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Skin Basics; Structure and Function
Abstract
Skin is the body’s protective barrier against a whole battery of environmental aggressors—both of natural and anthropogenic origins. It primarily protects against desiccation, and thus makes life on land possible. Every class of terrestrial organism has evolved an appropriate barrier against fluid loss from the body and almost all employ modifications of the cutaneous surface for this purpose. The formation of the barrier layer and its maintenance and renewal is the function of epidermal keratinocytes, although other cell types interacting with keratinocytes also play a significant role in regulation of this function. Besides, skin supports a large commensal microflora that is important in keeping in check the colonization of skin by pathogenic microbes.
... Ayrıca vücut sıcaklığını düzenleme, vücuttan çıkan aşırı sıvı kaybını önleme ve duyusal algıya katkı sağlama gibi önemli fonksiyonları vardır (1,2). Bu fonksiyonları yerine getirmek için morfolojik olarak farklı olan çok sayıda katmandan oluşan deri, dıştan içe doğru; epidermis, dermis ve hipodermis (subkutis) olmak üzere üç temel katmana sahiptir (Şekil 1) (3,4). ...
... Epidermisin en dış tabakası olan SC tabakası, yarı geçirgen bir yapıya sahiptir ve mikroorganizmaların invazyonuna ve kimyasal penetrasyona karşı fizyolojik bir bariyer oluşturur (10,4). SC nukleuslarını tamamen kaybetmiş ve yassılaşmış ölü fakat biyokimyasal olarak aktif keratinositlerden (korneositlerden) ve lamellar gövdelerden salgılanan, hücreler arası lipidler olarak tanımlanan lipid matrisinden (kolesterol, seramidler ve serbest yağ asitleri) oluşan cansız bir tabakadır (11). ...
... Subkutan yağ dokusu ya da subkutis olarak da adlandırılan bu tabaka dermisin altından uzanarak deriyi alttaki kas tabakasına bağlayan kısımdır. İntrauterin 1. trimesterde oluşmaya başlar, fonksiyonlarının maximum düzeye ulaşması 2-3 yaşında meydana gelir (4,17). Büyük kan damarları, sinirler, ter bezleri, yağ dokusu, yağ hücreleri, elastik ve kolajen liflerinden oluşur. ...
İnsan vücudunun yüzey alanı en geniş ve ağırlığı en fazla organı olan deri, dış çevreden gelebilecek fiziksel, kimyasal, biyolojik etkenlere karşı insan vücudu için koruyucu bir bariyer görevi görür. Ayrıca vücut sıcaklığının düzenlemesi, vücuttan çıkan aşırı kaybının önlemesi ve duyusal algıya katkı sağlama gibi önemli fonksiyonları vardır. Bu fonksiyonları yerine getirmek için deri epidermis, dermis ve derialtı dokusu olmak üzere üç temel katmandan oluşur. Cildin gelişimi ve olgunlaşma süreci yaş dönemlerine göre farklılık göstermektedir. Yenidoğan cilt yapısı; morfolojik ve fonksiyonel yönden yetişkin cilt yapısından farklıdır. Bunun nedeni yenidoğanların yaşamının ilk günlerinde, intrauterin ortamdaki sıcak ve sıvı ile dolu bir ortamdan, soğuk ve kuru olan dış ortama geçmesi, yenidoğan döneminden itibaren ciltte değişimlerin olması, yapı ve fonksiyonlarında gelişmelerin sürekli devam etmesidir. Bebek bezi dermatitinde temel unsur önlemektir. Geliştikten sonra genel amaç ise, enfeksiyonu azaltmak, ciltteki hasarı onarmak ve tekrar hasar oluşumunu önlemektir. Pişik cilt maserasyonu ve tahriş edici maddelerle uzun süreli temasta dahil olmak üzere birçok faktörün etkileşimi sonucu, cilt bariyerinin bozulmasına yol açan en yaygın cilt sorunlarından birisidir. Karmaşık ve multifaktöriyel bir etiyolojiye sahiptir. Pişiği önlemek ve yönetmek etiyolojisinin iyi bilinmesi ve nedensel faktörlerin ortadan kaldırılması ile mümkündür. Hem önleme hem de tedavi için farmakolojik olmayan pişik önleyici yaklaşımlar hava, bariyer, temizlik, bebek bezi ve eğitimi olmak üzere 5 maddede toplanmış ve “ABCDE” harfleri verilmiştir. Yenidoğanın deri bütünlüğünü korumak için önlemler, ebeveynler ve diğer bakım verenler tarafından güvenli bir şekilde sağlanmalıdır.
... A review of skin lipogenesis and metabolism necessitates a brief discussion of skin structure first. The skin is made up of 3 major layers: 1) The epidermis; 2) The dermis; 3) The hypodermis [22]. The epidermis is the outer layer that is visible to the eye and is mostly made up of keratinocytes. ...
... This first layer of skin can be divided into 4 further layers: 1) The stratum basale; 2) The stratum spinosum; 3) The stratum granulosum; 4) The stratum corneum. The stratum basale is the first layer of the epidermis, which is in contact with the dermis and is the source of proliferating keratinocytes that mature towards the skin surface [22]. The stratum spinosum functions to anchor the stratum basale and stratum spinosum to each other by producing cytoskeletal proteins; and also initiates the maturation process of keratinocytes [22]. ...
... The stratum basale is the first layer of the epidermis, which is in contact with the dermis and is the source of proliferating keratinocytes that mature towards the skin surface [22]. The stratum spinosum functions to anchor the stratum basale and stratum spinosum to each other by producing cytoskeletal proteins; and also initiates the maturation process of keratinocytes [22]. The stratum granulosum produces proteins of the corneocyte (or fully matured keratinocyte), lipids, and crosslinking enzymes that move upward to the surface [22]. ...
The obesity epidemic is a costly public health crisis that is not improving. In addition to the stigma and discomfort associated with carrying extra weight (at the expense of range of movement), obesity also goes hand-in-hand with co-morbidities like fatty liver disease, diabetes, cardiovascular disease, and increased risk of some forms of cancer. Currently there are no long-lasting treatments for obesity other than diet and exercise, which are not feasible for many populations that may not be equipped with the resources and/or support needed to lead a healthy lifestyle. Although there have been some pharmacological breakthroughs for treating obesity, each FDA-approved drug comes with unpleasant side-effects that make adherence unlikely. As a result, alternate approaches are necessary. In this review, we outline the relationship between skin lipid metabolism and whole-body glucose and lipid metabolism. Specifically, by summarizing studies that employed mice that were genetically modified to interrupt lipid metabolism in the skin. As a result, we propose that skin might be an overlooked, but viable target for combating obesity.
... The skin is the largest human organ which, covering the body as a fabric, is composed by several layers less than 2 mm thick (epidermis, dermis and hypodermis), exerts essential communicative, sensitive, and protective functions to ensure the skin homeostasis ( Figure 1) [1][2][3]. The outermost layer of this tissue, the stratum corneum (SC), represents the primary barrier for delivering active ingredients either locally or into the systemic circulation [2][3][4]. ...
... The skin is the largest human organ which, covering the body as a fabric, is composed by several layers less than 2 mm thick (epidermis, dermis and hypodermis), exerts essential communicative, sensitive, and protective functions to ensure the skin homeostasis ( Figure 1) [1][2][3]. The outermost layer of this tissue, the stratum corneum (SC), represents the primary barrier for delivering active ingredients either locally or into the systemic circulation [2][3][4]. ...
... The skin is the largest human organ which, covering the body as a fabric, is composed by several layers less than 2 mm thick (epidermis, dermis and hypodermis), exerts essential communicative, sensitive, and protective functions to ensure the skin homeostasis ( Figure 1) [1][2][3]. The outermost layer of this tissue, the stratum corneum (SC), represents the primary barrier for delivering active ingredients either locally or into the systemic circulation [2][3][4]. ...
... The skin is the largest human organ which, covering the body as a fabric, is composed by several layers less than 2 mm thick (epidermis, dermis and hypodermis), exerts essential communicative, sensitive, and protective functions to ensure the skin homeostasis ( Figure 1) [1][2][3]. The outermost layer of this tissue, the stratum corneum (SC), represents the primary barrier for delivering active ingredients either locally or into the systemic circulation [2][3][4]. ...
The skin is the largest and complex organ of human body, functioning as a physiological barrier to protect the internal milieu from external harmful agents, such as pathogens, environmental pollution, and UV light. This barrier, impermeable to all the ingredients applied on, is made by lipidic lamellae and an oxidative network that give cohesion and protection to the cells of the skin' Stratum Corneum. As consequence, the main problem of any delivery system is to penetrate through this barrier for enabling the percutaneous penetration of medical and cosmetic active ingredients, used to protect and repair the skin from the environmental aggressions. Emulsions are the most common delivery systems used to day as carrier loading and releasing active ingredients useful to protect and repair the skin. To maintain stability and effectiveness before and during their use, the emulsions have to contain not only selected and effective ingredients, but also emulsifiers, preservatives and other chemical compounds, which may cause allergic and sensitization reactions. The paper proposes, as skin protective agents the use of innovative specialized and biodegradable smart tissues to be used as alternative delivery systems to the emulsions. These innovative smart tissues are made by natural fibers that may bind into theirs structure the specialized active ingredients, designed for giving the requested functionality to the final product. The realized tissues, based on the use of waste materials of natural origin such as chitin nanofibrils and lignin, and having the same structure of the natural Extracellular Matrix, act as a fabric able to protect and repair the skin from the environmental insults. Moreover, they are biodegradable, skin-friendly and environmental-friendly, being free of any chemicals petrol-derived.
... The skin is the largest and most superficial organ of the body; it is capable of continual renewal and responsible for physiological functions such as thermoregulation, protection against pathogens and ultraviolet (UV) radiation, tactile sensations, secretions and excretions. Moreover, it is a visible organ that allows assessment of the health and well-being of an individual and reflects many aesthetic parameters [1][2][3]. Similar to other biological components of human body, the skin is subjected to a complex and cumulative ageing process throughout life, which occurs due to structural and physiological changes caused by factors that are intrinsic and extrinsic to the body [4][5][6][7][8][9]. ...
