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Squamous cell carcinoma (SCC) is a common skin cancer, often caused by exposure to ultraviolet radiation (UVR). Recent studies have shown that changes in DNA methylation play a crucial role in the development of cancers. However, methylation patterns of SCC are not well characterised. Identifying biomarkers for the risk of developing SCC could be helpful for early detection and diagnosis and can potentially improve treatment and prevention strategies. This study aimed to investigate methylation changes in the epidermis of mice exposed to UVR for 24 weeks. We examined the DNA methylation levels of 260 199 CpGs using the Illumina Infinium Mouse Methylation BeadChip and studied the epidermis of UVR‐exposed and unexposed mice every 4 weeks for 24 weeks (n = 39). We identified CpGs with large differences in methylation levels (β‐values) between UVR‐exposed and unexposed mice. We also observed differences in the epigenetic age of these mice. We identified CpGs in Rev, Ipmk, Rad51b, Fgfr2, Fgfr3 and Ctnnb1 that may serve as potential biomarkers for SCC risk and could be helpful for the early detection and prevention of SCC. Further investigations are necessary to determine the biological functions and clinical significance of these CpGs. [ABSTRACT FROM AUTHOR]

Cornulin (CRNN) and repetin (RPTN) belong to the fused‐type S100 protein family. Although these proteins have been reported to be expressed in the granular layer of the epidermis and have been suggested to be associated with barrier formation in the epidermis, their exact function remains unclear. This study examined the effects of ultraviolet B (UVB) irradiation on CRNN and RPTN expression in human skin xenotransplantation. The CRNN expression increased in the granular layer of UVB‐irradiated skin 2 days after UVB irradiation compared to that in sham‐irradiated skin. Interestingly, CRNN signals were observed not only in the cytoplasm, but also in the peripheral regions of granular keratinocytes. In contrast, RPTN was rarely expressed in sham‐irradiated skin; however, RPTN signals were markedly increased in the granular layer of the UVB‐irradiated skin. In addition, activation of ERK1/2 and STAT3 was observed in UVB‐irradiated skin. Accordingly, the present study demonstrated that CRNN and RPTN are novel proteins whose expression can be increased by UVB irradiation. The activation of ERK1/2 and STAT3 may be associated with the regeneration of a UVB‐damaged epidermis, and CRNN and RPTN may be induced to repair any dysfunction in the epidermal barrier during this regeneration process. [ABSTRACT FROM AUTHOR]

Antibody‐secreting cells (ASCs) produce immunoglobulin (Ig) G and IgE autoantibodies in secondary lymphoid organs. Evidence also suggests their existence in the skin in various chronic inflammatory conditions, and in association with CXCL12 and CXCL13, they regulate the recruitment/survival of ASCs and germinal center formation to generate ASCs, respectively. However, the presence of IgG and IgE in bullous pemphigoid (BP) lesions needs to be addressed. Here, we aimed to analyse BP skin for the presence of IgG and IgE and the factors contributing to their generation, recruitment, and persistence. Skin samples from 30 patients with BP were stained to identify ASCs and the immunoglobulin type they expressed. The presence of tertiary lymphoid organ (TLO) elements, which generate ASCs in non‐lymphoid tissues, and the chemokines CXCL12 and CXCL13, which regulate the migration/persistence of ASCs in lymphoid tissues and formation of TLOs, respectively, were evaluated in BP skin. BP skin harboured ASCs expressing the two types of antibodies IgG and IgE. ASCs were found in high‐grade cellular aggregates containing TLO elements: T cells, B cells, CXCL12+ cells, CXCL13+ cells and high endothelial venules. IgG+ ASCs were detected among these aggregates, whereas IgE+ ASCs were dispersed throughout the dermis. CXCL12+ fibroblast‐like cells were located close to ASCs. The inflammatory microenvironment of BP lesions may contribute to the antibody load characteristic of the skin of patients with BP by providing a site for the presence of ASCs. CXCL13 and CXCL12 expression may contribute to the generation and recruitment/survival of ASCs, respectively. [ABSTRACT FROM AUTHOR]

The evolutionary establishment of an internal biological clock is a primordial event tightly associated with a 24‐h period. Changes in the circadian rhythm can affect cellular functions, including proliferation, DNA repair and redox state. Even isolated organs, tissues and cells can maintain an autonomous circadian rhythm. These cell‐autonomous molecular mechanisms are driven by intracellular clock genes, such as BMAL1. Little is known about the role of core clock genes and epigenetic modifications in the skin. Our focus was to identify BMAL1‐driven epigenetic modifications associated with gene transcription by mapping the acetylation landscape of histones in epithelial cells responding to injury. We explored the role of BMAL1 in epidermal wound and tissue regeneration using a loss‐of‐function approach in vivo. We worked with BMAL1 knockout mice and a contraction‐resistance wound healing protocol, determining the histone modifications using specific antibodies to detect the acetylation levels of histones H3 and H4. We found significant differences in the acetylation levels of histones in both homeostatic and injured skin with deregulated BMAL1. The intact skin displayed varied acetylation levels of histones H3 and H4, including hyperacetylation of H3 Lys 9 (H3K9). The most pronounced changes were observed at the repair site, with notable alterations in the acetylation pattern of histone H4. These findings reveal the importance of histone modifications in response to injury and indicate that modulation of BMAL1 and its associated epigenetic events could be therapeutically harnessed to improve skin regeneration. [ABSTRACT FROM AUTHOR]

In photoaged human skin, type I collagen fragmentation impairs dermal extracellular matrix (ECM) integrity, resulting in collapsed/contracted fibroblasts with reduced type I procollagen synthesis. Injections of cross‐linked hyaluronic acid (CL‐HA) reverse these deleterious changes. To investigate the time course and effects of biochemical changes induced by injected CL‐HA, particularly whether fibroblast activation leads to accumulation/deposition of dermal collagen, we injected CL‐HA into photoaged skin of human participants over 60 years‐old and performed biochemical/microscopic analyses of skin samples. Beginning 1 week post‐injection and lasting 6–9 months, fibroblasts exhibited activation, including increased immunostaining and gene expression of markers of type I collagen synthesis, such as heat shock protein 47 and components of the transforming growth factor‐β pathway. At 1 week post‐injection, multiphoton microscopy revealed elongation/stretching of fibroblasts, indicating enhanced dermal mechanical support. At 4 weeks, second‐harmonic generation microscopy revealed thick collagen bundles densely packed around pools of injected CL‐HA. At 12 months, accumulation of thick collagen bundles was observed and injected CL‐HA remained present in substantial amounts. Thus, by occupying space in the dermal ECM, injected CL‐HA rapidly and durably enhances mechanical support, stimulating fibroblast elongation and activation, which results in thick, densely packed type I collagen bundles accumulating as early as 4 weeks post‐injection and continuing for at least a year. These observations indicate that early and prolonged clinical improvement following CL‐HA injection results from space‐filling and collagen deposition. As type I collagen has an estimated half‐life of 15 years, our data provide the foundations for optimizing the timing/frequency of repeat CL‐HA injections. [ABSTRACT FROM AUTHOR]

