Skin The skin is composed of two main layers: the epidermis, made of closely packed epithelial cells, and the dermis, made of dense, irregular connective tissue that houses blood vessels, hair follicles, sweat glands, and other structures. Beneath the dermis lies the hypodermis, which is composed mainly of loose connective and fatty tissues.

The Epidermis

The epidermis is composed of keratinized, stratified squamous epithelium. It is made of four or five layers of epithelial cells, depending on its location in the body. It does not have any blood vessels within it (i.e., it is avascular). Skin that has four layers of cells is referred to as “thin skin.” From deep to superficial, these layers are the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. Most of the skin can be classified as thin skin. “Thick skin” is found only on the palms of the hands and the soles of the feet. It has a fifth layer, called the stratum lucidum, located between the stratum corneum and the stratum granulosum (Figure 5.3).

Figure 5.3 Thin Skin versus Thick Skin These slides show cross-sections of the epidermis and dermis of (a) thin and (b) thick skin. Note the significant difference in the thickness of the epithelial layer of the thick skin. From top, LM × 40, LM × 40. (Micrographs provided by the Regents of University of Michigan Medical School © 2012)

The cells in all of the layers except the stratum basale are called keratinocytes. A keratinocyte is a cell that manufactures and stores the protein keratin. Keratin is an intracellular fibrous protein that gives hair, nails, and skin their hardness and water-resistant properties. The keratinocytes in the stratum corneum are dead and regularly slough away, being replaced by cells from the deeper layers (Figure 5.4).

Figure 5.4 Epidermis The epidermis is epithelium composed of multiple layers of cells. The basal layer consists of cuboidal cells, whereas the outer layers are squamous, keratinized cells, so the whole epithelium is often described as being keratinized stratified squamous epithelium. LM × 40. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)

Stratum Basale

The stratum basale (also called the stratum germinativum) is the deepest epidermal layer and attaches the epidermis to the basal lamina, below which lie the layers of the dermis. The cells in the stratum basale bond to the dermis via intertwining collagen fibers, referred to as the basement membrane. A finger-like projection, or fold, known as the dermal papilla (plural = dermal papillae) is found in the superficial portion of the dermis. Dermal papillae increase the strength of the connection between the epidermis and dermis; the greater the folding, the stronger the connections made (Figure 5.5).

Figure 5.5 Layers of the Epidermis The epidermis of thick skin has five layers: stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum.

The stratum basale is a single layer of cells primarily made of basal cells. A basal cell is a cuboidal-shaped stem cell that is a precursor of the keratinocytes of the epidermis. All of the keratinocytes are produced from this single layer of cells, which are constantly going through mitosis to produce new cells. As new cells are formed, the existing cells are pushed superficially away from the stratum basale. Two other cell types are found dispersed among the basal cells in the stratum basale. The first is a Merkel cell, which functions as a receptor and is responsible for stimulating sensory nerves that the brain perceives as touch. These cells are especially abundant on the surfaces of the hands and feet. The second is a melanocyte, a cell that produces the pigment melanin. Melanin gives hair and skin its color, and also helps protect the living cells of the epidermis from ultraviolet (UV) radiation damage.

In a growing fetus, fingerprints form where the cells of the stratum basale meet the papillae of the underlying dermal layer (papillary layer), resulting in the formation of the ridges on your fingers that you recognize as fingerprints. Fingerprints are unique to each individual and are used for forensic analyses because the patterns do not change with the growth and aging processes.

Stratum Spinosum

As the name suggests, the stratum spinosum is spiny in appearance due to the protruding cell processes that join the cells via a structure called a desmosome. The desmosomes interlock with each other and strengthen the bond between the cells. It is interesting to note that the “spiny” nature of this layer is an artifact of the staining process. Unstained epidermis samples do not exhibit this characteristic appearance. The stratum spinosum is composed of eight to 10 layers of keratinocytes, formed as a result of cell division in the stratum basale (Figure 5.6). Interspersed among the keratinocytes of this layer is a type of dendritic cell called the Langerhans cell, which functions as a macrophage by engulfing bacteria, foreign particles, and damaged cells that occur in this layer.

Figure 5.6 Cells of the Epidermis The cells in the different layers of the epidermis originate from basal cells located in the stratum basale, yet the cells of each layer are distinctively different. EM × 2700. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)

The keratinocytes in the stratum spinosum begin the synthesis of keratin and release a water-repelling glycolipid that helps prevent water loss from the body, making the skin relatively waterproof. As new keratinocytes are produced atop the stratum basale, the keratinocytes of the stratum spinosum are pushed into the stratum granulosum.