... The Golgi complex stores and transports these proteins to the extracellular matrix where there is the formation of elastic fibres. During this phase, the elastinbinding proteins (EBP) associate with tropoelastin monomers to become a complex form before being released on the cell surface (2). During the formation of elastic fibres, microfibrils components function as a scaffold where elastin will deposit and several other molecules are involved in the process, such as LOX, fibrillin, MAGPs, decorin, fibulins, among others. ...
Skin aging is a complex process that may be caused by factors that are intrinsic and extrinsic to the body. Ultraviolet (UV) radiation represents one of the main sources of skin damage over the years and characterizes a process known as photoaging. Among the changes that affect cutaneous tissue with age, the loss of elastic properties caused by changes in elastin production, increased degradation and/or processing produces a substantial impact on tissue esthetics and health. The occurrence of solar elastosis is one of the main markers of cutaneous photoaging and is characterized by disorganized and non-functional deposition of elastic fibers. The occurrence of UV radiation-induced alternative splicing of the elastin gene, which leads to inadequate synthesis of the proteins required for the correct assembly of elastic fibers, is a potential explanation for this phenomenon. Innovative studies have been fundamental for the elucidation of rarely explored photoaging mechanisms and have enabled the identification of effective therapeutic alternatives such as cosmetic products. This review addresses cutaneous photoaging and the changes that affect elastin in this process. This article is protected by copyright. All rights reserved.
... Skin serves as the body's first barrier against all harmful substances from the environment, protecting the body from chemicals, radiation, microbes, and mechanical forces. It also prevents internal fluid loss and importantly regulates body temperature (1,2). Thus, the condition of the skin is critically important for human well-being. ...
Background/aim:
Skin regeneration is the intrinsic ability to repair damaged skin tissues to regaining skin well-being. Processes of wound healing, a major part of skin regeneration, involve various types of cells, including keratinocytes and dermal fibroblasts, through their autocrine/paracrine signals. The releasable factors from keratinocytes were reported to influence dermal fibroblasts behavior during wound-healing processes. Here, we developed a strategy to modulate cytokine components and improve the secretome quality of HaCaT cells, a nontumorigenic immortalized keratinocyte cell line, via the treatment of cordycepin, and designated as cordycepin-induced HaCaT secretome (CHS).
Materials and methods:
The bioactivities of CHS were investigated in vitro on human dermal fibroblasts (HDF). The effects of CHS on HDF proliferation, reactive oxygen species-scavenging, cell migration, extracellular matrix production and autophagy activation were investigated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide cell viability assay, dichloro-dihydro-fluorescein diacetate, the wound-healing assay, reverse transcription polymerase chain reaction and immunofluorescent microscopy. Finally, Proteome Profiler™ Array was used to determine the composition of the secretome.
Results:
CHS induced fibroblast proliferation/migration, reactive oxygen species-scavenging property, regulation of extracellular matrix synthesis, and autophagy activation. Such enhanced bioactivities of CHS were related to the increase of some key cytokines, including C-X-C motif chemokine ligand 1, interleukin 1 receptor A, interleukin 8, macrophage migration-inhibitory factor, and serpin family E member 1.
Conclusion:
These findings highlight the implications of cordycepin alteration of the cytokine profile of the HaCaT secretome, which represents a novel biosubstance for the development of wound healing and skin regeneration products.
... When the skin undergoes photoaging, elastin changes shape and function to become thick and irregular. Elastic tissue can cause clinical manifestations of skin aging, namely the skin looks loose or has reduced elasticity [22].Collagen is a triple helical protein found in all parts of the body and functions as tissue binding, cell attachment, cell migration, new blood vessel formation (angiogenesis), tissue morphogenesis, and tissue repair. Collagen in vertebrates consists of 28 types which are numbered I-XXVIII. ...
The skin is the outermost organ that acts as a protector from the external environment both in the ligaments, muscles, and internal organs from exposure to direct sunlight (ultraviolet light) and dehydration, also functions as a sense of taste and touch as well as a defense against pressure and infection. The imbalance between oxidants and antioxidants is influenced by external factors and internal factors that will affect wrinkling and aging of the skin. Tomatoes contain substances such as citrulline, vitamin A, vitamin B2, vitamin B6, vitamin E, vitamin C, and protein, beta-carotene, lycopene, and water. The purpose of this study was to determine the activity of tomato fruit ethanol extract to increase elasticity, sebum and hydration in the skin of male white mice. Cream preparations of tomato fruit ethanol extract were formulated with concentrations of 2.5%, 5%, and 10%. The test was carried out on the skin of male mice for 4 weeks by measuring the levels of elasticity, sebum and hydration. The results of phytochemical screening of extracts contained flavonoids, saponins, steroids, triterpenoids, and glycosides. The measurement results in the fourth week of each group of cream preparations showed an increase in the levels of elasticity, sebum and hydration and was significantly different from the blank group (p<0.05) and the highest increase occurred in cream with 10% tomato extract concentration. The results of this study indicate that the preparation of tomato fruit ethanol extract cream can increase the elasticity, sebum and hydration levels of the skin.
... Besides, each layer can be prepared in a different structure that can provide several advantages. As mentioned earlier, the epidermis layer of the skin tissue has a lower cell content than the dermis, and barrier lipids prevent dehydration while acting as a shield against exogenous pathogen penetration through antimicrobial peptides and lipids [186,187]. In this more compact superficial layer (75-600 μm thick), there is no ECM accumulation and no blood vessels [188]. ...
Skin is the largest organ of the human body acting as a barrier to protect the body from external effects and trauma. As a result of external physical damages or physiological disorders such as diabetes, skin tissue is disrupted, and cellular integrity is lost in the wounded site. Design and production of functional bioactive wound dressing matrices to protect the injured area, assist the wound healing process and guide the regeneration of healthy tissue are of utmost importance. Considering the complexity of the wound healing process and challenging requirements to fulfill the clinical need in terms of both healing and regeneration, multi-layered fibrous membranes/scaffolds offer an effective strategy for the design and development of multi-functional wound-healing matrices. Such matrices act to stimulate the wound-healing cascade by combining different materials with different physicochemical and structural properties in each layer and integration of various bioactive molecules and therapeutic agents.
... The skin is the largest organ in the human body and plays a key role in protecting our body from the diverse external environment (Bouwstra et al., 2003). It is mainly composed of three layers that span from superficial to deep, including the epidermis, dermis, and hypodermis (Menon, 2015). The dermal skin contains components of the extracellular matrix, such as collagen fibers, that contribute to the strength and toughness of the skin (Ngan et al., 2015). ...
The transdermal administration of collagen is an important method used for wound healing and skin regeneration. However, due to the limitations of previous approaches, the process and degree of collagen transdermal absorption could only be quantitatively and qualitatively evaluated in vitro. In the present study, we introduced a novel approach that combines second-harmonic generation with two-photon excited fluorescence to visualize the dynamics of collagen transdermal absorption in vivo. High-resolution images showed that exogenous recombinant human collagen permeated the epidermis through hair follicles and sebaceous glands reached the dermis, and formed reticular structures in real time. We also validated these findings through traditional in vitro skin scanning and histological examination. Thus, our approach provides a reliable measurement for real-time evaluation of collagen absorption and treatment effects in vivo.
... The skin is the largest organ in the human body and plays a key role in protecting our bodies from the varied external environment [1]. It is mainly composed of three layers that span from super cial to deep, including the epidermis, dermis, and hypodermis [2]. The dermal skin contains components of the extracellular matrix, such as collagen bers, that contribute to the strength and toughness of the skin [3]. ...
The transdermal administration of collagen is an important method used for wound healing and skin regeneration. However, due to the limitations of previous approaches, the process and degree of collagen transdermal absorption could only be quantitatively and qualitatively assessed in vitro . In the present study, we introduced a novel approach combining second-harmonic generation with two-photon excited fluorescence to visualize the dynamics of collagen transdermal absorption in vivo . The high resolution images showed that the exogenous recombinant human collagen permeated through the epidermis, reached the dermis and formed reticular structures in real time. We also validated these findings through traditional in vitro skin scanning and histological examination. Thus, our approach provides a reliable method of measurement for the real-time evaluation of collagen absorption and treatment effects.
... Skin is the largest human organ which serves multiple important functions including protection from microbes, water loss, ultraviolet light; apart from thermoregulation and sensory functions [41]. The ECM provides tensile strength to the skin and is largely responsible for the biomechanical features of skin. ...
Development of scaffold from biopolymer can ease the requirements for donor skin autograft and plays an effective role in the treatment of burn wounds. In the current study, a porous foam based, bilayered hydrogel scaffold was developed using gelatin, hyaluronic acid and chondroitin sulfate (G-HA-CS). The fabricated scaffold was characterized physicochemically for pre- and post-sterilization efficacy by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). In-vitro studies proved that the scaffold promoted cellular proliferation. The efficacy of G-HA-CS scaffold was compared with Integra™ at different time points (7, 14, 21 and 42 days), in a swine second degree burn wound model. Remarkable healing potential of the scaffold was evident from the wound contraction rate, reduction of IL-6, TNF-α and C3. The expression of healing markers TGF-β1 and collagen 1 revealed significant skin regeneration with regulated fibroblast activation towards the late phase of healing (p<0.001 at day 21 and 42 vs. control). Expression of VEGFA, vimentin and N-cadherin were found to favour angiogenesis and skin regeneration. Mechanistically, scaffold promoted wound healing by modulation of CD-45, COX-2 and MMP-2. Thus, the promising results with foam based scaffold, comparable to Integra™ in swine burn injury model offers an innovative lead for clinical translation for effective management of burn wound.