Dermatological research relies on the availability of suitable models that most accurately reflect the in vivo situation. Primary keratinocytes obtained from skin reduction surgeries are not only limited by availability but have a short lifespan and show donor‐specific variations, which hamper the understanding of general mechanisms. The spontaneously immortalized keratinocyte cell line HaCaT displays chromosomal aberrations and is known to differentiate in an abnormal manner. To overcome these issues, we validated different engineered immortalized cell lines created from primary human keratinocytes (NHK) as model systems to study epidermal function. Cell lines either immortalized by the expression of SV40 large T antigen and hTERT (NHK‐SV/TERT) or by transduction with HPV E6/E7 (NHK‐E6/E7) were analysed for their growth and differentiation behaviour using 2D and 3D culture systems and compared to primary keratinocytes. Both cell lines displayed a robust proliferative behaviour but were still sensitive to contact inhibition. NHK‐E6/E7 could be driven into differentiation by Ca2+ switch, while NHK‐SV/TERT needed withdrawal from any proliferative signal to initiate a delayed onset of differentiation. In 3D epidermal models both cell lines were able to reconstitute a stratified epidermis and functional epidermal barrier. However, only NHK‐E6/E7 showed a degree of epidermal maturation and stratification that was comparable to primary keratinocytes. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum (PG) is a chronic neutrophilic disorder characterized by recurrent painful ulcers. Aseptic inflammation by neutrophils plays an essential role, and neutrophil extracellular traps (NETs) formation can contribute to the pathogenesis of PG. Seventy‐five patients were diagnosed as having PG in our department, among which 58 ulcerative, 4 bullous, 3 pustular and 10 vegetative type. We examined the 20 skin biopsy specimens (11 ulcerative, 3 bullous, 2 pustular and 4 vegetative type), and local NETs formation in various types of PG was compared among each type. The biopsied specimens were double labelled for myeloperoxidase, citrullinated histone H3. Immunofluorescent images indicated that the histopathologic location and depth of NETs formation in PG varied by the clinical subtypes. In ulcerative PG, NETs formation was observed in the upper to deep dermis. In bullous PG, NETs formation was mainly observed in the epidermis. Pustular type showed NETs formation in the epidermis near the pustules, and in vegetative type, showed NETs formation mainly in the upper dermis. These results indicate that NETting neutrophils play an important role in the pathogenesis of various forms of PG, although the location and depth of NETs formation in the skin lesion of PG differ depending on each type. Further studies are necessary to examine what factors identify different clinical features of PG. [ABSTRACT FROM AUTHOR]

The epidermis is an essential organ for life by retaining water and as a protective barrier. The epidermis is maintained through metabolism, in which basal cells produced from epidermal stem cells differentiate into spinous cells, granular cells and corneocytes, and are finally shed from the epidermal surface. This is epidermal turnover, and with aging, there is a decline in epidermis function. Other factors that may affect epidermal turnover include ultraviolet damage and genetic factors. These genetic factors are of particular interest as little is known. Although recent skin‐focused genome‐wide association studies (GWAS) have been conducted, the genetic regions associated with epidermal turnover are almost uninvestigated. Therefore, we conducted a GWAS on epidermal turnover in the Japanese population, using the corneocyte area, which correlates to the rate of epidermal turnover, as an indicator. As a result, rs2278431 (p = 1.29 × 10−7) in 19q13.2 was associated with corneocyte size. Furthermore, eQTL analysis suggested that rs2278431 was related to the SPINT2 gene. In addition, SPINT2 knockdown studies using epidermal keratinocytes revealed that SPINT2 is involved in keratinocyte proliferation and in corneocyte size regulation in reconstructed epidermis. These results suggest that rs2278431 is involved in the expression of SPINT2 and affects epidermal turnover. [ABSTRACT FROM AUTHOR]

The mechanotransduction of light‐touch sensory stimuli is considered to be the main physiological function of epidermal Merkel cells (MCs). Recently, however, MCs have been demonstrated to be also thermo‐sensitive, suggesting that their role in skin physiologically extends well beyond mechanosensation. Here, we demonstrate that in healthy human skin epidermal MCs express functional olfactory receptors, namely OR2AT4, just like neighbouring keratinocytes. Selective stimulation of OR2AT4 by topical application of the synthetic odorant, Sandalore®, significantly increased Piccolo protein expression in MCs, as assessed by quantitative immunohistomorphometry, indicating increased vesicle trafficking and recycling, and significantly reduced nerve growth factor (NGF) immunoreactivity within MCs, possibly indicating increased neurotrophin release upon OR2AT4 activation. Live‐cell imaging showed that Sandalore® rapidly induces a loss of FFN206‐dependent fluorescence in MCs, suggesting OR2AT4‐dependent MC depolarization and subsequent vesicle secretion. Yet, in contrast to keratinocytes, OR2AT4 stimulation by Sandalore® altered neither the number nor the proliferation status of MCs. These preliminary ex vivo findings demonstrate that epidermal MCs also exert OR‐dependent chemosensory functions in human skin, and invite one to explore whether these newly identified properties are dysregulated in selected skin disorders, for example, in pruritic dermatoses, and if these novel MC functions can be therapeutically targeted to maintain/promote skin health. [ABSTRACT FROM AUTHOR]

Exposure to the sun affects the skin and may eventually result in UV‐induced skin damage. It is generally known that hyaluronan (HA) is one of the main structural and functional components of the skin. However, UV‐related changes in the HA metabolism in the skin have not yet been elucidated. Using qRT‐PCR, confocal microscopy and LC–MS/MS we compared the naturally sun‐exposed (SE), sun‐protected, experimentally repeatedly UVA + UVB‐exposed and acutely (once) UVA + UVB irradiated skin of Caucasian women. The epidermis was harvested by means of suction blistering 24 h after the acute irradiation. In addition, the epidermis was compared with a UV‐irradiated in vitro reconstituted 3D epidermis (EpiDerm) and an in vitro 2D culture of normal human keratinocytes (NHEK). The amount of HA was found to be statistically significantly enhanced in the acutely irradiated epidermis. The acute UV evinced the upregulation of HA synthases (HAS2 and HAS3), hyaluronidases (HYAL2 and HYAL3), Cluster of differentiation 44 (CD44), and Cell Migration Inducing Proteins (CEMIP and CEMIP2), while only certain changes were recapitulated in the 3D epidermis. For the first time, we demonstrated the enhanced gene and protein expression of CEMIP and CEMIP2 following UV irradiation in the human epidermis. The data suggest that the HA metabolism is affected by UV in the irradiated epidermis and that the response can be modulated by the underlying dermis. [ABSTRACT FROM AUTHOR]

The translatability of research is highly dependent on models that recapitulate human tissues and organs. Here, we describe a procedure for the generation of human epidermis organotypic cultures (HEOCs) from primary keratinocytes isolated from foreskin and adult skin as well as from an immortalized keratinocyte cell line (KerTr). We tested several media conditions to develop a defined HEOC growing and expansion media. We characterized the HEOCs and show that in optimal culture conditions they express the proliferation marker Ki67, the basement membrane protein collagen 17 (col17) and the epidermal differentiation markers keratin 15 (K15), keratin 14 (K14), keratin 5 (K5), keratin 10 (K10), keratin 1 (K1), transglutaminase 1 (TGM1), transglutaminase 3 (TGM3) and filaggrin (FLG). Thus, they recapitulate the human epidermis and are stratified from the basal layer to the stratum corneum. These HEOC can be generated reproducibly on a large scale, making it an invaluable model for screening therapeutic compounds and also for the study of pathologies affecting the epidermis. [ABSTRACT FROM AUTHOR]

