Keratinocyte

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.{{Cite book|title=Janeway's immunobiology|last=Murphy, Kenneth (Kenneth M.)|others=Weaver, Casey|year=2017|isbn=9780815345053|edition= Ninth|location=New York, NY, USA|page=112|oclc=933586700}}

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.{{Cite book|title = Developmental Biology.|last = Gilbert|first = Scott F.|publisher = Sinauer Associates|year = 2000|isbn = 978-0878932436|chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK10037/|chapter = The Epidermis and the Origin of Cutaneous Structures.|quote = 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.|url-access = registration|url = https://archive.org/details/developmentalbio00gilb}}

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.{{cite journal |vauthors=Houben E, De Paepe K, Rogiers V |title=A keratinocyte's course of life |journal=Skin Pharmacology and Physiology |volume=20 |issue=3 |pages=122–32 |year=2007 |pmid=17191035 |doi=10.1159/000098163|s2cid=25671082 }} 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.{{cite journal |vauthors=Ghazizadeh S, Taichman LB |title=Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin |journal=The EMBO Journal |volume=20 |issue=6 |pages=1215–22 |date=March 2001 |pmid=11250888 |pmc=145528 |doi=10.1093/emboj/20.6.1215}}

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.{{cite journal |author=Koster MI |title=Making an epidermis |journal=Annals of the New York Academy of Sciences |volume=1170 |issue= 1|pages=7–10 |date=July 2009 |pmid=19686098 |pmc=2861991 |doi=10.1111/j.1749-6632.2009.04363.x|bibcode=2009NYASA1170....7K }} 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,{{cite journal |author=Halprin KM |title=Epidermal "turnover time"--a re-examination |journal=The British Journal of Dermatology |volume=86 |issue=1 |pages=14–9 |date=January 1972 |pmid=4551262 |doi=10.1111/j.1365-2133.1972.tb01886.x|s2cid=30165907 }} whereas in mice the estimated turnover time is 8–10 days.{{cite journal |vauthors=Potten CS, Saffhill R, Maibach HI |title=Measurement of the transit time for cells through the epidermis and stratum corneum of the mouse and guinea-pig |journal=Cell and Tissue Kinetics |volume=20 |issue=5 |pages=461–72 |date=September 1987 |pmid=3450396 |doi=10.1111/j.1365-2184.1987.tb01355.x|s2cid=22475141 }}