... Fibroblasts are cells of the dermis that are responsible for producing outstanding components of the extracellular matrix (e.g., elastin, collagen, and hyaluronic acid) that confer elasticity and strength to the skin. UVR causes degradation of the dermis fibers, leading to photoaging [12,47]. Additionally, it has been reported that a decrease in cell viability under UVB irradiation is the result of apoptosis as it is induced by the inability of cells to repair DNA damage caused by ROS [48]. ...
The research on compounds exhibiting photoprotection against ultraviolet radiation (UVR) is a matter of increasing interest. The methanolic extract of a cell culture of Buddleja cordata has potential photoprotective effects as these cells produce phenolic secondary metabolites (SMs). These metabolites are attributed with biological activities capable of counteracting the harmful effects caused by UVR on skin. In the present work, the methanolic extract (310–2500 µg/mL) of B. cordata cell culture showed a photoprotective effect on UVB-irradiated 3T3-Swiss albino fibroblasts with a significant increase in cell viability. The greatest photoprotective effect (75%) of the extract was observed at 2500 µg/mL, which was statistically comparable with that of 250 µg/mL verbascoside, used as positive control. In addition, concentrations of the extract higher than 2500 µg/mL resulted in decreased cell viability (≤83%) after 24 h of exposure. Phytochemical analysis of the extract allowed us to determine that it was characterized by high concentrations of total phenol and total phenolic acid contents (138 ± 4.7 mg gallic acid equivalents and 44.01 ± 1.33 mg verbascoside equivalents per gram of extract, respectively) as well as absorption of UV light (first and second bands peaking at 294 and 330 nm, respectively). Some phenylethanoid glycosides were identified from the extract.
... About 70% of the dermis dry weight consist of the collagen protein [67]. Skin layers show presence of collagen type I, III, IV and V [43]. Cutis Laxa is a collagen defect observed in skin when collagen fibres are unable to crosslink with the help of Lysyl oxidase. ...
... The ISTAP (2018), however, made only oblique reference to the epidermis and dermis by stating skin tears did not extend through to "the subcutaneous layer of the skin". The subcutis or hypodermis is comprised of fat and loose connective tissue (elastic fibres and collagen) and supports the attachment of the integumentary system to the underlying fascia, muscles and bone [32][33][34] . All definitions made reference (explicitly or implicitly) to the cause of a skin tear in terms of shearing, friction forces, bathing, turning, rubbing, trauma, blunt forces, and mechanical forces. ...
Skin tears are reported to be the most common wound found amongst elderly individuals, yet there is a lack of evidence and consensus on a definition for these age-related traumatic injuries. A consensus on definition is essential for benchmarking prevalence and incidence and informing clinical diagnosis, management and reporting. This paper examines the extent of similarity and heterogeneity between the published definitions of skin tears and the underpinning evidence for the same. Five criteria were used to evaluate and compare the published skin tear definitions – reference to skin pathology; cause of injury; effect of injury; site of injury; and reference to the population group being studied. As a result of the review and recent research findings, which explicitly demonstrate age-related changes to the structural and mechanical properties of skin and associated increased risk of skin tears, the authors present a new skin tear definition based on these findings. Skin tears are defined as trauma-induced partial or full thickness wounds which primarily occur on the extremities of older persons with age-related changes to the skin’s structural and mechanical support properties, and are commonly associated with elastosis and/or ecchymosis.
... The extracellular lipids form a lamellar structure composed of ceramides, cholesterol, and fatty acids. The stratum corneum provides a major barrier to water loss and the permeation of exogenous substances (1,2). The skin begins to form during embryogenesis in the third week of gestation. ...
Vernix caseosa, the waxy substance that coats the skin of newborn babies, has an extremely complex lipid composition. We have explored these lipids and identified non-hydroxylated 1-O-acylceramides (1-O-ENS) as a new class of lipids in vernix caseosa. These ceramides mostly contain saturated C11 to C38 ester-linked (1-O) acyls, saturated C12 to C39 amide-linked acyls, and C16 to C24 sphingoid bases. Since their fatty acyl chains are frequently branched, numerous molecular species were separable and detectable by HPLC/MS: we found more than 2,300 molecular species, 972 of which were structurally characterized. The most abundant 1-O-ENS contained straight-chain and branched fatty acyls with 20, 22, 24, or 26 carbons in the 1-O position, 24 or 26 carbons in the N-position, and sphingosine. 1-O-ENS were isolated using multistep TLC and HPLC and they accounted for 1 % of the total lipid extract. The molecular species of 1-O-ENS were separated on a C18 HPLC column using an acetonitrile/propan-2-ol gradient and detected by APCI MS, and the structures were elucidated by high-resolution and tandem MS. Medium-polarity 1-O-ENS likely contribute to the cohesiveness and to the waterproofing and moisturizing properties of vernix caseosa.
... Thus, skin prevents the loss of useful substances from an organism. Skin also undertakes various functions, including repairing itself, perspiring, detecting temperature and pressure, and providing additional structural support (2)(3)(4). The development and function of the skin are affected by multiple factors, including environmental factors and hormones (5). Recently, exosome studies have indicated that some exosomes are involved in the physiological and pathological processes of the skin (6,7). ...
Exosomes are one of the most potent intercellular communicators, which are able to communicate with adjacent or distant cells. Exosomes deliver various bioactive molecules, including membrane receptors, proteins, mRNA and microRNA, to target cells and serve roles. Recent studies have demonstrated that exosomes may regulate the functions and diseases of the skin, which is the largest organ of the human body. The abnormal functions of the skin lead to the progression of scleroderma, melanoma, baldness and other diseases. A previous study has demonstrated that epithelial progenitor cells are rich in several subunits of exosomes that may maintain the proliferative capacity of these epithelial progenitor cells, which is essential for the development of the epidermis. Exosomes derived from human adipose mesenchymal stem cells accelerate skin wound healing by optimizing fibroblast properties; this is beneficial for the recovery of postoperative and other wounds. Exosomes derived from adipocytes promote melanoma migration and invasion through fatty acid oxidation; therefore, in the clinic, it may be possible to improve the prognosis of patients with melanoma by reducing their body fat content. Exosomes derived from keratinocytes modulate melanocyte pigmentation, which has been utilized as a novel mechanism for the regulation of pigmentation in conditions including Moynahan syndrome and albinism. Meanwhile, scleroderma patients with vascular abnormalities may experience decreased serum exosome levels; it may therefore be possible to detect the exosome content in sera in order to diagnose and treat scleroderma. In addition, the use of exosomes has been suggested to promote or enhance hair growth, which has been demonstrated to be highly effective. These studies have provided new opportunities and therapeutic strategies for understanding how exosomes regulate intercellular communication in pathological processes of the skin.
... Skin is a vital organ that forms the outermost layer of the human body, thereby protecting it from the external environment and reflecting the general well-being of a human being [1]. Further, it exhibits different characteristics depending on its location on the body, such as color, thickness, elasticity, and sensitivity. ...
This study proposes two specific prototype systems used for the physical examination of skin diseases by a doctor. The objective of this study is to enhance the comfort level of the doctor while performing physical examination of skin diseases using a computer-assisted system. In the previous study, we found that physicians were more comfortable with the process of physical examination using some variety of a particular dialogue. In this study, we propose two prototype systems, namely, an icon-based model and a graphic user interface (GUI)-based model. These prototypes were evaluated by eight medical doctors through a focus group discussion (FGD) to obtain the desired model. From the results obtained by the doctors, it was found that the acceptance level of the GUI-based model was approximately 81% and that this model was better than the icon-based model. Further, the proposed prototype can be used as a reference model in future studies for developing a user interface system, particularly a system that requires physical examination of skin diseases.
The skin is one of the most vital parts of the human body and is the largest sense organ performing crucial functions in regulating the homeostatic functioning of the body’s mechanisms. It is divided into three layers, namely, epidermis, dermis and hypodermis, each performing a specific task of its own and further divided into sublayers or strata of cells along the thickness of the skin. A wound is defined as a cut or break that is capable of causing a break in the continuity of the skin surface, leading to disturbance at the injury site. The process of wound healing ensures closure of the wound and is a complex set of events performed by numerous soluble factors and cells. It occurs in four stages, starting from coagulation to prevent blood loss at the injury site followed by inflammation to prevent pathogen attack, a proliferative phase to ensure formation of a scar, and a remodelling phase to re-establish new tissues at the wound matrix. Wound dressing is a medical device used to prevent infection and promote the process of wound healing at the injury site. Conventional wound-dressing materials are generally used to merely cover the infection site and require frequent changing of the dressing with time. In order to overcome the shortcomings of conventional wound-dressing materials, advanced dressing materials with active components capable of enhancing the wound-healing process have been developed. Biopolymers used for fabricating advanced wound-dressing materials also serve as sustainable sources for developing healthcare products. This chapter describes some advanced wound-dressing materials that have been reported.
Simple Summary
The tumor environment is the place where the tumor resides implying that it might evolve in the role of disease progression, particularly in the phase of tumor dissemination. For cutaneous melanoma, in the early phase of disease advancement, the microenvironment is confined to the epidermal compartment since the dermo-epidermal basement membrane prevents dermal invasion. Here, poorly aggressive melanoma cells gain the aggressiveness necessary for disease progression. After dermo-epidermal membrane breakdown, the melanoma cells progressively lose keratinocyte control and engage in unusual partnerships mainly with dermal fibroblasts.