Recent data indicate that distinct skin areas show different microbial/chemical milieu. Keratinocytes (KC) respond to these stimuli by producing cytokine mediators. Therefore, we aimed to determine KC‐derived cytokine expression in distinct healthy skin regions (gland‐poor [GP], sebaceous gland‐rich [SGR] and apocrine gland‐rich [AGR]), and their changes in skin diseases of the given regions (atopic dermatitis [AD], papulopustular rosacea [PPR] and psoriasis). Cytokines were analysed at the mRNA and protein levels, and literature analysis was performed for functional categorization. The three regions showed characteristically different cytokine patterns. GP was featured by an IL‐25/IL‐33/IL‐36RA/IL‐38/IL‐18 cytokine milieu, SGR was characterized by IL‐23/IL‐17C/IL‐18, and AGR skin exhibited a mixed IL‐25/IL‐33/IL‐23/IL‐18 profile. Literature analyses revealed different homeostatic and proinflammatory roles of these cytokine patterns (Th2 related in GP, Th17 related in SGR and mixed Th2/Th17 in AGR). In skin diseases which are primarily epidermal cytokine‐driven (AD, PPR), the level of the regionally characteristic cytokines were further elevated, in contrast to the autoantigen‐driven psoriasis, where the cytokine pattern was independent from the localization. Healthy skin regions are equipped with different KC‐derived cytokine profiles, which may influence each region's capability of mediator production in certain types of dermatoses. [ABSTRACT FROM AUTHOR]

An in‐depth understanding of the mechanical properties of the dermis is indispensable to improve wound healing or slow‐down skin ageing. Despite crucial research issues for dermatological and cosmetic industries, very little is known about the mechanical behaviour of the dermis at nanoscale level. This knowledge is relevant not only to human skin but also to mouse skin since this animal model is widely used in basic and preclinical studies for skin biology and health. Here, we describe an original protocol that we developed to specifically measure the mechanical properties of mouse dermis using atomic force microscopy‐based nano‐indentation approach. Using horizontal cryosections (i.e. parallel to the skin surface) performed at different depths through the dermis of dorsal skin, our protocol allowed us to detect nanoscale mechanical changes between female and male dermis samples. We found that the dermis was softer (i) in females than in males and (ii) with depth within the dermis of male mice. We also quantified compositional differences between female and male skin dermis and found that increased extracellular matrix gene expression and type V collagen staining were associated with increased dermal stiffness in male mice, compared with females. Our results demonstrating a sexual dimorphism in the nanomechanical properties and molecular composition of mouse dermis, open the way to better consider sex‐related cutaneous differences to understand skin disease and to stimulate the development of female versus male‐specific products with more appropriate dermatological treatments and cosmetic interventions. [ABSTRACT FROM AUTHOR]

The decline of mitochondrial function throughout the lifespan is directly linked to the development of ageing phenotypes of the skin. Here, we assessed alterations in markers of epidermal mitochondrial energy metabolism as a function of skin age. Human skin samples from distinct anatomical regions were obtained during routine dermatological surgery from 21 young (27.6 ± 1.71 year) and 22 old (76.2 ± 1.73 year) donors. Sections of skin samples were analysed by immunohistochemistry for mitochondrial subunits of each electron transport chain complex (I‐V)/oxidative phosphorylation (OXPHOS), as well as proteins serving as a marker of mitochondrial mass (VDAC1) and the regulation of DNA transcription (TFAM). Staining intensities of ATP5F1A (comprising complex V) and TFAM in the epidermis of older subjects were significantly decreased compared with younger donors. Moreover, these effects were independent of UV exposure of the stained skin section. Overall, we demonstrate that ageing is associated with reduced protein levels of complex V of the mitochondrial respiratory chain and TFAM. These alterations may impair essential mitochondrial functions, exacerbating the cutaneous ageing process. [ABSTRACT FROM AUTHOR]

Skin ageing is an intricate physiological process affected by intrinsic and extrinsic factors. There is a demand to understand how the skin changes with age and photoexposure in individuals with Fitzpatrick skin types I‐III due to accelerated photoageing and the risk of cutaneous malignancies. To assess the structural impact of intrinsic and extrinsic ageing, we analysed 14 skin parameters from the photoprotected buttock and photoexposed dorsal forearm of young and ageing females with Fitzpatrick skin types II‐III (n = 20) using histomorphic techniques. Whilst the minimum viable epidermis (Emin) remained constant (Q > 0.05), the maximum viable epidermis (Emax) was decreased by both age and photoexposure (Q ≤ 0.05), which suggests that differences in epidermal thickness are attributed to changes in the dermal‐epidermal junction (DEJ). Changes in Emax were not affected by epidermal cell proliferation. For the first time, we investigated the basal keratinocyte morphology with age and photoexposure. Basal keratinocytes had an increased cell size, cellular height and a more columnar phenotype in photoexposed sites of young and ageing individuals (Q ≤ 0.05), however no significant differences were observed with age. Some of the most striking changes were observed in the DEJ, and a decrease in the interdigitation index was observed with both age and photoexposure (Q ≤ 0.001), accompanied by a decreased height of rête ridges and dermal papilla. Interestingly, young photoexposed skin was comparable to ageing skin across many parameters, and we hypothesise that this is due to accelerated photoageing. This study highlights the importance of skin care education and photoprotection from an early age. [ABSTRACT FROM AUTHOR]

It remains unclear how the multifunctional indoleamine neurohormone, melatonin, alters melanin production and melanocytes within intact human epidermis under physiologically relevant conditions. In the current pilot study, we aimed to clarify this in long‐term organ‐cultured, full‐thickness human eyelid skin, selected for its clinically recognized sensitivity to pigmentation‐modulatory hormones. Warthin‐Starry histochemistry showed that 100 μM melatonin significantly increased epidermal melanin content and melanocyte dendricity after 6 days of organ culture, even though tyrosinase activity in situ was inhibited, as assessed by quantitative immunohistomorphometry. While the higher melatonin dose tested here (200 μM) did not change epidermal melanization, but again inhibited tyrosinase activity, it increased the number and proliferation of both gp100+ epidermal melanocytes and keratinocytes as well as protein expression of the premelanosomal marker, gp100, ex vivo. Contrary to most previous studies, these eyelid skin organ culture results suggest that long‐term melatonin application exerts overall stimulatory, dose‐dependent effects on the epidermal pigmentary unit within intact human skin, which appear surprisingly tyrosinase‐independent. While these provocative preliminary findings require further work‐up and independent confirmation, they encourage one to systematically explore whether prolonged melatonin therapy can (re‐)stimulate melanogenesis and increase the pool/activity of epidermal melanocytes in hypopigmented skin lesions. [ABSTRACT FROM AUTHOR]

Skin surface pH has been identified as a key regulator of the epidermal homeostasis through its action on serine protease activity. These enzymes, like kallikreins (KLK), are responsible for the degradation of corneodesmosomes, the protein structures linking together corneocytes, and are regulated by Lympho‐Epithelial Kazal‐Type‐related Inhibitor (LEKTI). KLK activity increases at pH levels higher than physiological. An increase in skin surface pH has been observed in patients suffering from skin diseases characterized by impaired barrier function, like atopic dermatitis. In this work, we introduce an agent‐based model of the epidermis to study the impact of a change in skin surface pH on the structural and physiological properties of the epidermis, through the LEKTI‐KLK mechanism. We demonstrate that a less acidic pH, compared to the slightly acidic pH observed in healthy skin, is sufficient to significantly affect the water loss at the surface and the amount of irritant permeating through the epidermis. This weakening of the skin barrier function eventually results in a more intense skin inflammation following exposure to an external irritant. This work provides additional evidence that skin surface pH and serine proteases can be therapeutic targets to improve skin barrier integrity. [ABSTRACT FROM AUTHOR]