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.{{cite journal |vauthors=Proksch E, Brandner JM, Jensen JM |title=The skin: an indispensable barrier |journal=Experimental Dermatology |volume=17 |issue=12 |pages=1063–72 |date=December 2008 |pmid=19043850 |doi=10.1111/j.1600-0625.2008.00786.x|s2cid=31353914 }} Those elevations of extracellular calcium concentrations induces an increase in intracellular free calcium concentrations in keratinocytes.{{cite journal |vauthors=Hennings H, Kruszewski FH, Yuspa SH, Tucker RW |title=Intracellular calcium alterations in response to increased external calcium in normal and neoplastic keratinocytes |journal=Carcinogenesis |volume=10 |issue=4 |pages=777–80 |date=April 1989 |pmid=2702726 |doi=10.1093/carcin/10.4.777}} Part of that intracellular calcium increase comes from calcium released from intracellular stores{{cite journal |vauthors=Pillai S, Bikle DD |title=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=Journal of Cellular Physiology |volume=146 |issue=1 |pages=94–100 |date=January 1991 |pmid=1990023 |doi=10.1002/jcp.1041460113|s2cid=21264605 }} and another part comes from transmembrane calcium influx,{{cite journal | pmid=1645742 | year=1991 | last1=Reiss | first1=M | last2=Lipsey | first2=LR | last3=Zhou | first3=ZL | title=Extracellular calcium-dependent regulation of transmembrane calcium fluxes in murine keratinocytes | volume=147 | issue=2 | pages=281–91 | doi=10.1002/jcp.1041470213 | journal=Journal of Cellular Physiology| s2cid=25858560 }} through both calcium-sensitive chloride channels{{cite journal | pmid=1690740 | year=1990 | last1=Mauro | first1=TM | last2=Pappone | first2=PA | last3=Isseroff | first3=RR | title=Extracellular calcium affects the membrane currents of cultured human keratinocytes | volume=143 | issue=1 | pages=13–20 | doi=10.1002/jcp.1041430103 | journal=Journal of Cellular Physiology| s2cid=8072916 }} and voltage-independent cation channels permeable to calcium.{{cite journal | pmid=7684087 | year=1993 | last1=Mauro | first1=TM | last2=Isseroff | first2=RR | last3=Lasarow | first3=R | last4=Pappone | first4=PA | title=Ion channels are linked to differentiation in keratinocytes | volume=132 | issue=3 | pages=201–9 | journal=The Journal of Membrane Biology | doi=10.1007/BF00235738| s2cid=13063458 }} Moreover, it has been suggested that an extracellular calcium-sensing receptor (CaSR) also contributes to the rise in intracellular calcium concentration.{{cite journal | pmid=10469331 | year=1999 | last1=Tu | first1=CL | last2=Oda | first2=Y | last3=Bikle | first3=DD | title=Effects of a calcium receptor activator on the cellular response to calcium in human keratinocytes | volume=113 | issue=3 | pages=340–5 | doi=10.1046/j.1523-1747.1999.00698.x | journal=The Journal of Investigative Dermatology| doi-access=free }}
• Vitamin D₃ (cholecalciferol) regulates keratinocyte proliferation and differentiation mostly by modulating calcium concentrations and regulating the expression of genes involved in keratinocyte differentiation.{{cite journal | doi=10.1016/0092-8674(80)90406-7 | title=Calcium regulation of growth and differentiation of mouse epidermal cells in culture | year=1980 | last1=Hennings | first1=Henry | last2=Michael | first2=Delores | last3=Cheng | first3=Christina | last4=Steinert | first4=Peter | last5=Holbrook | first5=Karen | last6=Yuspa | first6=Stuart H. | journal=Cell | volume=19 | pages=245–54 | pmid=6153576 | issue=1| s2cid=23896865 }}{{cite journal | pmid=7910167 | year=1994 | last1=Su | first1=MJ | last2=Bikle | first2=DD | last3=Mancianti | first3=ML | last4=Pillai | first4=S | title=1,25-Dihydroxyvitamin D3 potentiates the keratinocyte response to calcium | volume=269 | issue=20 | pages=14723–9 | journal=The Journal of Biological Chemistry| doi=10.1016/S0021-9258(17)36685-1 | doi-access=free }} 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.{{cite journal | title=Cloning of Human 25-Hydroxyvitamin D-1 -Hydroxylase and Mutations Causing Vitamin D-Dependent Rickets Type 1 | year=1997 | last1=Fu | first1=G. K. | journal=Molecular Endocrinology | volume=11 | issue=13 | pages=1961–70 | pmid=9415400 | last2=Lin | first2=D | last3=Zhang | first3=MY | last4=Bikle | first4=DD | last5=Shackleton | first5=CH | last6=Miller | first6=WL | last7=Portale | first7=AA| doi=10.1210/mend.11.13.0035 | citeseerx=10.1.1.320.3485 }}
• Cathepsin E.{{cite journal | doi=10.1515/BC.2011.060 | title=The role of cathepsin E in terminal differentiation of keratinocytes | year=2011 | last1=Kawakubo | first1=Tomoyo | last2=Yasukochi | first2=Atsushi | last3=Okamoto | first3=Kuniaki | last4=Okamoto | first4=Yoshiko | last5=Nakamura | first5=Seiji | last6=Yamamoto | first6=Kenji | journal=Biological Chemistry | volume=392 | issue=6 | pages=571–85 | pmid=21521076| hdl=2324/25561 | s2cid=21148292 | hdl-access=free }}
• TALE homeodomain transcription factors.{{cite journal

| doi = 10.1242/jcs.077552

| title = TALE homeodomain proteins regulate site-specific terminal differentiation, LCE genes and epidermal barrier

| year = 2011

| last1 = Jackson

| first1 = B.