Abstract
Melanoma progression is a multistep evolution from a common melanocytic nevus through a radial superficial growth phase, the invasive vertical growth phase finally leading to metastatic dissemination into distant organs. Melanoma aggressiveness largely depends on the propensity to metastasize, which means the capacity to escape from the physiological microenvironment since tissue damage due to primary melanoma lesions is generally modest. Physiologically, epidermal melanocytes are attached to the basement membrane, and their adhesion/migration is under the control of surrounding keratinocytes. Thus, the epidermal compartment represents the first microenvironment responsible for melanoma spread. This complex process involves cell–cell contact and a broad range of secreted bioactive molecules. Invasion, or at the beginning of the microinvasion, implies the breakdown of the dermo-epidermal basement membrane followed by the migration of neoplastic melanocytic cells in the superficial papillary dermis. Correspondingly, several experimental evidences documented the structural and functional rearrangement of the entire tissue surrounding neoplasm that in some way reflects the atypia of tumor cells. Lastly, the microenvironment must support the proliferation and survival of melanocytes outside the normal epidermal–melanin units. This task presumably is mostly delegated to fibroblasts and ultimately to the self-autonomous capacity of melanoma cells. This review will discuss remodeling that occurs in the epidermis during melanoma formation as well as skin changes that occur independently of melanocytic hyperproliferation having possible pro-tumoral features.
Reactive oxygen species (ROS) are associated with various pathological conditions, including atherosclerosis and cancer. Photoaging, mainly caused by UVB-induced ROS, accelerates skin aging and collagen degradation. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates antioxidant enzymes and has demonstrated protective effects against chronic diseases. Jeju lava seawater (JLS), which is rich in minerals, is attracting attention for its health benefits. The current study investigates the antioxidant properties of JLS in human dermal fibroblasts (HDFs). experiments were conducted by culturing HDFs in JLS with different water hardness levels and irradiating UVB. The results show that JLS does not affect HDF viability, especially at high water hardness. JLS treatment enhances collagen production and upregulates Nrf2 and antioxidant enzymes such as NQO1 and HO-1. This mechanism involves the translocation of Nrf2 to the cell nucleus. JLS shows promise as an antioxidant, potentially mitigating the effects of oxidative stress and promoting collagen synthesis.
The skin is the largest organ of the body (it accounts for about 15% of total body weight in adults) and, together with its derived structure, forms the integumentary system. As the body's outermost layer, the skin is the first line of defence against external stimuli, making it also the most vulnerable part of the body to injury.
The skin has evolved into a protective barrier to enable the body to withstand physical, chemical, and biological assaults from pathogens. When the skin is compromised, the body activates the highly complex process of cutaneous wound healing to quickly close the wound, eliminate invading microbes, and strengthen the damaged area to restore the protective functions of the skin. Investigations using high-throughput sequencing platforms have begun to study the complex and diverse communities of microbes on the skin, known as the skin microbiota. The skin microbiota consists of trillion of microbes across bacterial, viral, and fungal families with different communities colonizing different locations of the body. The unique genetic, metabolic, and proteomic profiles of each microbial community may affect health, disease, and infection on the skin. How host-microbe interactions support healthy skin and wound healing is an urgent topic of research because dysbiosis, that is, perturbations to the skin microbiota, may result in the development of human skin diseases and ailments, including the development of chronic wounds. Studies have now shown that skin ailments such as atopic dermatitis, acne vulgaris, rosacea, psoriasis and even some skin cancers have skin microbiota different from normal skin. While common wound pathogens of chronic wounds have been identified through culture-dependent methods, it is now appreciated that the community of biofilm-forming microbes differs with some uniqueness across different types of wounds, such as venous ulcers, pressure ulcers, and diabetic foot ulcers. Understanding how specific skin microbes play an important role in wound healing and the overall health of the skin may lead to the next generation of therapeutics in which the skin microbiota is manipulated through probiotics, prebiotics, and skin microbiota transplants to prevent and treat skin ailments and chronic wounds.
Skin is one of the indispensable organs for life. The epidermis at the outermost surface provides a permeability barrier to infectious agents, chemicals, and excessive loss of water, while the dermis and subcutaneous tissue mechanically support the structure of the skin and appendages, including hairs and secretory glands. The integrity of the integumentary system is a key for general health, and many techniques have been developed to measure and control this protective function. In contrast, the effective skin barrier is the major obstacle for transdermal delivery and detection. Changes in the electrical properties of skin, such as impedance and ionic activity, is a practical indicator that reflects the structures and functions of the skin. For example, the impedance that reflects the hydration of the skin is measured for quantitative assessment in skincare, and the current generated across a wound is used for the evaluation and control of wound healing. Furthermore, the electrically charged structure of the skin enables transdermal drug delivery and chemical extraction. This paper provides an overview of the electrical aspects of the skin and summarizes current advances in the development of devices based on these features.
Ceramide, an intercellular lipid of the stratum corneum, plays an essential role in making the skin barrier. One problem with the use of medical adhesive tape or sheets for skin is that their repeated attachment and detachment may cause some damage to the skin. An attempt has been made to eliminate this problem by mixing ceramide into the adhesive of sheets, and has delivered excellent clinical results. This study aimed to investigate whether ceramide is transferred from the adhesive with added ceramide to the skin. An adhesive sheet was prepared by adding synthetic ceramide (CER) to UV-curable acrylic adhesive gel. After affixing the adhesive sheet to human skin for a certain period, it was peeled off and cut perpendicular to the adhesive surface. Synchrotron micro-infrared spectroscopy of the sectioned samples showed that the ceramide concentration in the gel sheet decreases as the application time to human skin increases. This is thought to be due to the release of CER from the gel sheet.
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Atopic dermatitis (AD) is a common pruritic skin disease in people and domestic animals that can be severely debilitating and stressful to the patient and the caregiver. The diagnosis of AD requires time consuming and expensive procedures, and treatment is often lifelong at considerable cost. Alterations in the lipid composition of the epidermis are a hallmark of the disease, and these may represent changes caused by the inflammation and defects in the lipid barrier. Liquid chromatography tandem mass spectrometry (LC-MS/MS) and, more recently, untargeted profiling using high-resolution time-of-flight instruments have been used to quantify the lipid composition in skin and other tissues, but these approaches are highly demanding in sample preparation and instrument time. In addition, these methods either detect only a limited number of lipids at the time or the identification of detected mass-to-charge ratio (m/z) is problematic when untargeted profiling is used. New lipidomic approaches that generate lipid profiles in a faster and more efficient manner can lead to a better understanding of these lipid changes.
The mass spectrometry analytical strategy used in this study, multiple reaction monitoring (MRM)-profiling, rapidly identifies discriminant lipids of the epidermis by flow injection. MRM-profiling is a small molecule accelerated discovery workflow performed in two parts using a triple quadrupole mass spectrometer with electrospray ionization as the ion source. Briefly, the first step consists of discovery experiments based on neutral loss and precursor ion scans to detect lipids in pooled samples by targeting class-specific chemical motifs such as polar heads of phospholipids or sphingoid bases of ceramides. The second step of the MRM-profiling is the screening of individual samples for the transitions detected in the discovery phase.
We first developed the experimental approach of the MRM-profiling methodology using epidermal samples of mice with AD-like inflammatory skin disease (chronic proliferative dermatitis, cpdm). Subsequently, we investigated lipid changes as the disease in mice progressed from minimal to severe. In order to select the most relevant ions, we utilized a two-tiered filter/wrapper feature-selection strategy. First, we built linear models linking the presence of every lipid monitored to disease stage information. The top 10 lipids, ranked based on η2 effect size, were used to build a predictive elastic-net (E-net) regression model linking the lipid ions detected by MRM-profiling with disease progression. The developed model accurately identified disease stages based on the variations in relative amounts of lipid ions corresponding to phosphatidylcholines, cholesterol esters, and glycerolipids-containing and eicosapentaenoic acid fatty acyl residues. Finally, we investigated the lipid profile of the epidermis in dogs with canine AD using the previously developed methodology. Epidermis from client owned patients and healthy controls were collected. Patients were sampled from affected and unaffected skin avoiding areas with secondary infections and the canine atopic dermatitis extent and severity index (CADESI-4) was recorded. The monitored lipids substantially separated the samples of healthy dogs from atopic dogs and distinguished the affected from the unaffected skin of patients. Samples were grouped into two cohorts for low-score and high-score CADESI-4, the first principal component was able to differentiate the control group from the low and high-score group. Differences in the lipid composition associated with low and high score CADESI-4 were significantly different only after separating the samples by sex of the dogs, demonstrating sexual dimorphism in the lipid changes associated with disease. The compositional data was feature extracted using the CADESI-4 to build linear models that identified oleic acid-containing triacylglycerides, long-chain acylcarnitines and sphingolipids as highly predictive lipids and were subsequently used to construct a predictive E-net regression. The lipid fingerprint obtained from the MRM-profiling was highly correlated (R2=0.89) with the classification of the standardized CADESI-4 score.
This research showed that changes in the lipid composition of the epidermis can be detected by MRM-profiling in atopic dogs even when the skin looks clinically healthy and that sex is a modifying factor in the lipid profile of canine atopic dermatitis (CAD). We expect that this research leads to a better understanding of the lipid changes in the epidermis during the onset of AD and as the chronic inflammatory process develops. The high prediction rate given by the lipid biomarkers for disease progression identified here by the machine learning strategy provides a potential molecular assessment tool for the diagnosis and monitoring of atopic dermatitis and the patient response to treatment.
As a noninvasive molecular analysis technique, ultraviolet resonance Raman (UVRR) spectroscopy represents a label‐free method suitable for characterizing biomolecules. Using UVRR spectroscopy, we collected spectral fingerprints of UV absorbing cellular components, including proteins, nucleic acids, and unsaturated lipids. This knowledge was used to guide the assignment of spectra derived from intact human cell lines (i.e., HSC‐3 and HaCaT) and from the apoptotic events induced by cisplatin. Notably, a jet‐flow system was employed to generate flowing cell suspensions during UVRR measurements, minimizing UV‐induced damage. A spectral marker is established based on the ratio of Raman intensities at 1485 and 1655 cm‐1 that correlates to the level of cell death due to apoptosis. Collectively, this work demonstrates that UVRR spectroscopy is a sensitive and informative probe of cellular physiology and molecular composition. The molecular insight obtained from UVRR measurements can be used to improve understanding of therapeutic treatment and guide drug development and the choice of therapeutic agents.
