Epidermis

The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis.<ref>Template:Cite book</ref> The epidermal layer provides a barrier to infection from environmental pathogens<ref name="Lookingbill">Template:Cite book</ref> and regulates the amount of water released from the body into the atmosphere through transepidermal water loss.<ref name="Proksch">Template:Cite journal</ref>

The epidermis is composed of multiple layers of flattened cells<ref name="Rooks">Template:Cite book</ref> that overlie a base layer (stratum basale) composed of columnar cells arranged perpendicularly. The layers of cells develop from stem cells in the basal layer. The thickness of the epidermis varies from 31.2μm for the penis to 596.6μm for the sole of the foot with most being roughly 90μm. Thickness does not vary between the sexes but becomes thinner with age.<ref name="Lintzeri Karimian Blume‐Peytavi Kottner 2022 pp. 1191–1200">Template:Cite journal</ref> The human epidermis is an example of epithelium, particularly a stratified squamous epithelium.

The word epidermis is derived through Latin Template:Ety, itself Template:Ety and Template:Ety. Something related to or part of the epidermis is termed epidermal.

Structure

Cellular components

The epidermis primarily consists of keratinocytes<ref name="Rooks" /> (proliferating basal and differentiated suprabasal), which comprise 90% of its cells, but also contains melanocytes, Langerhans cells, Merkel cells,<ref name="Andrews"/>Template:Rp and inflammatory cells. Epidermal thickenings called Rete ridges (or rete pegs) extend downward between dermal papillae.<ref>TheFreeDictionary > rete ridge Citing: The American Heritage Medical Dictionary Copyright 2007, 2004</ref> Blood capillaries are found beneath the epidermis, and are linked to an arteriole and a venule. The epidermis itself has no blood supply and is nourished almost exclusively by diffused oxygen from the surrounding air.<ref name=stucker>Template:Cite journal</ref> Cellular mechanisms for regulating water and sodium levels (ENaCs) are found in all layers of the epidermis.<ref name="2017-Hanukoglu">Template:Cite journal</ref>

Cell boundaries

Epidermal cells are tightly interconnected to serve as a tight barrier against the exterior environment. The junctions between the epidermal cells are of the adherens junction type, formed by transmembrane proteins called cadherins. Inside the cell, the cadherins are linked to actin filaments. In immunofluorescence microscopy, the actin filament network appears as a thick border surrounding the cells,<ref name="2017-Hanukoglu" /> although the actin filaments are actually located inside the cell and run parallel to the cell membrane. Because of the proximity of the neighboring cells and tightness of the junctions, the actin immunofluorescence appears as a border between cells.<ref name="2017-Hanukoglu" />

Layers

File:Skinlayers.png

Schematic image showing a section of epidermis, with epidermal layers labeled

The epidermis is composed of four or five layers, depending on the skin region.<ref>Template:Cite book</ref> Those layers from outermost to innermost are:<ref name="Lookingbill" />

cornified layer (stratum corneum)

File:Confocal image of the stratum corneum.jpg

Confocal image of the stratum corneum

Composed of 10 to 30 layers of polyhedral, anucleated corneocytes (final step of keratinocyte differentiation), with the palms and soles having the most layers. Corneocytes contain a protein envelope (cornified envelope proteins) underneath the plasma membrane, are filled with water-retaining keratin proteins, attached together through corneodesmosomes and surrounded in the extracellular space by stacked layers of lipids.<ref name="bensouillah">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> Most of the barrier functions of the epidermis localize to this layer.<ref name="elias">Template:Cite journal</ref>

clear/translucent layer (stratum lucidum, only in palms and soles)

This narrow layer is found only on the palms and soles. The epidermis of these two areas is known as "thick skin" because with this extra layer, the skin has 5 epidermal layers instead of 4.

granular layer (stratum granulosum)

File:Confocal image of the stratum granulosum.jpg

Confocal image of the stratum granulosum

Keratinocytes lose their nuclei and their cytoplasm appears granular. Lipids, contained into those keratinocytes within lamellar bodies, are released into the extracellular space through exocytosis to form a lipid barrier that prevents water loss from the body as well as entry of foreign substances. Those polar lipids are then converted into non-polar lipids and arranged parallel to the cell surface. For example glycosphingolipids become ceramides and phospholipids become free fatty acids.<ref name="bensouillah" />

spinous layer (stratum spinosum)

File:Confocal image of the stratum spinosum with some basal cell clusters.jpg

Confocal image of the stratum spinosum already showing some clusters of basal cells

Keratinocytes become connected through desmosomes and produce lamellar bodies, from within the Golgi, enriched in polar lipids, glycosphingolipids, free sterols, phospholipids and catabolic enzymes.<ref name="Proksch" /> Langerhans cells, immunologically active cells, are located in the middle of this layer.<ref name="bensouillah" />

basal/germinal layer (stratum basale/germinativum)

