Keratinocyte

File:Micrograph of keratinocytes, basal cells and melanocytes in the epidermis.jpg

Micrograph of keratinocytes, basal cells and melanocytes in the epidermis

File:Proliferative response induced by a tumor promoter in the epidermis of a wild-type mouse - image.pbio.v11.i07.g001.png

Keratinocytes (stained green) in the skin of a mouse

Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.<ref name="Rooks">Template:Cite book</ref> Basal cells in the basal layer (stratum basale) of the skin are sometimes referred to as basal keratinocytes.<ref name="Andrews">Template:Cite book</ref> Keratinocytes form a barrier against environmental damage by heat, UV radiation, water loss, pathogenic bacteria, fungi, parasites, and viruses. A number of structural proteins, enzymes, lipids, and antimicrobial peptides contribute to maintain the important barrier function of the skin. Keratinocytes differentiate from epidermal stem cells in the lower part of the epidermis and migrate towards the surface, finally becoming corneocytes and eventually being shed,<ref name=Gilbert2000 /><ref name=pmid17191035-2007 /><ref name=pmid11250888-2001 /><ref name=pmid19686098-2009 /> which happens every 40 to 56 days in humans.<ref name=pmid4551262-1972 />

Function

The primary function of keratinocytes is the formation of a barrier against environmental damage by heat, UV radiation, dehydration, pathogenic bacteria, fungi, parasites, and viruses.

Pathogens invading the upper layers of the epidermis can cause keratinocytes to produce proinflammatory mediators, particularly chemokines such as CXCL10 and CCL2 (MCP-1) which attract monocytes, natural killer cells, T-lymphocytes, and dendritic cells to the site of pathogen invasion.<ref>Template:Cite book</ref>

Structure

A number of structural proteins (filaggrin, keratin), enzymes (e.g. proteases), lipids, and antimicrobial peptides (defensins) contribute to maintain the important barrier function of the skin. Keratinization is part of the physical barrier formation (cornification), in which the keratinocytes produce more and more keratin and undergo terminal differentiation. The fully cornified keratinocytes that form the outermost layer are constantly shed off and replaced by new cells.<ref name=Gilbert2000>Template:Cite book</ref>

Cell differentiation

Epidermal stem cells reside in the lower part of the epidermis (stratum basale) and are attached to the basement membrane through hemidesmosomes. Epidermal stem cells divide in a random manner yielding either more stem cells or transit amplifying cells.<ref name=pmid17191035-2007>Template:Cite journal</ref> Some of the transit amplifying cells continue to proliferate then commit to differentiate and migrate towards the surface of the epidermis. Those stem cells and their differentiated progeny are organized into columns named epidermal proliferation units.<ref name=pmid11250888-2001>Template:Cite journal</ref>

During this differentiation process, keratinocytes permanently withdraw from the cell cycle, initiate expression of epidermal differentiation markers, and move suprabasally as they become part of the stratum spinosum, stratum granulosum, and eventually corneocytes in the stratum corneum.

Corneocytes are keratinocytes that have completed their differentiation program and have lost their nucleus and cytoplasmic organelles.<ref name=pmid19686098-2009>Template:Cite journal</ref> Corneocytes will eventually be shed off through desquamation as new ones come in.

At each stage of differentiation, keratinocytes express specific keratins, such as keratin 1, keratin 5, keratin 10, and keratin 14, but also other markers such as involucrin, loricrin, transglutaminase, filaggrin, and caspase 14.

In humans, it is estimated that keratinocytes turn over from stem cells to desquamation every 40–56 days,<ref name=pmid4551262-1972>Template:Cite journal</ref> whereas in mice the estimated turnover time is 8–10 days.<ref>Template:Cite journal</ref>

Factors promoting keratinocyte differentiation are:

• A calcium gradient, with the lowest concentration in the stratum basale and increasing concentrations until the outer stratum granulosum, where it reaches its maximum. Calcium concentration in the stratum corneum is very high in part because those relatively dry cells are not able to dissolve the ions.<ref name="Proksch">Template:Cite journal</ref> Those elevations of extracellular calcium concentrations induces an increase in intracellular free calcium concentrations in keratinocytes.<ref>Template:Cite journal</ref> Part of that intracellular calcium 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>
• Vitamin D₃ (cholecalciferol) regulates keratinocyte proliferation and differentiation mostly by modulating calcium concentrations and regulating the expression of genes involved in keratinocyte differentiation.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Keratinocytes are the only cells in the body with the entire vitamin D metabolic pathway from vitamin D production to catabolism and vitamin D receptor expression.<ref>Template:Cite journal</ref>
• Cathepsin E.<ref>Template:Cite journal</ref>
• TALE homeodomain transcription factors.<ref>Template:Cite journal</ref>
• Hydrocortisone.<ref name="cortisone">Template:Cite journal</ref>

