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Primary type of cell found in the epidermis
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.[1] Basal cells in the
basal layer (stratum basale) of the skin are sometimes referred to as basal keratinocytes.[2]
Keratinocytes form a barrier against environmental damage by
heat,
UV radiation,
water loss,
pathogenicbacteria,
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,[3][4][5][6] which happens every 40 to 56 days in humans.[7]
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.
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.[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 random 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
corneocytes in the
stratum corneum.
Corneocytes are keratinocytes that have completed their differentiation program and have lost their
nucleus and
cytoplasmicorganelles.[6] Corneocytes will eventually be shed off through
desquamation as new ones come in.
In humans, it is estimated that keratinocytes
turn over from stem cells to desquamation every 40–56 days,[7] whereas in
mice the estimated
turnover time is 8–10 days.[9]
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.[10] Those elevations of
extracellular calcium concentrations induces an increase in
intracellular free calcium concentrations in keratinocytes.[11] Part of that intracellular calcium increase comes from calcium released from intracellular stores[12] and another part comes from transmembrane calcium influx,[13] through both calcium-sensitive
chloride channels[14] and voltage-independent cation channels permeable to calcium.[15] Moreover, it has been suggested that an extracellular calcium-sensing
receptor (CaSR) also contributes to the rise in intracellular calcium concentration.[16]
Vitamin D3 (cholecalciferol) regulates keratinocyte
proliferation and differentiation mostly by modulating calcium concentrations and regulating the expression of
genes involved in keratinocyte differentiation.[17][18] 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.[19]
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.[23] 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. [24]
Keratinocytes contribute to protecting the body from
ultraviolet radiation (UVR) by taking up
melanosomes, vesicles containing the endogenous
photoprotectantmelanin, 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.[28]
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.[29][30]
At the opposite, epidermal keratinocytes, can contribute to de novo hair follicle formation during the healing of large wounds.[31]
Functional keratinocytes are needed for tympanic perforation healing.[32]
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.[35] In older mice, SOD2 deficiency delayed
wound closure and reduced epidermal thickness.[35]
^
abGilbert, Scott F. (2000).
"The Epidermis and the Origin of Cutaneous Structures.". Developmental Biology. Sinauer Associates.
ISBN978-0878932436. 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.
^Murphy, Kenneth (Kenneth M.) (2017). Janeway's immunobiology. Weaver, Casey (Ninth ed.). New York, NY, USA. p. 112.
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^Potten CS, Saffhill R, Maibach HI (September 1987). "Measurement of the transit time for cells through the epidermis and stratum corneum of the mouse and guinea-pig". Cell and Tissue Kinetics. 20 (5): 461–72.
doi:
10.1111/j.1365-2184.1987.tb01355.x.
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^Hennings H, Kruszewski FH, Yuspa SH, Tucker RW (April 1989). "Intracellular calcium alterations in response to increased external calcium in normal and neoplastic keratinocytes". Carcinogenesis. 10 (4): 777–80.
doi:
10.1093/carcin/10.4.777.
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^Pillai S, Bikle DD (January 1991). "Role of intracellular-free calcium in the cornified envelope formation of keratinocytes: differences in the mode of action of extracellular calcium and 1,25 dihydroxyvitamin D3". Journal of Cellular Physiology. 146 (1): 94–100.
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^Reiss, M; Lipsey, LR; Zhou, ZL (1991). "Extracellular calcium-dependent regulation of transmembrane calcium fluxes in murine keratinocytes". Journal of Cellular Physiology. 147 (2): 281–91.
doi:
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^Mauro, TM; Pappone, PA; Isseroff, RR (1990). "Extracellular calcium affects the membrane currents of cultured human keratinocytes". Journal of Cellular Physiology. 143 (1): 13–20.
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^Mauro, TM; Isseroff, RR; Lasarow, R; Pappone, PA (1993). "Ion channels are linked to differentiation in keratinocytes". The Journal of Membrane Biology. 132 (3): 201–9.
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^
abRheinwald, 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.
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^Barrandon, Y; Green, H (1987). "Cell migration is essential for sustained growth of keratinocyte colonies: The roles of transforming growth factor-alpha and epidermal growth factor". Cell. 50 (7): 1131–7.
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^Ito, M; Liu, Y; Yang, Z; Nguyen, J; Liang, F; Morris, RJ; Cotsarelis, G (2005). "Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis". Nature Medicine. 11 (12): 1351–4.
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^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
^Crissey, John Thorne; Parish, Lawrence C.; Holubar, Karl (2002). Historical Atlas of Dermatology and Dermatologists. Boca Raton, FL: CRC Press. p. 147.
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