| last2 = Brown

| first2 = S. J.

| last3 = Avilion

| first3 = A. A.

| last4 = O'Shaughnessy

| first4 = R. F. L.

| last5 = Sully

| first5 = K.

| last6 = Akinduro

| first6 = O.

| last7 = Murphy

| first7 = M.

| last8 = Cleary

| first8 = M. L.

| last9 = Byrne

| first9 = C.

| journal = Journal of Cell Science

| volume = 124

| issue = 10

| pages = 1681–1690

| pmid=21511732

| pmc=3183491

}}

• Hydrocortisone.{{cite journal | pmid=1052771 | year=1975 | last1=Rheinwald | first1=JG | last2=Green | first2=H | title=Serial cultivation of strains of human epidermal keratinocytes: The formation of keratinizing colonies from single cells | volume=6 | issue=3 | pages=331–43 | journal=Cell | doi=10.1016/S0092-8674(75)80001-8| s2cid=53294766 }}

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.{{cite journal | pmid=17114587 | year=2006 | last1=Truong | first1=AB | last2=Kretz | first2=M | last3=Ridky | first3=TW | last4=Kimmel | first4=R | last5=Khavari | first5=PA | title=P63 regulates proliferation and differentiation of developmentally mature keratinocytes | volume=20 | issue=22 | pages=3185–97 | doi=10.1101/gad.1463206 | pmc=1635152 | journal=Genes & Development}} 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.{{cite journal | vauthors = Qu J, Tanis SE, Smits JP, Kouwenhoven EN, Oti M, van den Bogaard EH, Logie C, Stunnenberg HG, van Bokhoven H, Mulder KW, Zhou H | title = Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape | journal = Cell Reports | volume = 25 | issue = 12 | pages = 3490–503 | date = December 2018 | pmid = 30566872 | doi = 10.1016/j.celrep.2018.11.039 | doi-access = free | hdl = 2066/200262 | hdl-access = free }}
• Vitamin A and its analogues.{{cite journal | pmid=6169442 | year=1981 | last1=Fuchs | first1=E | last2=Green | first2=H | title=Regulation of terminal differentiation of cultured human keratinocytes by vitamin A | volume=25 | issue=3 | pages=617–25 | journal=Cell | doi=10.1016/0092-8674(81)90169-0| s2cid=23796587 }}
• Epidermal growth factor.{{cite journal | pmid=299924 | year=1977 | last1=Rheinwald | first1=JG | last2=Green | first2=H | title=Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes | volume=265 | issue=5593 | pages=421–4 | journal=Nature | doi=10.1038/265421a0| bibcode=1977Natur.265..421R | s2cid=27427541 }}
• Transforming growth factor alpha.{{cite journal | pmid=3497724 | year=1987 | last1=Barrandon | first1=Y | last2=Green | first2=H | title=Cell migration is essential for sustained growth of keratinocyte colonies: The roles of transforming growth factor-alpha and epidermal growth factor | volume=50 | issue=7 | pages=1131–7 | journal=Cell | doi=10.1016/0092-8674(87)90179-6| s2cid=21054962 }}
• Cholera toxin.

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.{{Citation needed|date=June 2010}}

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.