Since keratinocyte differentiation inhibits keratinocyte proliferation, factors that promote keratinocyte proliferation should be considered as preventing differentiation. These factors include:

• The transcription factor p63, which prevents epidermal stem cells from differentiating into keratinocytes.<ref>Template:Cite journal</ref> Mutations in the p63 DNA-binding domain are associated with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity.<ref name="PMID30566872">Template:Cite journal</ref>
• Vitamin A and its analogues.<ref>Template:Cite journal</ref>
• Epidermal growth factor.<ref>Template:Cite journal</ref>
• Transforming growth factor alpha.<ref>Template:Cite journal</ref>
• Cholera toxin.<ref name="cortisone" />

Interaction with other cells

Within the epidermis keratinocytes are associated with other cell types such as melanocytes and Langerhans cells. Keratinocytes form tight junctions with the nerves of the skin and hold the Langerhans cells and intra-dermal lymphocytes in position within the epidermis. Keratinocytes also modulate the immune system: apart from the above-mentioned antimicrobial peptides and chemokines they are also potent producers of anti-inflammatory mediators such as IL-10 and TGF-β. When activated, they can stimulate cutaneous inflammation and Langerhans cell activation via TNFα and IL-1β secretion.Template:Citation needed

Keratinocytes contribute to protecting the body from ultraviolet radiation (UVR) by taking up melanosomes, vesicles containing the endogenous photoprotectant melanin, from epidermal melanocytes. Each melanocyte in the epidermis has several dendrites that stretch out to connect it with many keratinocytes. The melanin is then stored within keratinocytes and melanocytes in the perinuclear area as supranuclear "caps", where it protects the DNA from UVR-induced damage.<ref> Template:Cite journal</ref>

Role in wound healing

Wounds to the skin will be repaired in part by the migration of keratinocytes to fill in the gap created by the wound. The first set of keratinocytes to participate in that repair come from the bulge region of the hair follicle and will only survive transiently. Within the healed epidermis they will be replaced by keratinocytes originating from the epidermis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

At the opposite, epidermal keratinocytes, can contribute to de novo hair follicle formation during the healing of large wounds.<ref>Template:Cite journal</ref>

Functional keratinocytes are needed for tympanic perforation healing.<ref>Y Shen, Y Guo, C Du, M Wilczynska, S Hellström, T Ny, Mice Deficient in Urokinase-Type Plasminogen Activator Have Delayed Healing of Tympanic Membrane Perforations, PLOS ONE, 2012</ref>

Sunburn cells

A sunburn cell is a keratinocyte with a pyknotic nucleus and eosinophilic cytoplasm that appears after exposure to UVC or UVB radiation or UVA in the presence of psoralens. It shows premature and abnormal keratinization, and has been described as an example of apoptosis.<ref> Template:Cite journal</ref><ref> Template:Cite journal</ref>

Aging

With age, tissue homeostasis declines partly because stem/progenitor cells fail to self-renew or differentiate. DNA damage caused by exposure of stem/progenitor cells to reactive oxygen species (ROS) may play a key role in epidermal stem cell aging. Mitochondrial superoxide dismutase (SOD2) ordinarily protects against ROS. Loss of SOD2 in mouse epidermal cells was observed to cause cellular senescence that irreversibly arrested proliferation in a fraction of keratinocytes.<ref name="pmid26240345">Template:Cite journal</ref> In older mice, SOD2 deficiency delayed wound closure and reduced epidermal thickness.<ref name="pmid26240345" />

Civatte body

File:Civatte body.jpg

Civatte body

A Civatte body (named after the French dermatologist Achille Civatte, 1877–1956)<ref>Template:Cite book</ref> is a damaged basal keratinocyte that has undergone apoptosis, and consist largely of keratin intermediate filaments, and are almost invariably covered with immunoglobulins, mainly IgM.<ref name="SeemaPranay2013">Template:Cite journal</ref> Civatte bodies are characteristically found in skin lesions of various dermatoses, particularly lichen planus and discoid lupus erythematosus.<ref name="SeemaPranay2013"/> They may also be found in graft-versus-host disease, adverse drug reactions, inflammatory keratosis (such as lichenoid actinic keratosis and lichen planus-like keratosis), erythema multiforme, bullous pemphigoid, eczema, lichen planopilaris, febrile neutrophilic dermatosis, toxic epidermal necrolysis, herpes simplex and varicella zoster lesions, dermatitis herpetiformis, porphyria cutanea tarda, sarcoidosis, subcorneal pustular dermatosis, transient acantholytic dermatosis and epidermolytic hyperkeratosis.<ref name="SeemaPranay2013"/>

See also

• Epidermis
• Skin
• Corneocyte
• Keratin
• HaCaT
• List of human cell types derived from the germ layers
• Epidermidibacterium keratini
• List of distinct cell types in the adult human body

External links

• Template:Cite journal