Editing Epidermis (section)

== Structure ==

===Cellular components===
The epidermis primarily consists of [[keratinocytes]]<ref name="Rooks" /> ([[cell proliferation|proliferating]] basal and [[cell differentiation|differentiated]] suprabasal), which comprise 90% of its cells, but also contains [[melanocyte]]s, [[Langerhans cell]]s, [[Merkel cell]]s,<ref name="Andrews"/>{{rp|2–3}} and inflammatory cells. Epidermal thickenings called [[Rete pegs|Rete ridges]] (or rete pegs) extend downward between [[dermal papillae]].<ref>[http://medical-dictionary.thefreedictionary.com/rete+ridge TheFreeDictionary &gt; 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 [[circulatory system|blood supply]] and is nourished almost exclusively by diffused oxygen from the surrounding air.<ref name=stucker>{{cite journal | vauthors = Stücker M, Struk A, Altmeyer P, Herde M, Baumgärtl H, Lübbers DW | title = The cutaneous uptake of atmospheric oxygen contributes significantly to the oxygen supply of human dermis and epidermis | journal = The Journal of Physiology | volume = 538 | issue = Pt 3 | pages = 985–994 | date = February 2002 | pmid = 11826181 | pmc = 2290093 | doi = 10.1113/jphysiol.2001.013067 }}</ref> Cellular mechanisms for regulating [[water]] and [[sodium]] levels ([[Epithelial sodium channel|ENaC]]s) are found in all layers of the epidermis.<ref name="2017-Hanukoglu">{{cite journal | vauthors = Hanukoglu I, Boggula VR, Vaknine H, Sharma S, Kleyman T, Hanukoglu A | title = Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages | journal = Histochemistry and Cell Biology | volume = 147 | issue = 6 | pages = 733–748 | date = June 2017 | pmid = 28130590 | doi = 10.1007/s00418-016-1535-3 | s2cid = 8504408 | url = https://zenodo.org/record/890756 }}</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 [[microfilament|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|thumb|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>{{cite book|url=https://openstax.org/details/books/anatomy-and-physiology-2e |title=Anatomy and Physiology | edition = 2nd |publisher=OpenStax |page=164 | vauthors = Betts JG |display-authors=etal |year=2022 |isbn=978-1-711494-06-7}}</ref> Those layers from outermost to innermost are:<ref name="Lookingbill" />
; [[Keratin#Cornification|cornified layer]] (''[[stratum corneum]]''): [[File:Confocal image of the stratum corneum.jpg|thumb|Confocal image of the stratum corneum]]Composed of 10 to 30 layers of polyhedral, anucleated [[corneocyte]]s (final step of keratinocyte [[cell differentiation|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 [[desmosome|corneodesmosomes]] and surrounded in the [[extracellular]] space by stacked layers of [[lipids]].<ref name="bensouillah">{{cite web|title=Skin structure and function|url=http://www.radcliffe-oxford.com/books/samplechapter/7750/01_bensouillah-241a6c80rdz.pdf|url-status=dead|archive-url=https://web.archive.org/web/20101214062704/http://www.radcliffe-oxford.com/books/samplechapter/7750/01_bensouillah-241a6c80rdz.pdf|archive-date=2010-12-14|access-date=2015-01-07}}</ref> Most of the barrier functions of the epidermis localize to this layer.<ref name="elias">{{cite journal | vauthors = Elias PM | title = The skin barrier as an innate immune element | journal = Seminars in Immunopathology | volume = 29 | issue = 1 | pages = 3–14 | date = April 2007 | pmid = 17621950 | doi = 10.1007/s00281-007-0060-9 | s2cid = 20311780 }}</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|thumb|Confocal image of the stratum granulosum]]Keratinocytes lose their [[cell nucleus|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|thumb|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 apparatus|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 germinativum|stratum basale/germinativum]]''): [[File:Confocal image of the stratum basale showing some papillae.jpg|thumb|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]]. [[Melanocyte]]s 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 [[fingertip]]s and [[lip]]s. 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 (biology)|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. [[cell differentiation|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 [[cell division|growth]] over a period of about 48 days.