Natural oils include mineral oil with emollient, occlusive, and humectant properties and the plant-derived essential, coconut, and other vegetable oils, composed of triglycerides that microbiota lipases hydrolyze into glycerin, a potent humectant, and fatty acids (FAs) with varying physico-chemical properties. Unsaturated FAs have high linoleic acid used for synthesis of ceramide-I linoleate, a barrier lipid, but more pro-inflammatory omega-6:-3 ratios above 10:1, and their double bonds form less occlusive palisades. VCO FAs have a low linoleic acid content but shorter and saturated FAs that form a more compact palisade, more anti-inflammatory omega-6:-3 ratio of 2:1, close to 7:1 of olive oil, which disrupts the skin barrier, otherwise useful as a penetration enhancer. Updates on the stratum corneum illustrate how this review on the contrasting actions of NOs provide information on which to avoid and which to select for barrier repair and to lower inflammation in contact dermatitis genesis.
Eccrine sweat is secreted onto the skin's surface and is not harmful to normal skin, but can exacerbate eczematous lesions in atopic dermatitis. Although eccrine sweat contains a number of minerals, proteins, and proteolytic enzymes, how it causes skin inflammation is not clear. We hypothesized that it stimulates keratinocytes directly, as a danger signal. Eccrine sweat was collected from the arms of healthy volunteers after exercise, and levels of proinflammatory cytokines in the sweat were quantified by ELISA. We detected the presence of IL-1α, IL-1β, and high levels of IL-31 in sweat samples. To investigate whether sweat activates keratinocytes, normal human keratinocytes were stimulated with concentrated sweat. Western blot analysis demonstrated the activation of NF-κB, ERK, and JNK signaling in sweat-stimulated keratinocytes. Real-time PCR using total RNA and ELISA analysis of supernatants showed the upregulation of IL-8 and IL-1β by sweat. Furthermore, pretreatment with IL-1R antagonist blocked sweat-stimulated cytokine production and signal activation, indicating that bioactive IL-1 is a major factor in the activation of keratinocytes by sweat. Moreover, IL-31 seems to be another sweat stimulator that activates keratinocytes to produce inflammatory cytokine, CCL2. Sweat is secreted onto the skin's surface and does not come into contact with keratinocytes in normal skin. However, in skin with a defective cutaneous barrier, such as atopic dermatitis-affected skin, sweat cytokines can directly act on epidermal keratinocytes, resulting in their activation. In conclusion, eccrine sweat contains proinflammatory cytokines, IL-1 and IL-31, and activates epidermal keratinocytes as a danger signal.
Mutations in the filaggrin gene are associated with a broad range of skin and allergic diseases. The biology of this molecule and the role of mutations in its altered function offer new insights into a range of conditions not previously thought to be related to one another.
Outermost barriers are critical for terrestrial animals to avoid desiccation and to protect their bodies from foreign insults. Mammalian skin consists of two sets of barriers: stratum corneum (SC) and tight junctions (TJs). How acquisition of external antigens (Ags) by epidermal Langerhans cells (LCs) occur despite these barriers has remained unknown. We show that activation-induced LCs elongate their dendrites to penetrate keratinocyte (KC) TJs and survey the extra-TJ environment located outside of the TJ barrier, just beneath the SC. Penetrated dendrites uptake Ags from the tip where Ags colocalize with langerin/Birbeck granules. TJs at KC-KC contacts allow penetration of LC dendrites by dynamically forming new claudin-dependent bicellular- and tricellulin-dependent tricellular TJs at LC-KC contacts, thereby maintaining TJ integrity during Ag uptake. Thus, covertly under keratinized SC barriers, LCs and KCs demonstrate remarkable cooperation that enables LCs to gain access to external Ags that have violated the SC barrier while concomitantly retaining TJ barriers to protect intra-TJ environment.
The skin epidermis and its array of appendages undergo ongoing renewal by a process called homeostasis. Stem cells in the epidermis have a crucial role in maintaining tissue homeostasis by providing new cells to replace those that are constantly lost during tissue turnover or following injury. Different resident skin stem cell pools contribute to the maintenance and repair of the various epidermal tissues of the skin, including interfollicular epidermis, hair follicles and sebaceous glands. Interestingly, the basic mechanisms and signalling pathways that orchestrate epithelial morphogenesis in the skin are reused during adult life to regulate skin homeostasis.
The contents of epidermal lamellar bodies (LB) are delivered selectively to the intercellular spaces at the stratum granulosum (SG)-stratum corneum (SC) interface. We assessed the subcellular basis for LB secretion first by confocal microscopy, following labeling with Nile red or NBD-ceramide, which reveals a tubulo-reticular membrane system within the apical cytosol of the outermost SG cell layer under basal conditions, changing to a more peripheral staining pattern when secretion is stimulated. Ultrastructural study demonstrates that this network is composed of a widely disbursed trans-Golgi-like network (TGN), associated with arrays of contiguous LB, and deep invaginations of the SG-SC interface. Under basal conditions, limited fusion of apically directed LB leads to deep, interconnected invaginations of the apical plasma membrane, resulting in the formation of an extensive, honeycomb extension of the SG-SC interface. Still deeper invaginations and more extensive organelle fusion develop after the epidermis is acutely permeabilized by either acetone treatment, sonophoresis, or iontophoresis. Finally, nascent LB appear to bud off cisternae of the TGN, a process that appears to accelerate after barrier disruption. The deep invaginations of the SG-SC interface; the wide distribution of the TGN within the apical cytosol; the association of nascent LB with the TGN; and the rapid fusion of LB with these invaginations, deep within the cytosol, account for (i) the polarized secretion of LB from the apex of the outermost SG cell, and (ii) the rapid LB-secretory response to barrier perturbations. Finally, our results point to the outermost SG cell as a uniquely specialized secretory cell. We propose the term "secretory granulocyte" to encompass the specialized features of these cells.
Congenital cutis laxa, a rare syndrome with marked skin laxity and pulmonary and cardiovascular compromise, is due to defective
elastic fiber formation. In several cases, skin fibroblast tropoelastin production is markedly reduced yet reversed in vitro by transforming growth factor-β treatment. We previously showed that this reversal was due to elastin mRNA stabilization
in one cell strain, and here this behavior was confirmed in skin fibroblasts from two generations of a second family. cDNA
sequencing and heteroduplex analysis of elastin gene transcripts from three fibroblast strains in two kindreds now identify
two frameshift mutations (2012ΔG and 2039ΔC) in elastin gene exon 30, thus leading to missense C termini. No other mutations
were present in theELN cDNA sequences of all three affected individuals. Transcripts from both alleles in each kindred were unstable and responsive
to transforming growth factor-β. Exons 22, 23, 26A, and 32 were always absent. Since exon 30 underwent alternative splicing
in fibroblasts, we speculate that a differential splicing pattern could conceivably lead to phenotypic rescue. These two dominant-acting,
apparently de novo mutations in the elastin gene appear to be responsible for qualitative and quantitative defects in elastin, resulting in
the cutis laxa phenotype.
Dermal fibroblasts are a dynamic and diverse population of cells whose functions in skin in many respects remain unknown. Normal adult human skin contains at least three distinct subpopulations of fibroblasts, which occupy unique niches in the dermis. Fibroblasts from each of these niches exhibit distinctive differences when cultured separately. Specific differences in fibroblast physiology are evident in papillary dermal fibroblasts, which reside in the superficial dermis, and reticular fibroblasts, which reside in the deep dermis. Both of these subpopulations of fibroblasts differ from the fibroblasts that are associated with hair follicles. Fibroblasts engage in fibroblast-epidermal interactions during hair development and in interfollicular regions of skin. They also play an important role in cutaneous wound repair and an ever-increasing role in bioengineering of skin. Bioengineered skin currently performs important roles in providing (1) a basic understanding of skin biology, (2) a vehicle for testing topically applied products and (3) a resource for skin replacement.
Reduction of serum cholesterol levels with statin therapy decreases the risk of coronary heart disease. Inhibition of HMG-CoA reductase by statin results in decreased synthesis of cholesterol and other products downstream of mevalonate, which may produce adverse effects in statin therapy. We studied the reductions of serum ubiquinol-10 and ubiquinone-10 levels in hypercholesterolemic patients treated with atorvastatin. Fourteen patients were treated with 10 mg/day of atorvastatin, and serum lipid, ubiquinol-10 and ubiquinone-10 levels were measured before and after 8 weeks of treatment. Serum total cholesterol and LDL-cholesterol levels decreased significantly. All patients showed definite reductions of serum ubiquinol-10 and ubiquinone-10 levels, and mean levels of serum ubiquinol-10 and ubiquinone-10 levels decreased significantly from 0.81 +/- 0.21 to 0.46 +/- 0.10 microg/ml (p < 0.0001), and from 0.10 +/- 0.06 to 0.06 +/- 0.02 microg/ml (p = 0.0008), respectively. Percent reductions of ubiquinol-10 and those of total cholesterol showed a positive correlation (r = 0.627, p = 0.0165). As atorvastatin reduces serum ubiquinol-10 as well as serum cholesterol levels in all patients, it is imperative that physicians are forewarned about the risks associated with ubiquinol-10 depletion.