Inflammaging is a theory of ageing which purports that low‐level chronic inflammation leads to cellular dysfunction and premature ageing of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defence from the environment, particularly solar radiation. To better understand the impact of ageing and photoexposure on epidermal biology, we performed a system biology‐based analysis of photoexposed face and arm, and photoprotected buttock sites, from women between the ages of 20s to 70s. Biopsies were analysed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss and stratum corneum thickening. The SASP biomarkers IL‐8 and IL‐1RA/IL1‐α were consistently elevated in face across age and cis/trans‐urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic ageing were accelerated. Genes associated with differentiation and senescence showed increasing expression in the 30s whereas genes associated with hypoxia and glycolysis increased in the 50's. Proteomics comparing 60's vs 20's confirmed elevated levels of differentiation and glycolytic‐related proteins. Representative immunostaining for proteins of differentiation, senescence and oxygen sensing/hypoxia showed similar relationships. This system biology‐based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life. [ABSTRACT FROM AUTHOR]

Skin cancers are by far the most frequently diagnosed human cancers. The closely related transcriptional co‐regulator proteins YAP and TAZ (WWTR1) have emerged as important drivers of tumour initiation, progression and metastasis in melanoma and non‐melanoma skin cancers. YAP/TAZ serve as an essential signalling hub by integrating signals from multiple upstream pathways. In this review, we summarize the roles of YAP/TAZ in skin physiology and tumorigenesis and discuss recent efforts of therapeutic interventions that target YAP/TAZ in in both preclinical and clinical settings, as well as their prospects for use as skin cancer treatments. [ABSTRACT FROM AUTHOR]

Skin hyperpigmentation is commonly treated by topical drug application. Several naturally occurring compounds exhibit attractive biological effects including anti‐melanogenic activity. Chemically modified derivatives of those compounds are expected to be more efficient. However, efficacy and safety testing processes are of significant consideration to identify the most effective compound among them. Herein, we demonstrated a tiered approach to investigate the antipigmentation activity of 17 trans‐N‐coumaroyltyramine derivatives. First, we evaluated the in chemico antityrosinase activity, then the cytotoxicity of the most potent derivatives using a mitochondrial activity‐based assay, followed with the in vitro anti‐melanogenic activity in two dimensional (2D) monolayer human melanocytes. The selected derivatives were topically applied on a three dimensional (3D) pigmented‐reconstructed human epidermis (pRhE) containing melanocytes and keratinocytes to evaluate their depigmenting activity. Two of the 17 derivatives displayed a significant reduction in pigmentation in the 3D pRhE, comparable to kojic acid, a known tyrosinase inhibitor. In addition, a molecular docking experiment indicated an interaction of the three derivatives and tyrosinase, suggesting that these derivatives have potent anti‐melanogenic activity through tyrosinase inhibition. Our findings provide an alternative approach for investigating skin‐whitening agents, thereby facilitating the research and development of skin‐whitening products that need not be tested on animals. [ABSTRACT FROM AUTHOR]

The periderm is the outer layer of embryonic skin, which is essential for the development of the epidermis and the establishment of its barrier function. In humans, the periderm is a monolayer and is shed prenatally. The structure and fate of the mouse periderm remain puzzling. Using electron microscopy of mouse skin between the embryonic day 14.5 and the postnatal Day 2, we have assessed the periderm structure and its shedding patterns. In contrast to human periderm, the mouse periderm appears to be bilayered, comprising a presumably absorptive outer periderm with numerous microvilli and an inner periderm packed with specific (glycogen‐containing?) granules. The desmosomes between the inner periderm and the underlying epidermis are scarce, and they are totally absent between the inner and the outer periderm. The inner and outer periderms in mice are shed at different stages of development: the outer periderm is shed in utero in conjunction with barrier acquisition (E16‐18), while the inner periderm is retained postnatally. We assume that the bilayered structure of the mouse periderm and the postnatal retention of its inner layer represent the evolutionary adaptations in ancestral rodents which helps altricial newborns of their extant descendants to cope with acute dehydration right after birth and/or provides a substrate for proper bacterial colonization of newborn skin. [ABSTRACT FROM AUTHOR]

It was long considered that the role of epidermal keratinocytes is solely to construct a water‐impermeable protective membrane, the stratum corneum, at the uppermost layer of the skin. However, in the last two decades, it has been found that keratinocytes contain multiple sensory systems that detect environmental changes, including mechanical stimuli, sound, visible radiation, electric fields, magnetic fields, temperature and chemical stimuli, and also a variety of receptor molecules associated with olfactory or taste sensation. Moreover, neurotransmitters and their receptors that play crucial roles in the brain are functionally expressed in keratinocytes. Recent studies have demonstrated that excitation of keratinocytes can induce sensory perception in the brain. Here, we review the sensory and information processing capabilities of keratinocytes. We discuss the possibility that epidermal keratinocytes might represent the earliest stage in the development of the brain during the evolution of vertebrates. [ABSTRACT FROM AUTHOR]

Tissue engineering has been successful in reproducing human skin equivalents while incorporating new approaches such as three‐dimensional (3D) bioprinting. The latter method offers a plethora of advantages including increased production scale, ability to incorporate multiple cell types and printing on demand. However, the quality of printed skin equivalents compared to those developed manually has never been assessed. To leverage the benefits of this method, it is imperative that 3D‐printed skin should be structurally and functionally similar to real human skin. Here, we developed four bilayered human skin epidermal‐dermal equivalents: non‐printed dermis and epidermis (NN), printed dermis and epidermis (PP), printed epidermis and non‐printed dermis (PN), and non‐printed epidermis and printed dermis (NP). The effects of printing induced shear stress [0.025 kPa (epidermis); 0.049 kPa (dermis)] were characterized both at the cellular and at the tissue level. At cellular level, no statistically significant differences in keratinocyte colony‐forming efficiency (CFE) (p = 0.1641) were observed. In the case of fibroblasts, no significant differences in the cell alignment index (p < 0.1717) and their ability to contract collagen gel (p = 0.851) were detected. At the tissue levels, all the four skin equivalents were characterized using histological and immunohistochemical analysis with no significant differences found in either epidermal basal cell count, thickness of viable epidermis, and relative intensity of filaggrin and claudin‐1. Our results demonstrated that 3D printing can achieve the same high‐quality skin constructs as have been developed traditionally, thus opening new avenues for numerous high‐throughput industrial and clinical applications. [ABSTRACT FROM AUTHOR]

Pattern hair loss (PHL) is a chronic regressive condition of the scalp, where follicular miniaturisation and decreased scalp hair coverage occurs in affected areas. In all PHL cases, there is a measurable progressive shortening of the terminal hair growth duration, along with reduced linear growth rates. In both genders, PHL initially shows an increase in short telogen hairs ≤30 mm in length, reflecting a cycle completion of under 6 months in affected terminal hair follicles. To understand the miniaturisation process, we re‐examine the dynamics of miniaturisation and ask the question, "why do miniaturised hair follicles resist treatment?" In the light of recent developments in relation to hair regeneration, we looked back in the older literature for helpful clues "lost to time" and reprise a 1978 Hermann Pinkus observation of an array of elastin deposits beneath the dermal papilla following subsequent anagen/telogen transitions in male balding, originally described by Arao and Perkins who concluded that these changes provide a "morphologic marker of the entire biologic process in the balding scalp." Thus, we have reviewed the role of the elastin‐like bodies in hair pathology and we propose that alterations in elastin architecture may contribute to the failure of vellus‐like hair reverting back to their terminal status and may indicate a new area for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Particulate matter is suspected to be substantially involved in pollution‐induced health concerns. In fact, ultrafine particles (UFPs) contain polycyclic aromatic hydrocarbons (PAHs) known as mutagenic, cytotoxic and sometimes phototoxic. Since UFPs reach blood circulation from lung alveoli, deep skin is very likely contaminated by PAHs coming from either skin surface or blood. As photoreactive, benzo(a)pyrene (BaP) or indenopyrene (IcdP) is involved in the interplay between pollution and sunlight. In order to better characterize this process, experiments were carried out on reconstructed human epidermis (RHE) in a protocol mimicking realistic exposure. Concentrations of PAHs comparable to those generally reported in blood were used together with chronic irradiation to low dose UVA1. On a histological level, damaged cells mainly accumulated in a suprabasal situation, thus reducing living epidermis thickness. Stress markers such as IL1‐α or MMP3 secretion increased, and surprisingly, the histological position of Transglutaminase‐1 within epidermis was disturbed, whereas position of other differentiation markers (keratin‐10, filaggrin, loricrin) remained unchanged. When vitamin C was added in culture medium, a very significant protection involving all markers was noticed. In conclusion, we provide here a model of interest to understand the epidermal deleterious consequences of pollution and to select efficient protective compounds. [ABSTRACT FROM AUTHOR]