<ref name="Iizuka">{{cite journal | vauthors = Iizuka H | title = Epidermal turnover time | journal = Journal of Dermatological Science | volume = 8 | issue = 3 | pages = 215–217 | date = December 1994 | pmid = 7865480 | doi = 10.1016/0923-1811(94)90057-4 }}</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>{{Cite journal |last=Bikle |first=Daniel D. |last2=Xie |first2=Zhongjian |last3=Tu |first3=Chia-Ling |date=July 2012 |title=Calcium regulation of keratinocyte differentiation |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC3491811/ |journal=Expert Review of Endocrinology & Metabolism |volume=7 |issue=4 |pages=461–472 |doi=10.1586/eem.12.34 |issn=1744-6651 |pmc=3491811 |pmid=23144648}}</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>{{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 = 777–780 | date = April 1989 | pmid = 2702726 | doi = 10.1093/carcin/10.4.777 }}</ref> Part of that intracellular increase comes from calcium released from intracellular stores<ref>{{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 }}</ref> and another part comes from transmembrane calcium influx,<ref>{{cite journal | vauthors = Reiss M, Lipsey LR, Zhou ZL | title = Extracellular calcium-dependent regulation of transmembrane calcium fluxes in murine keratinocytes | journal = Journal of Cellular Physiology | volume = 147 | issue = 2 | pages = 281–291 | date = May 1991 | pmid = 1645742 | doi = 10.1002/jcp.1041470213 | s2cid = 25858560 }}</ref> through both calcium-sensitive [[chloride channels]]<ref>{{cite journal | vauthors = Mauro TM, Pappone PA, Isseroff RR | title = Extracellular calcium affects the membrane currents of cultured human keratinocytes | journal = Journal of Cellular Physiology | volume = 143 | issue = 1 | pages = 13–20 | date = April 1990 | pmid = 1690740 | doi = 10.1002/jcp.1041430103 | s2cid = 8072916 }}</ref> and voltage-independent cation channels permeable to calcium.<ref>{{cite journal | vauthors = Mauro TM, Isseroff RR, Lasarow R, Pappone PA | title = Ion channels are linked to differentiation in keratinocytes | journal = The Journal of Membrane Biology | volume = 132 | issue = 3 | pages = 201–209 | date = March 1993 | pmid = 7684087 | doi = 10.1007/BF00235738 | s2cid = 13063458 }}</ref> Moreover, it has been suggested that an extracellular calcium-sensing [[cell surface receptor|receptor]] (CaSR) also contributes to the rise in intracellular calcium concentration.<ref>{{cite journal | vauthors = Tu CL, Oda Y, Bikle DD | title = Effects of a calcium receptor activator on the cellular response to calcium in human keratinocytes | journal = The Journal of Investigative Dermatology | volume = 113 | issue = 3 | pages = 340–345 | date = September 1999 | pmid = 10469331 | doi = 10.1046/j.1523-1747.1999.00698.x | doi-access = free }}</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 (biology)|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">{{cite book | title = Developmental Biology | chapter = The Epidermis and the Origin of Cutaneous Structures | vauthors = Gilbert SF | chapter-url = https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A2929 | publisher = Sinauer Associates | year = 2000 | isbn = 978-0-87893-243-6 | url-access = registration | url = https://archive.org/details/developmentalbio00gilb }}</ref>

This inner layer is a [[germ layer|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 [[granularity|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 [[granule (cell biology)|granule]]s 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>{{cite journal | vauthors = Weschler CJ, Langer S, Fischer A, Bekö G, Toftum J, Clausen G | title = Squalene and cholesterol in dust from danish homes and daycare centers | journal = Environmental Science & Technology | volume = 45 | issue = 9 | pages = 3872–3879 | date = May 2011 | pmid = 21476540 | doi = 10.1021/es103894r | bibcode = 2011EnST...45.3872W | s2cid = 1468347 | url = https://backend.orbit.dtu.dk/ws/files/5602736/plugin-es103894r.pdf }}</ref>

Epidermal [[developmental biology|development]] is a product of several [[growth factor]]s, 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 [[cell division|division]].
* [[Keratinocyte growth factor]] (KGF or [[FGF7]]) is a [[paracrine]] growth factor produced by the underlying [[dermis|dermal]] [[fibroblast]]s in which the [[cell proliferation|proliferation]] of basal cells is regulated.