Skin is a highly vulnerable and visible organ that interfaces with the environment. The structural and functional relationships of the skin are complex. Therefore, the anatomical structure of skin is important so that an appreciable understanding of the barrier function, penetration, absorption, and immunological aspects of skin in response to chemicals, particles, or other insult can be well understood. Skin is an integrated, dynamic organ that has a myriad of biological functions that go far beyond its role as a barrier to the external environment (Table 1). It can serve as an environmental barrier by protecting the major internal organs, as a diffusion barrier that minimizes insensible water loss that could result in dehydration, and as a metabolic barrier that can metabolize a compound so that it may be excretable after absorption has occurred. The skin plays role in thermoregulation where blood vessels constrict to retain heat and dilate to dissipate heat. Hair in humans and the fur of lower mammals serve as insulation devices, while sweating facilitates heat loss by evaporation. Skin can serve as an immunological affector axis by having Langerhans cells in the epidermis to process antigens and also as an effector axis by establishing an inflammatory response when exposed to a foreign insult. It has a welldeveloped stroma that supports all of the other organs. Numerous receptors in skin can sense the modalities of touch, pain, and heat. Skin may also serve as an independent endocrine organ that synthesizes vitamin D by converting 7-dehydrocholesterol through two hydroxylations in the body to activate vitamin D. The first is in the liver that converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol, and the other occurs in the kidney and also in the skin and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D]. Skin is also a target for androgens, which regulate sebum production, and a target for insulin that regulates carbohydrate and lipid metabolism. The dermis of skin has sebaceous glands that can secrete sebum, which is a complex mixture of lipids that function as antibacterial agents or as a water-repellent shield in some animals. In addition, the skin contains both apocrine and eccrine sweat glands that produce a secretion, which contains scent that functions in territorial demarcation. The integument also plays a role in the biosynthesis of keratin, collagen, melanin, lipids, and carbohydrates, as well as in respiration and biotransformation of xenobiotics. The purpose of this chapter is to overview the anatomical structure and function of skin from a multifaceted perspective. In general, the basic architecture of the integument is similar in all mammals. However, differences may exist in the thickness of the epidermal layers (Table 2) and dermis in various regions of the body between species and within the same species. A thick stratum corneum can be found in glabrous skin areas such as the palmar and plantar surfaces where considerable abrasive action occurs. A thin epidermis can be found in areas where there is a heavy protective coat of hair or fur. Understanding these variations in the skin is extremely important in studies involving biopharmaceutics, dermatological formulations, cutaneous pharmacology, drug delivery, nanoparticle penetration, and dermatotoxicology.
The skin, commonly viewed as our body’s largest organ, is strategically positioned at the interface between the external and internal environments. Therefore, it appears to have evolved not only to sense a hugely diverse range of stressors and insults but also to integrate and respond to these stimuli. Common skin stressors include ultraviolet radiation (UVR), mechanical, chemical, and (micro)biological insults. In doing so, the skin is likely to be much more critical in maintaining our total body homeostasis than previously thought. Indeed, the new field of cutaneous neuro-immuno-endocrinology focuses on the multifactorial nature of skin composed of several closely networked systems linking peripheral and central stress axes. Modulation of this peripheral sensor, therefore, is likely to have significant consequences for human health and disease. This chapter will scope out, in brief, how our skin can participate as a fundamentally important antenna to protect, educate, and beguile our other body systems, and how these are linked into the natural world around us.
The purpose of the present manuscript is to review the chemical and physical properties of epidermal lipids and to relate these properties to the formation and function of the permeability barrier of the skin. Lipids accumulate in small organelles known as lamellar granules as epidermal keratinocytes differentiate. This lipid is extruded into the intercellular spaces where it undergoes enzymatic processing to produce a lipid mixture consisting of ceramides, cholesterol and fatty acids. This intercellular lipid is uniquely organized into a multilamellar complex that fills most of the intercellular space of the stratum corneum. The barrier properties of the stratum corneum are related to the phase behavior of the intercellular lipids. It has been proposed that a structurally unusual acylglucosylceramide is thought to be involved in assembly of the lamellar granules, and a related acylceramide may have a major influence on the organization of the lamellae in the stratum corneum.
Mammals are covered by the epidermis, consisting of a soft inner portion, called the Malpighian layer, and a hardened outer cornified portion. The inner part maintains the tissue by proliferation and differentiation of its cellular components, the outer part protects the organism from the environment. On the surface of the epidermis inscriptions occur forming characteristic ridges and sulci (Fig. 1). The inner surface may be smooth or rough, forming branching ridges and mounds enclosing valleys and craters (Montagna and Parakkal 1974). Thus the architecture of the epidermis varies from site to site in relation to its surface and undersurface structures. In general the epidermis is thicker over glabrous skin than over hairy skin, it is thickest on the palm, sole, paw, muzzle and tail. In man its thickness varies from 0.8 to 1.4 mm. The epidermis merges with mucous epithelia of the eye, nose, ear, mouth, rectum and genitalia and its continuity is interrupted by appendages of the skin.
As the largest organ comprising more than 10% of the body mass in humans, the skin serves as the physical barrier for the body. The bulk of it is made up of dermis, but it is the epidermis that is vested with the function of producing, maintaining and renewing the superficial and crucial compartment, the stratum corneum (SC). This layer of terminally differentiated keratinocytes provides the physical basis for several types of barrier functions including: barrier to water permeability, penetration of xenobiotics, and microbial and parasitic invasion. Additionally the SC barrier helps to maintain the integrity of other components by providing 1) defense against UV radiation and free radical injury, 2) the immune barrier and 3) crucial skin functions such as thermoregulation, waste elimination and sensory transduction (heat, cold, pain, etc.).
Background and Design:
Previous studies that compared transepidermal water loss in subjects of different race and sex showed minimal differences in basal permeability barrier function. These studies often did not assess the ability of the stratum corneum to withstand or recover from insults to the epidermal permeability barrier. We compared epidermal permeability barrier function in the following human subjects (age range, 22 to 38 years): white (n=8) vs Asian (n=6); male (n=7) vs female (n=7); and skin type II/III (n=14) vs skin type V/VI (n=7) (scale, I to VI). Basal transepidermal water loss was measured by evaporimetry (three sites) on the volar aspect of the forearm. Barrier integrity then was assessed by determining the number of tape strippings required to reach a transepidermal water loss greater than or equal to 20 g/m2 per hour. The rates of barrier recovery then were compared at 6, 24, and 48 hours and 1 week after abrogation.Results:
Neither the number of tape strippings required to perturb the barrier nor the rates of barrier recovery were significantly different in white vs Asian subjects or in female vs male subjects. However, patients with skin types II/III re- quired only 29.6±2.4 tape strippings to perturb the barrier, while the skin type V/VI group required 66.7±6.9 tape strippings. Furthermore, while barrier function in skin type II/ III recovered by approximately 20% by 6 hours and 55% by 48 hours, barrier function in skin type V/VI, independent of race, recovered more quickly, 43% and 72% at 6 and 48 hours, respectively. Finally, neither the differences in barrier integrity nor in rates of recovery could be attributed to variations in cohesiveness, since stripping appears to remove the same weight of stratum corneum in both groups.Conclusions:
Darkly pigmented skin displays both a more resistant barrier and one that recovers more quickly after perturbation by tape stripping than does the skin of individuals with lighter pigmentation. These findings have potential implications for transdermal delivery of topical or systemic therapeutic agents, the ability of individuals with different skin types to withstand environmental or occupational insults, and the influence of acquired hyperpigmentation or pigment loss to influence permeability.(Arch Dermatol. 1995;131:1134-1138)
Human fetal skin heals without scar formation when it is transplanted to a subcutaneous location on an adult athymic mouse and subsequently wounded. In contrast, human fetal skin of identical gestational age heals with scar formation when transplanted to a cutaneous location on the athymic mouse recipient. To determine if mouse (adult) or human (fetal) fibroblasts are healing the graft wounds, we performed indirect immunohistochemistry for mouse and human collagen types I and III. Full-thickness skin grafts (n = 51) from human fetuses at 18 weeks' (n = 4) or 24 weeks' (n = 2) gestational age were placed onto athymic mice in two locations: cutaneously onto a fascial bed and subcutaneously in a pocket under the murine panniculus carnosus. Linear incisions were made in each graft 7 days after transplantation. Grafts were harvested at 7, 14, and 21 days after wounding and stained with hematoxylin and eosin or Mallory's trichrome. Immunohistochemistry for either human collagen type I or type III or for mouse collagen type I was performed. The subcutaneous grafts healed with human collagen types I and III in a scarless pattern. The wound collagen pattern was reticular and unrecognizable from the surrounding dermis. Hair follicles and sebaceous gland patterns were unchanged in the wounded dermis. Conversely, the cutaneous grafts healed with mouse collagen in a scar pattern with disorganized collagen fibers and no appendages. Mouse collagen scar was present along the base of the cutaneous grafts and as a thin capsule around the subcutaneous grafts. We conclude that (1) subcutaneous grafts heal with human fetal collagen and no scar formation, and (2) cutaneous grafts heal with mouse collagen in a scar pattern. Fetal fibroblasts can heal fetal skin wounds without scar despite being perfused by adult serum and inflammatory cells in an adult environment. These data suggest that the fetal fibroblast is the major effector cell for scarless fetal skin repair.
We measured enzymic and non-enzymic antioxidants in human epidermis and dermis from six healthy volunteers undergoing surgical procedures. Epidermis was separated from dermis by currettage and antioxidants were measured by high-performance liquid chromatography (HPLC) or standard spectrophotometric methods. The concentration of every antioxidant (referenced to skin wet weight) was higher in the epidermis than in the dermis.
Among the enzymic antioxidants, the activities of superoxide dismutase, glutathione peroxidase, and glutathione reductase were higher in the epidermis compared to the dermis by 126, 61 and 215%, respectively. Catalase activity in particular was much higher (720%) in the epidermis. Glucose-6-phosphate dehydrogenase and isocitrate dehydrogenase, which provide reduced nicotinamide adenine dinucleotide phosphate (NADPH), also showed higher activity in the epidermis than the dermis by 111% and 313%, respectively.
Among the lipophilic antioxidants, the concentration of α-tocopherol was higher in the epidermis than the dermis by 90%. The concentration of ubiquinol 10 was especially higher in the epidermis, by 900%. Among the hydrophilic antioxidants, concentrations of ascorbic acid and uric acid were also higher in the epidermis than in the dermis by 425 and 488%, respectively. Reduced glutathione and total glutathione were higher in the epidermis than in the dermis by 513 and 471%.