{{cite journal

|author1=Brenner M |author2=Hearing VJ. | date = May–June 2008

| title = The Protective Role of Melanin Against UV Damage in Human Skin

| journal = Photochemistry and Photobiology

| volume = 84

| issue = 3

| pages = 539–549

| doi = 10.1111/j.1751-1097.2007.00226.x

| pmid = 18435612

| pmc = 2671032

}}

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.{{cite journal | pmid=16288281 | year=2005 | last1=Ito | first1=M | last2=Liu | first2=Y | last3=Yang | first3=Z | last4=Nguyen | first4=J | last5=Liang | first5=F | last6=Morris | first6=RJ | last7=Cotsarelis | first7=G | title=Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis | volume=11 | issue=12 | pages=1351–4 | doi=10.1038/nm1328 | journal=Nature Medicine| s2cid=52869761 }}{{cite journal | pmid=16203973 | year=2005 | last1=Claudinot | first1=S | last2=Nicolas | first2=M | last3=Oshima | first3=H | last4=Rochat | first4=A | last5=Barrandon | first5=Y | title=Long-term renewal of hair follicles from clonogenic multipotent stem cells | volume=102 | issue=41 | pages=14677–82 | doi=10.1073/pnas.0507250102 | pmc=1253596 | journal=Proceedings of the National Academy of Sciences of the United States of America| bibcode=2005PNAS..10214677C | doi-access=free }}

At the opposite, epidermal keratinocytes, can contribute to de novo hair follicle formation during the healing of large wounds.{{cite journal | pmid=17507982 | year=2007 | last1=Ito | first1=M | last2=Yang | first2=Z | last3=Andl | first3=T | last4=Cui | first4=C | last5=Kim | first5=N | last6=Millar | first6=SE | last7=Cotsarelis | first7=G | title=Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding | volume=447 | issue=7142 | pages=316–20 | doi=10.1038/nature05766 | journal=Nature| bibcode=2007Natur.447..316I | s2cid=887738 }}

Functional keratinocytes are needed for tympanic perforation healing.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

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.

{{cite journal

| author = Young AR

| date = June 1987

| title = The sunburn cell

| journal = Photodermatology

| volume = 4

| issue = 3

| pages = 127–134

| pmid = 3317295

}}

{{cite journal

|vauthors=Sheehan JM, Young AR | date = June 2002

| title = The sunburn cell revisited: an update on mechanistic aspects

| journal = Photochemical and Photobiological Sciences

| volume = 1

| issue = 6

| pages = 365–377

| doi = 10.1039/b108291d

| pmid = 12856704

| bibcode = 2002PhPhS...1..365S

| s2cid = 21184034

}}

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.{{cite journal |vauthors=Velarde MC, Demaria M, Melov S, Campisi J |title=Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=112 |issue=33 |pages=10407–12 |date=August 2015 |pmid=26240345 |pmc=4547253 |doi=10.1073/pnas.1505675112 |bibcode=2015PNAS..11210407V |doi-access=free }} In older mice, SOD2 deficiency delayed wound closure and reduced epidermal thickness.

File:Civatte body.jpg

A Civatte body (named after the French dermatologist Achille Civatte, 1877–1956){{cite book |last1=Crissey |first1=John Thorne |last2=Parish |first2=Lawrence C. |last3=Holubar |first3=Karl |title=Historical Atlas of Dermatology and Dermatologists |date=2002 |publisher=CRC Press |location=Boca Raton, FL |isbn=1-84214-100-7 |page=147}} 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.{{cite journal|last1=Seema|first1=Chhabra|last2=Pranay|first2=Tanwar|last3=Kumar|first3=AroraSandeep|title=Civatte bodies: A diagnostic clue|journal=Indian Journal of Dermatology|volume=58|issue=4|year=2013|page=327|issn=0019-5154|doi=10.4103/0019-5154.113974|pmid=23919028|pmc=3726905 |doi-access=free }} Civatte bodies are characteristically found in skin lesions of various dermatoses, particularly lichen planus and discoid lupus erythematosus. 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.

• 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

{{Reflist|30em}}

{{Commons category|Keratinocytes}}

• {{cite journal |vauthors=Tang L, Wu JJ, Ma Q, etal |title=Human lactoferrin stimulates skin keratinocyte function and wound re-epithelialization |journal=The British Journal of Dermatology |volume=163 |issue=1 |pages=38–47 |date=July 2010 |pmid=20222924 |doi=10.1111/j.1365-2133.2010.09748.x|s2cid=2387064 }}

{{Skin Layers and Appendages}}

Category:Skin anatomy

Category:Sequestering cells

Category:Human cells