Keratinocyte

Keratinocytes (stained green) in the skin of a mouse

A keratinocyte is the predominant cell type in the epidermis, the outermost layer of the skin, constituting 90% of the cells found there.^[1] Those keratinocytes found in the basal layer (stratum basale) of the skin are sometimes referred to as "basal cells" or "basal keratinocytes".^[2]

Function

The primary function of keratinocytes is the formation of a barrier against environmental damage by pathogenic bacteria, fungi, parasites, and viruses, heat, UV radiation and water loss. Once pathogens start to invade the upper layers of the epidermis, keratinocytes can react by producing proinflammatory mediators, particularly chemokines such as CXCL10 and CCL2 which attract leukocytes to the site of pathogen invasion.

Structure

A number of structural proteins (filaggrin, keratin), enzymes (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.^[3]

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 stochastic manner yielding either more stem cells or transit amplifying cells.^[4] 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.^[5]

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 become corneocytes in the stratum corneum.

Corneocytes are keratinocytes that have completed their differentiation program and have lost their nucleus and cytoplasmic organelles.^[6] 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 turnover from stem cells to desquamation every 40–56 days.^[7] whereas in mice the estimated turnover time is 8–10 days.^[8]

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.^[9] Those elevations of extracellular calcium concentrations induces an increase in intracellular free calcium concentrations in keratinocytes.^[10] Part of that intracellular calcium increase comes from calcium released from intracellular stores^[11] and another part comes from transmembrane calcium influx,^[12] through both calcium-sensitive chloride channels^[13] and voltage-independent cation channels permeable to calcium.^[14] Moreover, it has been suggested that an extracellular calcium-sensing receptor (CaSR) also contributes to the rise in intracellular calcium concentration.^[15]
• Vitamin D3 (cholecalciferol) regulates keratinocyte proliferation and differentiation mostly by modulating calcium concentrations and regulating the expression of genes involved in keratinocyte differentiation.^[16][17] 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.^[18]
• Cathepsin E.^[19]
• TALE homeodomain transcription factors.^[20]
• Hydrocortisone.^[21]

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 preventing epidermal stem cells to differentiate into keratinocytes.^[22]
• Vitamin A and its analogues.^[23]
• Epidermal growth factor.^[24]
• transforming growth factor alpha.^[25]
• Cholera toxin^[21]

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.

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.^[26]

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.^[27][28]

At the opposite, epidermal keratinocytes, can contribute to de novo hair follicle formation during the healing of large wounds.^[29]

Keratinocytes migrate with a rolling motion during the process of wound healing.^[30][31]

Functional keratinocytes are needed for tympanic perforation healing.^[32]

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.^[33][34]

See also

• Epidermis
• Skin
• Corneocyte
• Keratin
• HaCaT

References

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3. Gilbert, Scott F. (2000). "The Epidermis and the Origin of Cutaneous Structures.". Developmental Biology. Sinauer Associates. ISBN 978-0878932436. Throughout life, the dead keratinized cells of the cornified layer are shed (humans lose about 1.5 grams of these cells each day*) and are replaced by new cells, the source of which is the mitotic cells of the Malpighian layer. Pigment cells (melanocytes) from the neural crest also reside in the Malpighian layer, where they transfer their pigment sacs (melanosomes) to the developing keratinocytes.
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18. Fu, G. K.; Lin, D; Zhang, MY; Bikle, DD; Shackleton, CH; Miller, WL; Portale, AA (1997). "Cloning of Human 25-Hydroxyvitamin D-1 -Hydroxylase and Mutations Causing Vitamin D-Dependent Rickets Type 1". Molecular Endocrinology 11 (13): 1961–70. doi:10.1210/me.11.13.1961. PMID 9415400.
19. Kawakubo, Tomoyo; Yasukochi, Atsushi; Okamoto, Kuniaki; Okamoto, Yoshiko; Nakamura, Seiji; Yamamoto, Kenji (2011). "The role of cathepsin E in terminal differentiation of keratinocytes". Biological Chemistry 392 (6): 571–85. doi:10.1515/BC.2011.060. PMID 21521076.
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21. Rheinwald, JG; Green, H (1975). "Serial cultivation of strains of human epidermal keratinocytes: The formation of keratinizing colonies from single cells". Cell 6 (3): 331–43. doi:10.1016/S0092-8674(75)80001-8. PMID 1052771.
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23. Fuchs, E; Green, H (1981). "Regulation of terminal differentiation of cultured human keratinocytes by vitamin A". Cell 25 (3): 617–25. doi:10.1016/0092-8674(81)90169-0. PMID 6169442.
24. Rheinwald, JG; Green, H (1977). "Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes". Nature 265 (5593): 421–4. doi:10.1038/265421a0. PMID 299924.
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26. Brenner M, Hearing VJ. (May–June 2008). "The Protective Role of Melanin Against UV Damage in Human Skin". Photochemistry and Photobiology 84 (3): 539–549. doi:10.1111/j.1751-1097.2007.00226.x. PMC 2671032. PMID 18435612.
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28. Claudinot, S; Nicolas, M; Oshima, H; Rochat, A; Barrandon, Y (2005). "Long-term renewal of hair follicles from clonogenic multipotent stem cells". Proceedings of the National Academy of Sciences of the United States of America 102 (41): 14677–82. doi:10.1073/pnas.0507250102. PMC 1253596. PMID 16203973.
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External links

• Tang L, Wu JJ, Ma Q, et al. (July 2010). "Human lactoferrin stimulates skin keratinocyte function and wound re-epithelialization". The British Journal of Dermatology 163 (1): 38–47. doi:10.1111/j.1365-2133.2010.09748.x. PMID 20222924.