Thus the antioxidant capacity of the human epidermis is far greater than that of dermis. As the epidermis composes the outermost 10% of the skin and acts as the initial barrier to oxidant assault, it is perhaps not surprising that it has higher levels of antioxidants.
Surface tissues of the body such as the skin and intestinal tract are in direct contact with the external environment and are thus continuously exposed to large numbers of microorganisms. To cope with the substantial microbial exposure, epithelial surfaces produce a diverse arsenal of antimicrobial proteins that directly kill or inhibit the growth of microorganisms. In this Review, we highlight new advances in our understanding of how epithelial antimicrobial proteins protect against pathogens and contribute to microbiota-host homeostasis at the skin and gut mucosae. Further, we discuss recent insights into the regulatory mechanisms that control antimicrobial protein expression. Finally, we consider how impaired antimicrobial protein expression and function can contribute to disease.
Tight junctions (TJ) are barrier forming cell–cell junctions that are found in a variety of cell types and tissues but their existence in mammalian epidermis has been shown only in the last years. A variety of TJ proteins were identified in mammalian epidermis, comprising several members of the claudin family, occludin, and JAM-A as well as ZO-1 and MUPP-1. TJ proteins exhibit complex expression and localization patterns in the epidermis. Nonetheless, even though several TJ proteins are found in various layers, typical TJ structures are only found in the stratum granulosum. TJ are important for barrier function of the skin, especially for inside–out barrier. In addition, TJ proteins might also be involved in additional functions in epidermal cells. Localization and expression of TJ proteins are altered in several skin diseases, e.g. psoriasis. Meanwhile several TJ modulators are known from simple epithelia. We discuss their putative usability for drug delivery into and through the skin.
In addition to its role as a component of the mitochondrial respiratory chain and our only lipid-soluble antioxidant synthesized endogenously, in recent years coenzyme Q (CoQ) has been found to have an increasing number of other important functions required for normal metabolic processes. A number of genetic mutations that reduce CoQ biosynthesis are associated with serious functional disturbances that can be eliminated by dietary administration of this lipid, making CoQ deficiencies the only mitochondrial diseases which can be successfully treated at present. In connection with certain other diseases associated with excessive oxidative stress, the level of CoQ is elevated as a protective response. Aging, certain experimental conditions and several human diseases reduce this level, resulting in serious metabolic disturbances. Since dietary uptake of this lipid is limited, up-regulation of its biosynthetic pathway is of considerable clinical interest. One approach for this purpose is administration of epoxidated all-trans polyisoprenoids, which enhance both CoQ biosynthesis and levels in experimental systems.
The natural selection hypothesis suggests that lighter skin colour evolved to optimise vitamin D production. Some authors question if vitamin D deficiency leads to sufficient health problems to act as a selection pressure. This paper reviews the numerous effects of vitamin D deficiency on human health and argues that vitamin D deficiency is sufficient to pose as a potent selection pressure for lighter skin colour. Vitamin D deficiency manifesting as rickets and osteomalacia are sufficient to impair reproductive success, but additionally, animal studies and some clinical observations suggest that vitamin D may have more direct impact on human fertility. Vitamin D deficiency may lead to a whole host of clinical conditions which impair health and increase mortality rates: increase susceptibility to bacterial and viral infections; rickets, osteomalacia and osteoporosis, with increased risk of falls and fractures; increased risk of cancers; hypertension and cardiovascular disease; maturity onset diabetes; autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and Type 1 diabetes; and gum disease. We submit that at higher latitudes, lighter skin colour evolved to facilitate vitamin D production under conditions of low ultra-violet B radiation in order to avoid a plethora of ill health, reproductive difficulties and early mortality.
The fascinating topic of skin barrier continues to engage researchers from diverse disciplines both in academia and industry. Much of the information on the basic biology of barrier formation, its ontogeny as well as repair and homeostasis comes from studies on animal models. A smaller number of human studies have validated the usefulness of animal models, while highlighting some essential differences. We submit that the human skin barrier is unique in several ways, as much due to our adaptive ability as our control over the environment (macro and micro) that none of the other species have exerted. The human skin is not only exposed to the greatest variations of environment due to our phenomenal mobility but also to the largest number of xenobiotics, both chemical and microbial, resulting from human activity. In this overview, we attempt to evaluate the interdependent relation of skin barriers to environmental stressors hoping to raise interest in some of the lesser known or neglected aspects of human skin barriers as they relate to skin health and dysfunctions.
Please cite this paper as: The skin: an indispensable barrier. Experimental Dermatology 2008.Abstract: The skin forms an effective barrier between the organism and the environment preventing invasion of pathogens and fending off chemical and physical assaults, as well as the unregulated loss of water and solutes. In this review we provide an overview of several components of the physical barrier, explaining how barrier function is regulated and altered in dermatoses. The physical barrier is mainly localized in the stratum corneum (SC) and consists of protein-enriched cells (corneocytes with cornified envelope and cytoskeletal elements, as well as corneodesmosomes) and lipid-enriched intercellular domains. The nucleated epidermis also contributes to the barrier through tight, gap and adherens junctions, as well as through desmosomes and cytoskeletal elements. During epidermal differentiation lipids are synthesized in the keratinocytes and extruded into the extracellular domains, where they form extracellular lipid-enriched layers. The cornified cell envelope, a tough protein/lipid polymer structure, resides below the cytoplasmic membrane on the exterior of the corneocytes. Ceramides A and B are covalently bound to cornified envelope proteins and form the backbone for the subsequent addition of free ceramides, free fatty acids and cholesterol in the SC. Filaggrin is cross-linked to the cornified envelope and aggregates keratin filaments into macrofibrils. Formation and maintenance of barrier function is influenced by cytokines, 3',5'-cyclic adenosine monophosphate and calcium. Changes in epidermal differentiation and lipid composition lead to a disturbed skin barrier, which allows the entry of environmental allergens, immunological reaction and inflammation in atopic dermatitis. A disturbed skin barrier is important for the pathogenesis of contact dermatitis, ichthyosis, psoriasis and atopic dermatitis.
Eight stages in the development of the human embryonic and fetal periderm have been established, primarily on the basis of surface morphology, major changes in epidermal stratification, and differentiation. The changes in the periderm observed with the scanning electron microscope have been correlated with and supplemented by cytologic studies with the transmission electron microscope in the periderm and other epidermal layers. Light microscopy was used to determine what proportion of the epidermal thickness is accounted for by the periderm and what relationship individual periderm cells have with underlying cells. The results yield a comprehensive, three-dimensional image of the human epidermis during development and support a concept of the periderm as a layer of "dynamic" cells which project superficial blebs, expand in surface area, then regress at the onset of keratinization, leaving only cellular remnants associated with the adult type epidermis.
One of the genetically distinct collagens (type III) normally found in skin, aorta, and intestine is missing from the tissues of patients with the Ehlers-Danlos syndrome type IV. While skin fibroblasts from other individuals synthesize both types I and III collagen. Ehlers-Danlos syndrome IV cells synthesize only type I. These results suggest that the fragile skin, blood vessels, and intestines of Ehlers-Danlos syndrome IV patients result from an absence of type III collagen.
The elastic system of normal human skin was studied by light and electron microscopy. By light microscopy three different types of fibers were observed: oxytalan, elaunin, and elastic. The most superficial ones (oxytalan fibers) are very thin and directed perpendicularly to the dermoepidermal junction. They start from a plexus with the tinctorial characteristics of elaunin fibers which is connected with the thicker elastic fibers of the reticular dermis. At the electron microscopic level the oxytalan fibers are formed by bundles of tubular microfibrils 10 to 12 nm in diameter. In the deepest layers of the dermis an amorphous material is seen in the core of these bundles. In the elaunin fibers the amorphous material is sparse, while in the elastic fibers it is abundant and compact.
As reviewed in this article, the stratum corneum must now be accorded the respect due to a structurally heterogeneous tissue possessing a selected array of enzymatic activity. The sequestration of lipids to intercellular domains and their organization into a unique multilamellar system have broad implications for permeability barrier function, water retention, desquamation, and percutaneous drug delivery. Yet, the functions and organization of specific lipid species in this membrane system are still unknown. Certain novel insights have resulted from comparative studies in avians and marine mammals. Further elucidation of the molecular architecture and interactions of lipid and nonlipid components of the stratum corneum intercellular domains will be a prerequisite for a comprehensive understanding of stratum corneum function.
To the Editor.—
No small person himself, Lowell Goldsmith is to be commended for proving that the skin is the largest of the middle weight organs.1 Whether the skin is biggest or not, however, I fear that Dr Goldsmith has entered an argument that should not exist, though he cannot be faulted because concern over such things is characteristic of our superficially oriented society. Surely the central issue was settled long ago, and the integument won it appendagesdown: the skin is the most important organ. The heart serves it. The bones support it. The muscles move it (and it even has its own). It protects all the stuff on the inside (which, I trust, would all fall out without it). Only the nervous system comes close, but where would it be without the embryonic ectoderm? Furthermore, as Ashley Montagu has so convincingly documented in his book on the importance
A skin biopsy contains the macromolecules present in most connective tissues: collagens, elastin, glycoproteins, and proteoglycans. The specific combination and assembly of these matrix components and their interactions with other structures (e.g., epidermal appendages, nerve and vascular networks) and cells are responsible for the distinction among specific regions of the dermis. The matrix components are interactive and interdependent and modification of one of them, by extrinsic (environmental) and/or intrinsic (systemic, genetic, age-related) factors, may have consequences on the tissue as a whole. The skin, therefore, provides a window through which it is possible to examine how mutations in one connective tissue macromolecule can change the interactions among matrix components and affect tissue structure and organization. Light and electron microscopic studies of skin from patients with inherited connective tissue disorders (e.g., Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome, cutis laxa) have led us to the following generalizations about what components change, how individual collagen or elastic fibers are altered and how individual alterations affect overall dermal organization: 1) There is a limited change in the repertoire of collagen fibrils in the skin; 2) there appears to be a greater range of abnormal structure in dermal elastic fibers than in the collagen fibrils; 3) the morphology of the fibroblastic cells may provide clues to the defect in matrix components; 4) similar structural abnormalities result from different molecular defect; 5) a molecular defect in one connective tissue molecule has consequences for the structural properties of other connective tissue components; and 6) although structural alterations in connective tissue fibers are rarely specific for a given disease, there are characteristic patterns of structural change in the matrix that may be used to confirm a diagnosis. These generalizations show that mutations rarely affect only a single aspect of macromolecular function and because of the interactions of matrix components in this complex organ (skin) often disturb the organization of the entire dermis. Genotype-phenotype relationships are important to understand if effective therapies are to be designed. The structure of skin should provide the next level of integration in our efforts to determine how mutations produce disease.