Stratum Granulosum

The stratum granulosum has a grainy appearance due to further changes to the keratinocytes as they are pushed from the stratum spinosum. The cells (three to five layers deep) become flatter, their cell membranes thicken, and they generate large amounts of the proteins keratin, which is fibrous, and keratohyalin, which accumulates as lamellar granules within the cells (see Figure 5.5). These two proteins make up the bulk of the keratinocyte mass in the stratum granulosum and give the layer its grainy appearance. The nuclei and other cell organelles disintegrate as the cells die, leaving behind the keratin, keratohyalin, and cell membranes that will form the stratum lucidum, the stratum corneum, and the accessory structures of hair and nails.

Stratum Lucidum

The stratum lucidum is a smooth, seemingly translucent layer of the epidermis located just above the stratum granulosum and below the stratum corneum. This thin layer of cells is found only in the thick skin of the palms, soles, and digits. The keratinocytes that compose the stratum lucidum are dead and flattened (see Figure 5.5). These cells are densely packed with eleiden, a clear protein rich in lipids, derived from keratohyalin, which gives these cells their transparent (i.e., lucid) appearance and provides a barrier to water.

Stratum Corneum

The stratum corneum is the most superficial layer of the epidermis and is the layer exposed to the outside environment (see Figure 5.5). The increased keratinization (also called cornification) of the cells in this layer gives it its name. There are usually 15 to 30 layers of cells in the stratum corneum. This dry, dead layer helps prevent the penetration of microbes and the dehydration of underlying tissues, and provides a mechanical protection against abrasion for the more delicate, underlying layers. Cells in this layer are shed periodically and are replaced by cells pushed up from the stratum granulosum (or stratum lucidum in the case of the palms and soles of feet). The entire layer is replaced during a period of about 4 weeks. Cosmetic procedures, such as microdermabrasion, help remove some of the dry, upper layer and aim to keep the skin looking “fresh” and healthy.

Dermis

The dermis might be considered the “core” of the integumentary system (derma- = “skin”), as distinct from the epidermis (epi- = “upon” or “over”) and hypodermis (hypo- = “below”). It contains blood and lymph vessels, nerves, and other structures, such as hair follicles and sweat glands. The dermis is made of two layers of connective tissue that compose an interconnected mesh of elastin and collagenous fibers, produced by fibroblasts (Figure 5.7).

Figure 5.7 Layers of the Dermis This stained slide shows the two components of the dermis—the papillary layer and the reticular layer. Both are made of connective tissue with fibers of collagen extending from one to the other, making the border between the two somewhat indistinct. The dermal papillae extending into the epidermis belong to the papillary layer, whereas the dense collagen fiber bundles below belong to the reticular layer. LM × 10. (credit: modification of work by “kilbad”/Wikimedia Commons)

Papillary Layer

The papillary layer is made of loose, areolar connective tissue, which means the collagen and elastin fibers of this layer form a loose mesh. This superficial layer of the dermis projects into the stratum basale of the epidermis to form finger-like dermal papillae (see Figure 5.7). Within the papillary layer are fibroblasts, a small number of fat cells (adipocytes), and an abundance of small blood vessels. In addition, the papillary layer contains phagocytes, defensive cells that help fight bacteria or other infections that have breached the skin. This layer also contains lymphatic capillaries, nerve fibers, and touch receptors called the Meissner corpuscles.

Reticular Layer

Underlying the papillary layer is the much thicker reticular layer, composed of dense, irregular connective tissue. This layer is well vascularized and has a rich sensory and sympathetic nerve supply. The reticular layer appears reticulated (net-like) due to a tight meshwork of fibers. Elastin fibers provide some elasticity to the skin, enabling movement. Collagen fibers provide structure and tensile strength, with strands of collagen extending into both the papillary layer and the hypodermis. In addition, collagen binds water to keep the skin hydrated. Collagen injections and Retin-A creams help restore skin turgor by either introducing collagen externally or stimulating blood flow and repair of the dermis, respectively.

Hypodermis

The hypodermis (also called the subcutaneous layer or superficial fascia) is a layer directly below the dermis and serves to connect the skin to the underlying fascia (fibrous tissue) of the bones and muscles. It is not strictly a part of the skin, although the border between the hypodermis and dermis can be difficult to distinguish. The hypodermis consists of well-vascularized, loose, areolar connective tissue and adipose tissue, which functions as a mode of fat storage and provides insulation and cushioning for the integument.

Pigmentation

The color of skin is influenced by a number of pigments, including melanin, carotene, and hemoglobin. Recall that melanin is produced by cells called melanocytes, which are found scattered throughout the stratum basale of the epidermis. The melanin is transferred into the keratinocytes via a cellular vesicle called a melanosome (Figure 5.8).

Figure 5.8 Skin Pigmentation The relative coloration of the skin depends of the amount of melanin produced by melanocytes in the stratum basale and taken up by keratinocytes.