File:Confocal image of the stratum basale showing some papillae.jpg

Confocal image of the stratum basale already showing some papillae

Composed mainly of proliferating and non-proliferating keratinocytes, attached to the basement membrane by hemidesmosomes. Melanocytes are present, connected to numerous keratinocytes in this and other strata through dendrites. Merkel cells are also found in the stratum basale with large numbers in touch-sensitive sites such as the fingertips and lips. They are closely associated with cutaneous nerves and seem to be involved in light touch sensation.<ref name="bensouillah" />

Malpighian layer (stratum malpighii)

This is usually defined as both the stratum basale and stratum spinosum.<ref name="Rooks" />

The epidermis is separated from the dermis, its underlying tissue, by a basement membrane.

Cellular kinetics

Cell division

As a stratified squamous epithelium, the epidermis is maintained by cell division within the stratum basale. Differentiating cells delaminate from the basement membrane and are displaced outward through the epidermal layers, undergoing multiple stages of differentiation until, in the stratum corneum, losing their nucleus and fusing to squamous sheets, which are eventually shed from the surface (desquamation). Differentiated keratinocytes secrete keratin proteins, which contribute to the formation of an extracellular matrix that is an integral part of the skin barrier function. In normal skin, the rate of keratinocyte production equals the rate of loss,<ref name="Rooks" /> taking about two weeks for a cell to journey from the stratum basale to the top of the stratum granulosum, and an additional four weeks to cross the stratum corneum.<ref name="Lookingbill" /> The entire epidermis is replaced by new cell growth over a period of about 48 days.<ref name="Iizuka">Template:Cite journal</ref>

Calcium concentration

Keratinocyte differentiation throughout the epidermis is in part mediated by a calcium gradient, increasing from the stratum basale until the outer stratum granulosum, where it reaches its maximum, and decreasing in the stratum corneum. Calcium concentration in the stratum corneum is very low in part because those relatively dry cells are not able to dissolve the ions.<ref>Template:Cite journal</ref> This calcium gradient parallels keratinocyte differentiation and as such is considered a key regulator in the formation of the epidermal layers.<ref name="Proksch" />

Elevation of extracellular calcium concentrations induces an increase in intracellular free calcium concentrations.<ref>Template:Cite journal</ref> Part of that intracellular increase comes from calcium released from intracellular stores<ref>Template:Cite journal</ref> and another part comes from transmembrane calcium influx,<ref>Template:Cite journal</ref> through both calcium-sensitive chloride channels<ref>Template:Cite journal</ref> and voltage-independent cation channels permeable to calcium.<ref>Template:Cite journal</ref> Moreover, it has been suggested that an extracellular calcium-sensing receptor (CaSR) also contributes to the rise in intracellular calcium concentration.<ref>Template:Cite journal</ref>

Development

Epidermal organogenesis, the formation of the epidermis, begins in the cells covering the embryo after neurulation, the formation of the central nervous system. In most vertebrates, this original one-layered structure quickly transforms into a two-layered tissue; a temporary outer layer, the embryonic periderm, which is disposed once the inner basal layer or stratum germinativum has formed.<ref name="Gilbert-2003">Template:Cite book</ref>

This inner layer is a germinal epithelium that gives rise to all epidermal cells. It divides to form the outer spinous layer (stratum spinosum). The cells of these two layers, together called the Malpighian layer(s) after Marcello Malpighi, divide to form the superficial granular layer (Stratum granulosum) of the epidermis.<ref name="Gilbert-2003" />

The cells in the stratum granulosum do not divide, but instead form skin cells called keratinocytes from the granules of keratin. These skin cells finally become the cornified layer (stratum corneum), the outermost epidermal layer, where the cells become flattened sacks with their nuclei located at one end of the cell. After birth these outermost cells are replaced by new cells from the stratum granulosum and throughout life they are shed at a rate of 30 – 90 milligrams of skin flakes every hour, or 0.720 - 2.16 grams per day.<ref>Template:Cite journal</ref>

Epidermal development is a product of several growth factors, two of which are:<ref name="Gilbert-2003" />

• Transforming growth factor Alpha (TGFα) is an autocrine growth factor by which basal cells stimulate their own division.
• Keratinocyte growth factor (KGF or FGF7) is a paracrine growth factor produced by the underlying dermal fibroblasts in which the proliferation of basal cells is regulated.