This research sought to quantify the handicapping effect of skin conditions in a far more rigorous way than had previously been attempted. One hundred people who had attended a hospital outpatient clinic during a specified period for treatment of their acne, psoriasis or eczema were interviewed in their homes. A comprehensive and structured interview schedule was used and interviewees were encouraged to talk at length about the impact that their skin conditions had had on their lives. Detailed data were collected that show the serious effect that these diseases can have in several domains. The findings record not only the physical discomfort and inconvenience sufferers may meet but also the consequences for their personal and social life and daily functioning. There is evidence from interviewees' employment experiences of limited opportunities, and functional and interpersonal difficulties in the workplace. 64% of people said that their skin disease affected their socio-economic activity. The extent to which sufferers experienced embarrassment, anxiety, a lack of confidence and depression is documented. 40% of people felt that their social life was affected and there was evidence of particular stresses and demands in personal relationships. The social impact of skin disease is discussed.
The development of physiochemical techniques for the fractionation and characterization of complex macromolecules, in addition to biologic and cell culture techniques, has provided significant advances toward an understanding of the role of these substances in normal and pathologic states. This review focuses on recent developments concerning acid mucopolysaccharides. Sufficient biochemistry has been included so that clinical manifestations in the mucopolysaccharidoses may be interpreted in the light of current metabolic concepts, but the review is not intended for those whose primary interest may extend to detailed considerations of acid mucopolysaccharide structure and metabolism.
Small skin biopsies of thirty-nine human subjects were assayed for the qualitative and quantitative analysis of glycosaminoglycans.
The following results were obtained:
Skin protects the organism from injury, maintains its homeostasis, adapts it to its environment, enhances or forms locomotory devices, secretes substances that attract or repel, and fashions certain purely ornamental structures.
The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.
Human fetal skin heals without scar formation when it is transplanted to a subcutaneous location on an adult athymic mouse and subsequently wounded. In contrast, human fetal skin of identical gestational age heals with scar formation when transplanted to a cutaneous location on the athymic mouse recipient. To determine if mouse (adult) or human (fetal) fibroblasts are healing the graft wounds, we performed indirect immunohistochemistry for mouse and human collagen types I and III. Full-thickness skin grafts (n = 51) from human fetuses at 18 weeks' (n = 4) or 24 weeks' (n = 2) gestational age were placed onto athymic mice in two locations: cutaneously onto a fascial bed and subcutaneously in a pocket under the murine panniculus carnosus. Linear incisions were made in each graft 7 days after transplantation. Grafts were harvested at 7, 14, and 21 days after wounding and stained with hematoxylin and eosin or Mallory's trichrome. Immunohistochemistry for either human collagen type I or type III or for mouse collagen type I was performed. The subcutaneous grafts healed with human collagen types I and III in a scarless pattern. The wound collagen pattern was reticular and unrecognizable from the surrounding dermis. Hair follicles and sebaceous gland patterns were unchanged in the wounded dermis. Conversely, the cutaneous grafts healed with mouse collagen in a scar pattern with disorganized collagen fibers and no appendages. Mouse collagen scar was present along the base of the cutaneous grafts and as a thin capsule around the subcutaneous grafts. We conclude that (1) subcutaneous grafts heal with human fetal collagen and no scar formation, and (2) cutaneous grafts heal with mouse collagen in a scar pattern. Fetal fibroblasts can heal fetal skin wounds without scar despite being perfused by adult serum and inflammatory cells in an adult environment. These data suggest that the fetal fibroblast is the major effector cell for scarless fetal skin repair.
To prove the existence of human intraepidermal nerve fibers at the electron microscopic level, we used both conventional and immunohistochemical ultrastructural techniques. Specimens were obtained from skin of the back, one of the most densely innervated areas of the human epidermis. The immunohistochemical marker protein gene product 9.5 was chosen because it is highly potent in labeling nerves. Thin nerve fibers were found in the basal, spinous, and granular layers of the epidermis with both techniques used, although it was more difficult to identify the nervous structures with the conventional method. The nerves appeared in the intercellular spaces and contacted keratinocyte cell bodies or cilia by membrane-membrane apposition, but without any specialized structures. Nerve fibers in the very superficial part of the vital human epidermis have not been described before at the ultrastructural level.
The basement membrane underlying epithelium of skin is generally believed to be of epithelial origin, but a mesenchymal contribution to the basement membrane has not been directly examined. The purpose of this study was to directly evaluate both epithelial and mesenchymal contributions to the basement membrane. Fetal bovine keratinocytes cultured on the surface of collagen gels in the absence of fibroblasts did not produce an ultrastructurally recognizable basement membrane; however, when these cells were cultured in the presence of dermal fibroblasts a basement membrane at the keratinocyte-fibroblast interface was produced after 1 week which was very similar in biochemical composition and ultrastructural appearance to dermal-epidermal basement membrane in human skin. When dual species cultures of bovine keratinocytes and human fibroblasts were analyzed by indirect immunofluorescent microscopy (IF)1 with human specific antibodies against basement membrane components, dermal fibroblasts were shown to synthesize and deposit type IV collagen, type VII collagen, and laminin in a linear manner into the basement membrane zone. Fetal bovine keratinocytes cultured in the presence or absence of fibroblasts synthesized and deposited type IV collagen, type VII collagen, laminin, K-laminin, kalinin, and basement membrane associated heparan sulfate proteoglycan (HSPG) into the underlying basement membrane zone. In organ culture, a subpopulation of fibroblasts initially migrating from human foreskin explants was found to stain strongly for types VII and IV collagen and laminin by IF whereas after subculture all cells showed a uniform low staining. Based on these observations we propose that differentiated fibroblasts exist adjacent to epithelial tissues in vivo which produce basement membrane components and assist in basement membrane assembly.
Cytochrome P450 enzymes metabolize various endogenous and exogenous small molecular weight compounds. Transport-associated proteins, such as P-glycoprotein, multidrug resistance-associated protein and lung resistance protein are overexpressed in drug-resistant cell lines, as well as in human tumors from various histologic origins, including malignant melanoma. Little is known about the expression and function of cytochrome enzymes and multidrug resistance-associated transport proteins in human skin; therefore, the aim of this study was to analyze the expression pattern of cytochrome enzymes and multidrug resistance-associated transport proteins in proliferating human epidermal keratinocytes under constitutive conditions and after induction with various inducers. Reverse transcription-polymerase chain reaction revealed constitutive expression of cytochromes 1A1, 1B1, 2B6, 2E1, and 3A5 in keratinocytes and showed expression of cytochrome 3A4 after incubation with dexamethasone. The expression of cytochrome 1A1 was enhanced on the mRNA level after induction with benzanthracene. Reverse transcription-polymerase chain reaction analysis of the multidrug resistance-associated transport proteins revealed constitutive expression of multidrug resistance-associated proteins 1 and 3-6, and lung resistance protein in human epithelial keratinocytes and was negative for multidrug resistance 1 and 2. Expression of 1 was seen after induction with dexamethasone. Reverse transcription-polymerase chain reaction results were confirmed by immunoblots which showed expression of cytochromes 1A1, 2B6, 2E1, and 3A, multidrug resistance-associated proteins 1, 3, and 5 as well as multidrug resistance 1 after induction with dexamethasone. Immunohistology showed positive immunofluorescence in skin specimens for cytochromes 1A1, 2B6, 2E1, and 3A and multidrug resistance-associated protein 1 and multidrug resistance 1. Constitutive activity of cytochrome 1A1, 2B, 2E1, and 3A enzymes was measured by catalytic assays. These results show that keratinocytes of the human skin express various transport-associated enzymes and detoxifying metabolic enzymes. Previous studies have revealed that cytochrome enzymes and transport-associated proteins play complementary parts in drug disposition by biotransformation (phase I) and anti-transport (phase III) and act synergistically as a drug bioavailability barrier.
Recent studies highlight characteristics of epidermal stem cells that were not fully appreciated before. Stem cells are multipotential and signals exchanged with their neighbours help to regulate exit from the stem cell compartment and differentiation along specific lineages. Stem cells exhibit a high degree of spatial organisation, and cell clustering and motility contribute to the assembly and maintenance of the epidermis.
Collagens and proteins with collagen-like domains form large superfamilies in various species, and the numbers of known family members are increasing constantly. Vertebrates have at least 27 collagen types with 42 distinct polypeptide chains, >20 additional proteins with collagen-like domains and approximately 20 isoenzymes of various collagen-modifying enzymes. Caenorhabditis elegans has approximately 175 cuticle collagen polypeptides and two basement membrane collagens. Drosophila melanogaster has far fewer collagens than many other species but has approximately 20 polypeptides similar to the catalytic subunits of prolyl 4-hydroxylase, the key enzyme of collagen synthesis. More than 1300 mutations have so far been characterized in 23 of the 42 human collagen genes in various diseases, and many mouse models and C. elegans mutants are also available to analyse the collagen gene family and their modifying enzymes.