Melanin occurs in two primary forms. Eumelanin exists as black and brown, whereas pheomelanin provides a red color. Dark-skinned individuals produce more melanin than those with pale skin. Exposure to the UV rays of the sun or a tanning salon causes melanin to be manufactured and built up in keratinocytes, as sun exposure stimulates keratinocytes to secrete chemicals that stimulate melanocytes. The accumulation of melanin in keratinocytes results in the darkening of the skin, or a tan. This increased melanin accumulation protects the DNA of epidermal cells from UV ray damage and the breakdown of folic acid, a nutrient necessary for our health and well-being. In contrast, too much melanin can interfere with the production of vitamin D, an important nutrient involved in calcium absorption. Thus, the amount of melanin present in our skin is dependent on a balance between available sunlight and folic acid destruction, and protection from UV radiation and vitamin D production.

It requires about 10 days after initial sun exposure for melanin synthesis to peak, which is why pale-skinned individuals tend to suffer sunburns of the epidermis initially. Dark-skinned individuals can also get sunburns, but are more protected than are pale-skinned individuals. Melanosomes are temporary structures that are eventually destroyed by fusion with lysosomes; this fact, along with melanin-filled keratinocytes in the stratum corneum sloughing off, makes tanning impermanent.

Too much sun exposure can eventually lead to wrinkling due to the destruction of the cellular structure of the skin, and in severe cases, can cause sufficient DNA damage to result in skin cancer. When there is an irregular accumulation of melanocytes in the skin, freckles appear. Moles are larger masses of melanocytes, and although most are benign, they should be monitored for changes that might indicate the presence of cancer (Figure 5.9).

Figure 5.9 Moles Moles range from benign accumulations of melanocytes to melanomas. These structures populate the landscape of our skin. (credit: the National Cancer Institute)

Hair

Hair is a keratinous filament growing out of the epidermis. It is primarily made of dead, keratinized cells. Strands of hair originate in an epidermal penetration of the dermis called the hair follicle. The hair shaft is the part of the hair not anchored to the follicle, and much of this is exposed at the skin’s surface. The rest of the hair, which is anchored in the follicle, lies below the surface of the skin and is referred to as the hair root. The hair root ends deep in the dermis at the hair bulb, and includes a layer of mitotically active basal cells called the hair matrix. The hair bulb surrounds the hair papilla, which is made of connective tissue and contains blood capillaries and nerve endings from the dermis (Figure 5.11).

Just as the basal layer of the epidermis forms the layers of epidermis that get pushed to the surface as the dead skin on the surface sheds, the basal cells of the hair bulb divide and push cells outward in the hair root and shaft as the hair grows. The medulla forms the central core of the hair, which is surrounded by the cortex, a layer of compressed, keratinized cells that is covered by an outer layer of very hard, keratinized cells known as the cuticle. These layers are depicted in a longitudinal cross-section of the hair follicle (image), although not all hair has a medullary layer. Hair texture (straight, curly) is determined by the shape and structure of the cortex, and to the extent that it is present, the medulla. The shape and structure of these layers are, in turn, determined by the shape of the hair follicle. Hair growth begins with the production of keratinocytes by the basal cells of the hair bulb. As new cells are deposited at the hair bulb, the hair shaft is pushed through the follicle toward the surface. Keratinization is completed as the cells are pushed to the skin surface to form the shaft of hair that is externally visible. The external hair is completely dead and composed entirely of keratin. For this reason, our hair does not have sensation. Furthermore, you can cut your hair or shave without damaging the hair structure because the cut is superficial. Most chemical hair removers also act superficially; however, electrolysis and yanking both attempt to destroy the hair bulb so hair cannot grow.

The wall of the hair follicle is made of three concentric layers of cells. The cells of the internal root sheath surround the root of the growing hair and extend just up to the hair shaft. They are derived from the basal cells of the hair matrix. The external root sheath, which is an extension of the epidermis, encloses the hair root. It is made of basal cells at the base of the hair root and tends to be more keratinous in the upper regions. The glassy membrane is a thick, clear connective tissue sheath covering the hair root, connecting it to the tissue of the dermis.

Hair serves a variety of functions, including protection, sensory input, thermoregulation, and communication. For example, hair on the head protects the skull from the sun. The hair in the nose and ears, and around the eyes (eyelashes) defends the body by trapping and excluding dust particles that may contain allergens and microbes. Hair of the eyebrows prevents sweat and other particles from dripping into and bothering the eyes. Hair also has a sensory function due to sensory innervation by a hair root plexus surrounding the base of each hair follicle. Hair is extremely sensitive to air movement or other disturbances in the environment, much more so than the skin surface. This feature is also useful for the detection of the presence of insects or other potentially damaging substances on the skin surface. Each hair root is connected to a smooth muscle called the arrector pili that contracts in response to nerve signals from the sympathetic nervous system, making the external hair shaft “stand up.” The primary purpose for this is to trap a layer of air to add insulation. This is visible in humans as goose bumps and even more obvious in animals, such as when a frightened cat raises its fur. Of course, this is much more obvious in organisms with a heavier coat than most humans, such as dogs and cats.