Emerging evidence has pointed to the noxious effects of senescent cells in various tissues, and senescent cells in the epidermis are known to accumulate with age. We hypothesized that there is a mechanism by which senescent cells in the epidermis are preferentially removed and that the function of such removal mechanism declines as age increases. In this study, we investigated whether Notch signalling is involved in such senescent cell removal. We found that Notch1 receptor was expressed more highly in p16INK4a‐positive senescent cells than in surrounding cells in human epidermis both in young and old subjects. On the other hand, the expression of its ligand JAG1 was decreased in the epidermis of aged subjects. When normal epidermal cells and UVB‐irradiated senescent cells were mixed and three‐dimensional reconstructed epidermis was developed in vitro, the senescent cells were preferentially removed from the basal layer and located in the upper layer. We also found that the depletion of senescent cells from the basal layer was suppressed by JAG1 knockdown in normal cells or using a Notch signalling inhibitor. From these results, Notch signalling may be involved in senescent cell removal in the epidermis and the age‐related decrease of JAG1 expression in the basal layer may lead to accumulation of senescent cells owing to reduced activation of Notch signalling. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator‐activated receptors (PPARs) are a family of nuclear hormone receptors. In skin, PPARs modulate inflammation, lipid synthesis, keratinocyte differentiation and proliferation and thus are important for skin barrier homeostasis. Accordingly, PPAR expression is altered in various skin conditions that entail epidermal barrier impairment, that is atopic dermatitis (AD) and psoriasis. Using human epidermal equivalents (HEEs), we established models of acute epidermal barrier impairment devoid of immune cells. We assessed PPAR and cytokine expression after barrier perturbation and examined effects of keratinocyte‐derived cytokines on PPAR expression. We show that acetone or SDS treatment causes graded impairment of epidermal barrier function. Furthermore, we demonstrate that besides IL‐1β and TNFα, IL‐33 and TSLP are highly relevant markers for acute epidermal barrier impairment. Both SDS‐ and acetone‐mediated epidermal barrier impairment reduce PPARG expression levels, whereas only SDS enhances PPARD expression. In line with findings in IL‐1β and TNFα‐treated HEEs, abrogation of IL‐1 signalling restores PPARG expression and limits the increase of PPARD expression in SDS‐induced epidermal barrier impairment. Thus, following epidermal barrier perturbation, keratinocyte‐derived IL‐1β and partly TNFα modulate PPARG and PPARD expression. These results emphasize a role for PPARγ and PPARβ/δ in acute epidermal barrier impairment with possible implications for diseases such as AD and psoriasis. [ABSTRACT FROM AUTHOR]

Expression of microRNAs (miRNAs) is often dysregulated in several cancers, including non‐melanoma skin cancer (NMSC). Individuals with vitiligo possess a deregulated miRnome along with a lower risk of developing NMSCs. We used data sets from our previously published studies on vitiligo epidermis to construct functional miRNA‐mRNA networks to understand the molecular basis underlying the lower incidence of NMSC observed in individuals with vitiligo. miRTarBase database was used to fetch the experimentally validated targets of differentially expressed miRNAs and two protein‐protein interaction (PPI) networks were constructed for the miRNA‐mRNA interactions (230 downregulated targets of 5 upregulated miRNAs and 47 upregulated mRNAs targeted by 12 downregulated miRNAs). Pathway enrichment analysis identified RNA biogenesis and transport as well as cell adhesion to be perturbed in vitiligo. Further, oncogenic transcription factors (OTFs) that were upregulated in publicly available squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) microarray data were compared with that of vitiligo to decode skin cancer‐specific molecular signatures. We identified three significantly upregulated miRNAs, miR‐31‐5p, miR‐31‐3p and miR‐194‐3p in lesional epidermis that could negatively regulate seven oncogenic transcription factors, FOXC1, AR, SP1, YY1, GLI2, TP53 and RARA, known to be over‐expressed in SCC or BCC. Taken together, our study identified a perturbed miRNA‐regulated transcriptome, which potentially confers protection to vitiligo skin from an increased incidence of NMSC. [ABSTRACT FROM AUTHOR]

Ultrasonic imaging is one of the most important diagnostic tools in clinical medicine due to its cost, availability and good correlation with pathological results. High‐frequency ultrasound (HFUS) is a technique used in skin science that has been little explored, especially in comparison with other sites and imaging techniques. HFUS shows real‐time images of the skin layers, appendages and skin lesions in vivo and can significantly contribute to advances in skin science. This review summarizes the potential applications of HFUS in dermatology and cosmetology, with a focus on quantitative tools that can be used to assess various skin conditions. Our findings showed that HFUS imaging is a reproducible and powerful tool for the diagnosis, clinical management and therapy monitoring of skin conditions. It is also a helpful tool for assessing the performance of dermatological products. This technique may eventually become essential for evaluating the performance of dermatological and cosmetic products. [ABSTRACT FROM AUTHOR]

Skin appearance is essential for self‐esteem and quality of life; consequently, skin care products represent a huge market. In particular, cosmeceuticals constitute a hybrid category of skin care formulations, at the interphase of cosmetics and pharmaceuticals, rationally designed to target (patho) physiological mechanisms aiming to enhance skin health and appearance. Cosmeceuticals are marketed as anti‐ageing, anti‐wrinkle, hair regrowth, skin whitening and wound healing agents with special emphasis on scar‐free healing. An overview on recent cutting‐edge advances concerning the discovery and development of enhanced performance cosmeceuticals by drug repositioning approaches is presented here. In this context, we propose "target repositioning," a new term, to highlight that druggable protein targets implicated in multiple diseases (hubs in the diseasome) can be exploited to accelerate the discovery of molecularly targeted cosmeceuticals that can promote skin health as an added benefit, which is a novel concept not described before. In this direction, emphasis is placed on the role of mouse models, for often untreatable skin diseases, as well as recent breakthroughs on monogenic rare skin syndromes, in promoting compound repositioning to innovative cosmeceuticals. [ABSTRACT FROM AUTHOR]

Culturing skin cells outside of the body has been a cornerstone of dermatological investigation for many years; however, human skin equivalent systems typically lack the full complexity of native skin. Notably, skin appendages, such as hair follicles and sweat glands, remain a challenge to generate or maintain in cell cultures and reconstruct in damaged skin. Recent work from our lab has demonstrated methods for generating appendage‐bearing skin tissue—known as skin organoids—from pluripotent stem cells. Here, we will summarize this work and other related works, and then discuss the potential future applications of skin organoids in dermatological research. [ABSTRACT FROM AUTHOR]