Function

Barrier

The epidermis serves as a barrier to protect the body against microbial pathogens, oxidant stress (UV light), and chemical compounds, and provides mechanical resistance to minor injury. Most of this barrier role is played by the stratum corneum.<ref name="elias" />

Characteristics

• Physical barrier: Epidermal keratinocytes are tightly linked by cell–cell junctions associated to cytoskeletal proteins, giving the epidermis its mechanical strength.<ref name="Proksch" />
• Chemical barrier: Highly organized lipids, acids, hydrolytic enzymes, and antimicrobial peptides<ref name="Proksch" /> inhibit passage of external chemicals and pathogens into the body.
• Immunologically active barrier: The humoral and cellular constituents of the immune system<ref name="Proksch" /> found in the epidermis actively combat infection.
• Water content of the stratum corneum drops towards the surface, creating hostile conditions for pathogenic microorganism growth.<ref name="elias" />
• An acidic pH (around 5.0) and low amounts of water make the epidermis hostile to many microorganic pathogens.<ref name="elias" />
• Non-pathogenic microorganisms on the surface of the epidermis help defend against pathogens by competing for food, limiting its availability, and producing chemical secretions that inhibit the growth of pathogenic microbiota.<ref name="elias" />

Permeability

• Psychological stress, through an increase in glucocorticoids, compromises the stratum corneum and thus the barrier function.<ref>Template:Cite journal</ref>
• Sudden and large shifts in humidity alter stratum corneum hydration in a way that could allow entry of pathogenic microorganisms.<ref>Template:Cite journal</ref>

Skin hydration

The ability of the skin to hold water is primarily due to the stratum corneum and is critical for maintaining healthy skin.<ref>Template:Cite journal</ref> Skin hydration is quantified using corneometry.<ref name="pmid2459872">Template:Cite journal</ref> Lipids arranged through a gradient and in an organized manner between the cells of the stratum corneum form a barrier to transepidermal water loss.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Skin color

The amount and distribution of melanin pigment in the epidermis is the main reason for variation in skin color in Homo sapiens. Melanin is found in the small melanosomes, particles formed in melanocytes from where they are transferred to the surrounding keratinocytes. The size, number, and arrangement of the melanosomes vary between racial groups, but while the number of melanocytes can vary between different body regions, their numbers remain the same in individual body regions in all human beings. In white and Asian skin the melanosomes are packed in "aggregates", but in black skin they are larger and distributed more evenly. The number of melanosomes in the keratinocytes increases with UV radiation exposure, while their distribution remain largely unaffected.<ref>Template:Cite book</ref>

Touch

The skin contains specialized epidermal touch receptor cells called Merkel cells. Historically, the role of Merkel cells in sensing touch has been thought to be indirect, due their close association with nerve endings. However, recent work in mice and other model organisms demonstrates that Merkel cells intrinsically transform touch into electrical signals that are transmitted to the nervous system.<ref>Template:Cite journal</ref>

Clinical significance

Laboratory culture of keratinocytes to form a 3D structure (artificial skin) recapitulating most of the properties of the epidermis is routinely used as a tool for drug development and testing.

Hyperplasia

Epidermal hyperplasia (thickening resulting from cell proliferation) has various forms:

• Acanthosis is diffuse epidermal hyperplasia (thickening of the skin, and not to be confused with acanthocytes).<ref name="Kumar">Template:Cite book</ref> It implies increased thickness of the Malpighian layer (stratum basale and stratum spinosum).<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> Acanthosis nigricans is a black, poorly defined, velvety hyperpigmented acanthosis, usually observed in the back of neck, axilla, and other folded regions of the skin.

• Focal epithelial hyperplasia (Heck's disease) is an asymptomatic, benign neoplastic condition characterized by multiple white to pinkish papules that occur diffusely in the oral cavity.<ref>Template:Cite journal</ref><ref name="Andrews">Template:Cite book</ref>Template:Rp
• Pseudoepitheliomatous hyperplasia (PEH) is a benign condition characterized by hyperplasia of the epidermis and epithelium of skin appendages,<ref name="ChakrabartiChakrabarti2014"/> with irregular squamous strands extending down into the dermis,<ref name="Lynch2004">Template:Cite journal</ref> and closely simulating squamous cell carcinoma (SCC).<ref name="ChakrabartiChakrabarti2014">Template:Cite journal</ref>

• Acanthosis-nigricans4.jpg

  Acanthosis nigricans

• Hecks disease.jpg

  Heck's disease

• Histopathology of pseudoepitheliomatous hyperplasia, low magnification.jpg

  Pseudoepitheliomatous hyperplasia (PEH), low magnification, with acanthotic squamous epithelium with irregular thick finger-like downgrowths into the underlying dermis.

• Histopathology of pseudoepitheliomatous hyperplasia, high magnification.jpg

  PEH, high magnification, with reactive-appearing squamous downgrowths with no significant cytologic atypia.

In contrast, hyperkeratosis is a thickening of the stratum corneum, and is not necessarily due to hyperplasia.

Additional images

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See also

• List of distinct cell types in the adult human body
• Skin repair