Hair Growth

Hair grows and is eventually shed and replaced by new hair. This occurs in three phases. The first is the anagen phase, during which cells divide rapidly at the root of the hair, pushing the hair shaft up and out. The length of this phase is measured in years, typically from 2 to 7 years. The catagen phase lasts only 2 to 3 weeks, and marks a transition from the hair follicle’s active growth. Finally, during the telogen phase, the hair follicle is at rest and no new growth occurs. At the end of this phase, which lasts about 2 to 4 months, another anagen phase begins. The basal cells in the hair matrix then produce a new hair follicle, which pushes the old hair out as the growth cycle repeats itself. Hair typically grows at the rate of 0.3 mm per day during the anagen phase. On average, 50 hairs are lost and replaced per day. Hair loss occurs if there is more hair shed than what is replaced and can happen due to hormonal or dietary changes. Hair loss can also result from the aging process, or the influence of hormones.

Hair Color

Similar to the skin, hair gets its color from the pigment melanin, produced by melanocytes in the hair papilla. Different hair color results from differences in the type of melanin, which is genetically determined. As a person ages, the melanin production decreases, and hair tends to lose its color and becomes gray and/or white.

Nails

The nail bed is a specialized structure of the epidermis that is found at the tips of our fingers and toes. The nail body is formed on the nail bed, and protects the tips of our fingers and toes as they are the farthest extremities and the parts of the body that experience the maximum mechanical stress (Figure 5.13). In addition, the nail body forms a back-support for picking up small objects with the fingers. The nail body is composed of densely packed dead keratinocytes. The epidermis in this part of the body has evolved a specialized structure upon which nails can form. The nail body forms at the nail root, which has a matrix of proliferating cells from the stratum basale that enables the nail to grow continuously. The lateral nail fold overlaps the nail on the sides, helping to anchor the nail body. The nail fold that meets the proximal end of the nail body forms the nail cuticle, also called the eponychium. The nail bed is rich in blood vessels, making it appear pink, except at the base, where a thick layer of epithelium over the nail matrix forms a crescent-shaped region called the lunula (the “little moon”). The area beneath the free edge of the nail, furthest from the cuticle, is called the hyponychium. It consists of a thickened layer of stratum corneum.

Figure 5.13 Nails The nail is an accessory structure of the integumentary system.

Sweat Glands

When the body becomes warm, sudoriferous glands produce sweat to cool the body. Sweat glands develop from epidermal projections into the dermis and are classified as merocrine glands; that is, the secretions are excreted by exocytosis through a duct without affecting the cells of the gland. There are two types of sweat glands, each secreting slightly different products.

An eccrine sweat gland is a type of gland that produces a hypotonic sweat for thermoregulation. These glands are found all over the skin’s surface, but are especially abundant on the palms of the hand, the soles of the feet, and the forehead (Figure 5.14). They are coiled glands lying deep in the dermis, with the duct rising up to a pore on the skin surface, where the sweat is released. This type of sweat, released by exocytosis, is hypotonic and composed mostly of water, with some salt, antibodies, traces of metabolic waste, and dermicidin, an antimicrobial peptide. Eccrine glands are a primary component of thermoregulation in humans and thus help to maintain homeostasis.

Figure 5.14 Eccrine Gland Eccrine glands are coiled glands in the dermis that release sweat that is mostly water.

An apocrine sweat gland is usually associated with hair follicles in densely hairy areas, such as armpits and genital regions. Apocrine sweat glands are larger than eccrine sweat glands and lie deeper in the dermis, sometimes even reaching the hypodermis, with the duct normally emptying into the hair follicle. In addition to water and salts, apocrine sweat includes organic compounds that make the sweat thicker and subject to bacterial decomposition and subsequent smell. The release of this sweat is under both nervous and hormonal control, and plays a role in the poorly understood human pheromone response. Most commercial antiperspirants use an aluminum-based compound as their primary active ingredient to stop sweat. When the antiperspirant enters the sweat gland duct, the aluminum-based compounds precipitate due to a change in pH and form a physical block in the duct, which prevents sweat from coming out of the pore.

Sebaceous Glands

A sebaceous gland is a type of oil gland that is found all over the body and helps to lubricate and waterproof the skin and hair. Most sebaceous glands are associated with hair follicles. They generate and excrete sebum, a mixture of lipids, onto the skin surface, thereby naturally lubricating the dry and dead layer of keratinized cells of the stratum corneum, keeping it pliable. The fatty acids of sebum also have antibacterial properties, and prevent water loss from the skin in low-humidity environments. The secretion of sebum is stimulated by hormones, many of which do not become active until puberty. Thus, sebaceous glands are relatively inactive during childhood.