The hair follicle is a classical model for studying epithelial–mesenchymal interactions. Given the critical role of fibroblast growth factor 8 (Fgf8) in embryonic development, we generated a mouse model that overexpresses Fgf8 specifically in the epidermis. Interestingly, these mutant mice exhibited stunted, smaller bodies and severe hypotrichosis. Histological analysis showed that the hair follicles in the mutants were arrested at stage 2 of hair development. The density of hair follicles in the mutant mice was also lower compared to that in the control mice. Overexpression of Fgf8 inhibited the proliferation of epidermal cells and simultaneously promoted apoptosis, leading to the arrest of hair follicle development. Further analysis showed that sonic hedgehog (Shh) and bone morphogenetic protein 4 (Bmp4) were downregulated and upregulated, respectively. To summarize, our study demonstrates that FGF signalling plays an important role in the regulation of hair follicle development. [ABSTRACT FROM AUTHOR]

The emergence of hair is a defining event during mammalian skin development, but the cellular mechanisms leading to the opening of the hair follicle canal remain poorly characterized. Our previous studies have shown that early hair buds possess a central column of differentiated keratinocytes expressing Keratin 79 (K79), which marks the future hair follicle opening. Here, we report that during late embryogenesis and early postnatal development, K79+ cells at the distal tips of these columns downregulate E‐cadherin, change shape, recede and undergo cell death. These changes likely occur independently of sebaceous glands and the growing hair shaft, and serve to create an orifice for hair to subsequently emerge. Defects in this process may underlie phenomena such as ingrown hair or may potentially contribute to upper hair follicle pathologies including acne, hidradenitis suppurativa and infundibular cysts. [ABSTRACT FROM AUTHOR]

Acne is an inflammatory skin disease of the pilosebaceous unit, involving four essential factors: hyperseborrhoea combined to a modification of sebum composition, colonization by Cutibacterium (C.) acnes, hyperkeratinization and secreted inflammation. Understanding and mimicking compromised skin is essential to further develop appropriate therapeutic solutions. This study aimed to develop new in vitro 3D models mimicking acneic skin, by combining two main factors involved in the physiopathology, namely, altered sebum composition and C. acnes invasion. Normal human keratinocytes were first used to generate reconstructed human epidermis (RHE) that were then left untreated (control) or treated topically with a combination of both peroxidized squalene and C. acnes cultures. Once validated, this model considered relevant to mimic acneic skin, was further improved by using different phylotypes of C. acnes strains specifically isolated from healthy and acneic patients. While both phylotypes IB and II did not significantly alter RHE, C. acnes IA1 strains induce major acneic skin hallmarks such as hyperkeratinization, secreted inflammation and altered barrier function. Interestingly, these results are obtained independently of the origin of IA1 phylotypes (acneic vs. healthy patient), thus suggesting a role of the ecosystem in controlling C. acnes virulence in healthy skin. In conclusion, by combining two major factors involved in the physiopathology of acne, we (1) succeeded to design in vitro 3D models mimicking this skin disorder and (2) highlighted how C. acnes phylotypes can have an impact on epidermal physiology. These relevant models will be suitable for the substantiation of therapeutic molecules dedicated to acne treatment. [ABSTRACT FROM AUTHOR]

Recently, increasing attention has been paid to senescence‐associated secretory phenotype (SASP), a phenomenon that senescent cells secrete molecules such as inflammatory cytokines and matrix metalloproteinases (MMPs), due to its noxious effects on the surrounding tissue. Senescent cells in the blood and liver are known to be properly depleted by macrophages. In the dermis, accumulation of senescent cells has been reported and is thought to be involved with skin ageing. In this study, to elucidate the clearance mechanism of senescent cells in the dermis, we focused on macrophage functions. Our co‐culture experiments of senescent fibroblasts and macrophages revealed a two‐step clearance mechanism: first, TNF‐α secreted from macrophages induces apoptosis in senescent fibroblasts, and then, dead cells are phagocytosed by macrophages. Furthermore, it was suggested that SASP factors suppress both of the two steps of the senescent cell clearance by macrophages. From these findings, normally senescent cells in the dermis are thought to be removed by macrophages, but when senescent cells are excessively accumulated owing to oxidative stress, ultraviolet (UV) ray or other reasons, SASP was suggested to suppress the macrophage‐dependent clearance functions and thereby cause further accumulation of senescent cells. [ABSTRACT FROM AUTHOR]

Human skin is particularly vulnerable to age‐related deterioration and undergoes profound structural and functional changes, reflected in the external skin appearance. Skin ageing is characterized by features such as wrinkling or loss of elasticity. Even if research advances have been done concerning the molecular mechanisms that underlie these changes, very few studies have been conducted concerning the structure stiffness of the skin organ as a whole. In this study, we showed, thanks to human skin reconstructs and the Japanese Medaka fish model, that biomechanics is a new biomarker of skin ageing. We revealed that global stiffness measurement by Atomic Force Microscopy, since modulated through ageing in these models, can be a new biomarker of skin ageing, and reflects the profound reorganization of the dermis extracellular matrix, as shown by Transmission Electron Microscopy. Moreover, our data unveiled that the Japanese Medaka fish could represent a highly relevant integrated model to study skin ageing in vivo. [ABSTRACT FROM AUTHOR]

Differentiation of normal human keratinocytes (NHK) grown in vitro as a monolayer to confluency can be triggered with an acute increase in concentration of extracellular Ca++. Over several days, induced by Ca++, the cells form pseudostratified sheets that somewhat resemble the basic organization of the intact skin. This experimental system is widely used in studies of keratinocyte biology and skin pathology. However, expression pattern of the genes considered as markers for cells in specific layers of epidermis in vivo does not always match the specific pattern observed in vitro and might lead to misinterpretation of data. Here, we demonstrate that among 18 markers of terminally differentiated keratinocytes of stratum granulosum (SG) and stratum corneum (SC) in vivo, only four (CDSN, KPRP, LCE1C and SPRR4) have reproduced their expression pattern in vitro. Our data suggest that findings based on two‐dimensional (2D) Ca++‐induced terminal differentiation of NHK in vitro should be subjected to additional scrutiny before conclusions could be made and, if possible, verified in other experimental system that might more faithfully represent the in vivo microenvironment. [ABSTRACT FROM AUTHOR]

The proper development and function of skin and hair are dependent on proteolytic activities. Specifically, the matriptase-prostasin cascade is a series of proteolytic reactions in the epidermis integral to normal regulation of desquamation. An increasing amount of research describing this pathway has recently become available, and the importance of this pathway is exhibited by the association of genetic defects in this pathway with human diseases of the skin and hair. Given the relevance of this pathway to dermatology, we provide a review of the current understanding of its relevance to distinct clinical entities, including ichthyosis-hypotrichosis and Netherton syndromes. [ABSTRACT FROM AUTHOR]

Epidermal energy metabolism is relevant to skin physiology, ageing and photodamage. While selected hormones stimulate epidermal keratinocyte mitochondrial activity, its negative regulation remains unknown. In several cell types, cannabinoid receptor 1 (CB1) is expressed both on the cell membrane (cmCB1) and on the mitochondrial outer membrane (mtCB1), where its stimulation directly suppresses mitochondrial functions. In the current pilot study, we investigated if CB1 is a negative regulator of human epidermal energy metabolism under physiological conditions. Using organcultured full-thickness human skin specimens of healthy individuals, we showed that antagonizing the homeostatic CB1 signalling by the administration of the CB1 inverse agonist AM251 increased respiratory chain complex I and II/IV activity. The effect was CB1-dependent, since the CB1-selective agonist arachidonyl-2'-chloroethylamide could prevent the effect. Moreover, the phenomenon was also reproduced by siRNAmediated down-regulation of CB1. As revealed by the unaltered expression of several relevant markers (TFAM, VDAC1, MTCO1 and NDUFS4), modulation of CB1 signalling had no effect on the epidermal mitochondrial mass. Next, by using immunoelectron microscopy, we found that human epidermal keratinocytes express both cmCB1 and mtCB1. Finally, by using equipotent extracellularly restricted (hemopressin) as well as cell-permeable (AM251) inverse agonists, we found that mitochondrial activity is most likely exclusively regulated by mtCB1. Thus, our data identify mtCB1 as a novel negative regulator of keratinocyte mitochondrial activity in intact human epidermis, and raise the question, whether topical therapeutic interventions capable of selectively activating mtCB1 can reduce excessive mitochondrial ROS production resulting from dysregulated mitochondrial activity during skin ageing or photodamage. [ABSTRACT FROM AUTHOR]

An inadequate response from macrophages, key orchestrators of the wound healing process, has been implicated in the pathophysiology of impaired healing in diabetes. This study explored the utility of nanoparticles presenting the α‐gal (Galα1‐3Galβ1‐4GlcNAc‐R) epitope to induce anti‐Gal antibody‐mediated local transient recruitment of macrophages to accelerate wound closure and healing in a diabetic murine model. α1,3galactosyltrasferase knockout mice were stimulated to produce anti‐Gal antibodies and subsequently diabetes was induced by streptozotocin‐induced β‐cell destruction. Six mm full‐thickness skin wounds were made and α‐gal nanoparticles (AGN) were topically applied on postwounding days 0 and 1. Wounds were analysed histologically for macrophage invasion and markers of wound healing, including epithelialization, vascularization and granulation tissue deposition through postoperative day 12. We found that application of AGN transiently but significantly increased macrophage recruitment into the wounds of diabetic mice. Treated wounds demonstrated more rapid closure and enhanced wound healing as demonstrated by significantly accelerated rates of epithelialization, vascularization and granulation tissue deposition. Thus, topical treatment of full‐thickness wounds in diabetic mice with α‐gal nanoparticles induced a transient but significant increase in macrophage recruitment resulting in an accelerated rate of wound healing. Using α‐gal nanoparticles as a topical wound healing adjunct is a simple, safe and effective means of augmenting dysregulated macrophage recruitment present in the diabetic state. [ABSTRACT FROM AUTHOR]

Long non‐coding RNAs have been implicated in the regulation of a plethora of biological processes, yet it has been challenging to verify that they are truly not coding for proteins. Terminal differentiation‐induced non‐coding RNA (TINCR) is a 3.7‐kilobase mRNA that is highly abundant in epidermal keratinocytes prior to cornification. Here, we report the presence of an evolutionarily conserved open reading frame in TINCR and the identification of peptides derived from this open reading frame in the proteome of human stratum corneum. Our results demonstrate that TINCR is a protein‐coding RNA and suggest that the TINCR‐encoded protein is involved in keratinocyte cornification. [ABSTRACT FROM AUTHOR]

The water and glycerol channel, aquaporin‐3 (AQP3), plays an important role in the skin epidermis, with effects on hydration, permeability barrier repair and wound healing; therefore, information about the mechanisms regulating its expression is important for a complete understanding of skin function physiologically and in disease conditions. We previously demonstrated that histone deacetylase inhibitors (HDACi) induce the mRNA and protein expression of AQP3, in part through the p53 family, transcription factors for which acetylation is known to affect their regulatory activity. Another set of transcription factors previously shown to induce AQP3 expression and/or regulate skin function are the peroxisome proliferator‐activated receptors (PPARs). Since there are reports that PPARs are also acetylated, we examined the involvement of these nuclear hormone receptors in HDACi‐induced AQP3 expression. We first verified that a PPARγ agonist upregulated AQP3 mRNA and protein levels and that this increase was blocked by a PPARγ antagonist. We then showed that the PPARγ antagonist also inhibited AQP3 expression induced both by a broad‐spectrum HDACi and an HDAC3‐selective inhibitor. Interestingly, a PPARα antagonist also inhibited HDACi‐induced AQP3 expression. These antagonist effects were observed in both primary mouse and normal human keratinocytes. Furthermore, PPARγ overexpression enhanced HDACi‐stimulated AQP3 mRNA levels. Thus, our results suggest that PPARγ and/or PPARα may play a role in regulating AQP3 levels in the skin; based on the ability of PPAR agonists to promote epidermal differentiation and/or inhibit proliferation, topical PPAR agonists might be considered as a therapy for hyperproliferative skin disorders, such as psoriasis. [ABSTRACT FROM AUTHOR]

Sensitive skin is defined by the occurrence of unpleasant sensations such as tingling, burning, tautness, itching or pain. Mechanisms explaining sensitive skin are controversial, and many hypotheses have been proposed. Because sensitive skin is primarily characterized by a wide variety of neuropathic‐like symptoms, it is highly likely that neurosensory dysfunction in the skin represents one of the pathological mechanisms of sensitive skin. This hypothesis does not exclude other explanations like role of keratinocyte, transient receptor potential channels, vasculature or environmental factors. Nevertheless, the role of the nervous system in the development of sensitive skin is crucial, and growing evidence supports this hypothesis. Pain and pruritus described by patients with sensitive skin correspond to neuropathic component, and its assessment shows an increase in neuropathic measures (DN‐4, Douleur Neuropathique 4) compared with control. These sensations are similar to the sensations observed in small‐fibre neuropathy (SFN), which is a group of disorders that affect thin nerve fibres. One study on the pathophysiology of sensitive skin demonstrated that intra‐epidermal nerve fibre density, especially of peptidergic C‐fibres, was lower in the sensitive skin group. A recent study showed a modification in heat‐pain detection threshold in patients with sensitive skin. All these results indicate that C‐fibre damage can help explain sensitive skin. Consequently, the role of the nervous system is increasingly obvious. Nevertheless, keratinocytes and other epidermal cells closely participate in sensory transduction. Therefore, the results of neurophysiological studies should be interpreted in the light of this information that the whole epidermis represents a huge polymodal nociceptor. [ABSTRACT FROM AUTHOR]

Fragmentation of collagen fibrils and aberrant elastic material (solar elastosis) in the dermal extracellular matrix (ECM) is among the most prominent features of photodamaged human skin. These alterations impair the structural integrity and create a dermal microenvironment prone to skin disorders. The objective of this study was to determine the physical properties (surface roughness, stiffness and hardness) of the dermal ECM in photodamaged and subject‐matched sun‐protected human skin. Skin samples were sectioned and analysed by histology, atomic force microscopy and nanoindentation. Dermal ECM collagen fibrils were more disorganized (ie, rougher surface), and the dermal ECM was stiffer and harder, in photodamaged forearm, compared to sun‐protected underarm skin. Cleavage of collagen fibrils in sun‐protected underarm dermis by recombinant human matrix metalloproteinase‐1 resulted in rougher collagen fibril surface and reduced dermal stiffness and hardness. Degradation of elastotic material in photodamaged skin by treatment with purified neutrophil elastase reduced stiffness and hardness, without altering collagen fibril surface roughness. Additionally, expression of two members of the lysyl oxidase gene family, which insert cross‐links that stiffen and harden collagen fibrils, was elevated in photodamaged forearm dermis. These data elucidate the contributions of fragmented collagen fibrils, solar elastosis and elevated collagen cross‐linking to the physical properties of the dermal ECM in photodamaged human skin. This new knowledge extends current understanding of the impact of photodamage on the dermal ECM microenvironment. [ABSTRACT FROM AUTHOR]

The biomechanical properties of the collagenous dermal matrix are well described but responses to mechanical force by the hair follicles have not been characterised so far. We applied a pulling force on hair follicles to visualise and quantify changes in the keratin‐14 and involucrin‐positive cell layers of the follicles using nuclear dimensions as an indicator of tissue deformation. Moreover, we used second‐harmonic generation imaging to visualise changes in the dermal collagen. We report how the anatomical regions of the follicle respond to the force. Nuclei of the isthmus region were most affected. The nuclei in both K14‐positive outer root sheath cells and in involucrin‐positive cells were significantly compressed, whereas the response in the infundibulum and suprabulbar regions was more variable. The deformation of the nuclei did not correlate with lamin A/C expression. The changes in the collagenous matrix were distinct at different depths of the dermis as collagen fibrils were compressed closer to each other in the region adjacent to upper suprabulbar follicle and pulled apart near the infundibulum. Thus, the responses to the force are locally defined and the cells in the permanent and cycling parts of the follicle behave differently. [ABSTRACT FROM AUTHOR]

Skin surface is constantly exposed to environmental and secreted stressors such as UV, air pollution and peroxidized sebum. The current study aims to use reconstructed human skin equivalents to demonstrate topical stressor‐induced hyperpigmentation and evaluate bioactives' potential protective effect. Given that polycyclic aromatic hydrocarbons are representative airborne particle‐bound organic compounds with known relevance to pigmentation pathways, benzo(a)pyrene was selected as surrogate environmental toxin. On the other hand, squalene monohydroperoxides are well‐characterized sebum peroxidation product under UV and pollutant exposure, thus are used as another representative skin stressor. With 3‐day continuous exposure, 30 pmol/cm2 of benzo(a)pyrene and 3.4 nmol/cm2 of squalene monohydroperoxides induced significant viability loss, inflammatory response, and approximately 10 shades of pigmentation increase in pigmented living skin equivalents. At the same time, pretreatment and co‐treatment with 12‐hydroxystearic acid (12‐HSA, 20 μmol/L) or niacinamide (5 mmol/L) ameliorated such stressor‐induced consequences. Niacinamide was particularly effective against benzo(a)pyrene damage, probably as a substrate for important NAD+ dependent detoxification pathways, while 12‐HSA was potent against squalene monohydroperoxides through barrier enhancing, anti‐inflammatory, and anti‐oxidative mechanisms. In summary, topical stressor‐induced hyperpigmentation was achieved in vitro, with known bioactives showing protective benefits. [ABSTRACT FROM AUTHOR]

Members of the Acomys genus, known as spiny mice, are unique among mammals in being perfectly capable of regenerating large areas of skin that have been removed. During this regenerative process hairs, sebaceous glands, erector pili muscles, adipocytes and the panniculus carnosus all regenerate and the dermis does not scar. We review here the processes that the epidermis and the individual components of the dermis undergo during spiny mouse regeneration as well as the molecules that have been identified as potentially important in regeneration. We then relate this to what has been proposed as playing a role in studies from the laboratory mouse, Mus musculus. Differences in the immune systems of spiny mice and laboratory mice are also highlighted as this is suggested to play a part not only in the perfect wound healing that embryos display but also in regeneration in lower vertebrates. [ABSTRACT FROM AUTHOR]

While every jawed vertebrate, or its recent ancestor, possesses teeth, skin appendages are characteristic of the living clades: skin denticles (odontodes) in chondrichthyans, dermal scales in teleosts, ducted multicellular glands in amphibians, epidermal scales in squamates, feathers in birds and hair‐gland complexes in mammals, all of them showing a dense periodic patterning. While the odontode origin of teleost scales is generally accepted, the origin of both feather and hair is still debated. They appear long before mammals and birds, at least in the Jurassic in mammaliaforms and in ornithodires (pterosaurs and dinosaurs), and are contemporary to scales of early squamates. Epidermal scales might have appeared several times in evolution, and basal amniotes could not have developed a scaled dry integument, as the function of hair follicle requires its association with glands. In areas such as amnion, cornea or plantar pads, the formation of feather and hair is prevented early in embryogenesis, but can be easily reverted by playing with the Wnt/BMP/Shh pathways, which both imply the plasticity and the default competence of ectoderm. Conserved ectodermal/mesenchymal signalling pathways lead to placode formation, while later the crosstalk differs, as well as the final performing tissue(s): both epidermis and dermis for teeth and odontodes, mostly dermis for teleosts scales and only epidermis for squamate scale, feather and hair. We therefore suggest that tooth, dermal scale, epidermal scale, feather and hair evolved in parallel from a shared placode/dermal cell unit, which was present in a common ancestor, an early vertebrate gnathostome with odontodes, ca. 420 million years ago. [ABSTRACT FROM AUTHOR]

Carbonylated proteins (CPs) are synthesized by reactions between amino groups in proteins and reactive aldehyde compounds (RAC) yielded from lipid peroxidation initiated by reactive oxygen species (ROS). In the skin, CPs are detected in a higher frequency at sun‐exposed sites of the skin in elderly subjects. Since CPs in the stratum corneum (SC) have been reported to correlate with skin water content and transepidermal water loss, it is considered that the accumulation of CPs in the SC involves the loss of skin moisture functions. However, the roles of CPs in the dermis on skin physiology are still unclear. The purpose of this study was to investigate the roles of CPs in the dermis during the progression of photoaged skin and to propose a method to prevent or reduce the synthesis of CPs. The exposure of human normal dermal fibroblasts to CPs increased intracellular ROS levels and the synthesis of intracellular CPs. In addition, CPs caused morphological changes of fibroblasts. Furthermore, CPs caused alterations of mRNA expression levels of dermal matrix‐related proteins, such as upregulating MMP‐1 and IL‐8. These results indicated that CPs disrupt construction of the dermal matrix. On the other hand, α‐tocopherol and β‐carotene suppressed the synthesis of RAC during lipid peroxidation which resulted in the reduction of UVA‐induced CPs in the SC. From these results, we propose that extracellular CPs increase intracellular ROS levels and contribute to alterations of the dermal matrix. To prevent the synthesis of CPs, the application of α‐tocopherol or β‐carotene could be effective. [ABSTRACT FROM AUTHOR]

Thioglycolate is a potent depilatory agent. In addition, it has been proposed to be useful as a penetration enhancer for transepidermal drug delivery. However, the effects on hair structure and stress responses it elicits in epidermal keratinocytes have not been fully characterised. We have used label‐free confocal and fluorescence lifetime imaging supported by electron microscopy to demonstrate how thioglycolate damages hair cuticle cells by generating breakages along the endocuticle and leading to swelling of cortex cells. Maleimide staining of free SH‐groups and a decrease in the average fluorescence lifetime of endogenous fluorophores demonstrate a specific change in protein structure in both hair cuticle and cortex. We found that the thioglycolate damages cornified envelopes isolated from the stratum corneum of the epidermis. However, thioglycolate‐treated epidermal equivalent cultures recover within 48 hours, which highlights the reversibility of the damage. HaCaT keratinocytes respond to thioglycolate by increased proliferation, onset of differentiation and expression of the chaperone protein Hsp 70, but not Hsp 27. Up‐regulation of involucrin can be blocked by an application of c‐Jun N–terminal kinase (JNK) inhibitor, but the up‐regulation of Hsp 70 takes place regardless of the presence of the JNK inhibitor. [ABSTRACT FROM AUTHOR]