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The Journal of Clinical Investigation Apr 2019Allergic diseases have in common a dysfunctional epithelial barrier, which allows the penetration of allergens and microbes, leading to the release of type 2 cytokines... (Review)
Review
Allergic diseases have in common a dysfunctional epithelial barrier, which allows the penetration of allergens and microbes, leading to the release of type 2 cytokines that drive allergic inflammation. The accessibility of skin, compared with lung or gastrointestinal tissue, has facilitated detailed investigations into mechanisms underlying epithelial barrier dysfunction in atopic dermatitis (AD). This Review describes the formation of the skin barrier and analyzes the link between altered skin barrier formation and the pathogenesis of AD. The keratinocyte differentiation process is under tight regulation. During epidermal differentiation, keratinocytes sequentially switch gene expression programs, resulting in terminal differentiation and the formation of a mature stratum corneum, which is essential for the skin to prevent allergen or microbial invasion. Abnormalities in keratinocyte differentiation in AD skin result in hyperproliferation of the basal layer of epidermis, inhibition of markers of terminal differentiation, and barrier lipid abnormalities, compromising skin barrier and antimicrobial function. There is also compelling evidence for epithelial dysregulation in asthma, food allergy, eosinophilic esophagitis, and allergic rhinosinusitis. This Review examines current epithelial barrier repair strategies as an approach for allergy prevention or intervention.
Topics: Allergens; Animals; Cell Differentiation; Epidermis; Humans; Hypersensitivity; Inflammation; Keratinocytes
PubMed: 30776025
DOI: 10.1172/JCI124608 -
Journal of Anatomy Apr 2019Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the...
Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the use of such technology is the ability to produce tissue models that accurately reproduce the microanatomy of the native tissue. Current artificial cell-based skin systems lack thorough characterisation, are not representative of human skin, and can show variation. In this study, we have developed a novel full thickness model of human skin comprised of epidermal and dermal compartments. Using an inert porous scaffold, we created a dermal construct using human fibroblasts that secrete their own extracellular matrix proteins, which avoids the use of animal-derived materials. The dermal construct acts as a foundation upon which epidermal keratinocytes were seeded and differentiated into a stratified keratinised epithelium. In-depth morphological analyses of the model demonstrated very close similarities with native human skin. Extensive immunostaining and electron microscopy analysis revealed ultrastructural details such as keratohyalin granules and lamellar bodies within the stratum granulosum, specialised junctional complexes, and the presence of a basal lamina. These features reflect the functional characteristics and barrier properties of the skin equivalent. Robustness and reproducibility of in vitro models are important attributes in experimental practice, and we demonstrate the consistency of the skin construct between different users. In summary, a new model of full thickness human skin has been developed that possesses microanatomical features reminiscent of native tissue. This skin model platform will be of significant interest to scientists researching the structure and function of human skin.
Topics: Basement Membrane; Cell Differentiation; Cells, Cultured; Dermis; Epidermis; Extracellular Matrix Proteins; Fibroblasts; Humans; In Vitro Techniques; Keratinocytes; Microscopy, Electron; Skin; Tissue Engineering
PubMed: 30740672
DOI: 10.1111/joa.12942 -
International Journal of Molecular... Apr 2022Keratinocyte differentiation is an essential process for epidermal stratification and stratum corneum formation. Keratinocytes proliferate in the basal layer of the... (Review)
Review
Keratinocyte differentiation is an essential process for epidermal stratification and stratum corneum formation. Keratinocytes proliferate in the basal layer of the epidermis and start their differentiation by changing their functional or phenotypical type; this process is regulated via induction or repression of epidermal differentiation complex (EDC) genes that play a pivotal role in epidermal development. Epidermal development and the keratinocyte differentiation program are orchestrated by several transcription factors, signaling pathways, and epigenetic regulators. The latter exhibits both activating and repressive effects on chromatin in keratinocytes via the ATP-dependent chromatin remodelers, histone demethylases, and genome organizers that promote terminal keratinocyte differentiation, and the DNA methyltransferases, histone deacetylases, and Polycomb components that stimulate proliferation of progenitor cells and inhibit premature activation of terminal differentiation-associated genes. In addition, microRNAs are involved in different processes between proliferation and differentiation during the program of epidermal development. Here, we bring together current knowledge of the mechanisms controlling gene expression during keratinocyte differentiation. An awareness of epigenetic mechanisms and their alterations in health and disease will help to bridge the gap between our current knowledge and potential applications for epigenetic regulators in clinical practice to pave the way for promising target therapies.
Topics: Cell Differentiation; Chromatin; Epidermis; Epigenesis, Genetic; Keratinocytes
PubMed: 35563264
DOI: 10.3390/ijms23094874 -
Indian Journal of Dermatology,... 2022Background Melasma is an acquired dyschromia with several histologic alterations in the epidermis, basement membrane and upper dermis. The treatment of melasma is... (Randomized Controlled Trial)
Randomized Controlled Trial
Histological changes in facial melasma after treatment with triple combination cream with or without oral tranexamic acid and/or microneedling: A randomised clinical trial.
Background Melasma is an acquired dyschromia with several histologic alterations in the epidermis, basement membrane and upper dermis. The treatment of melasma is challenging due to the irregular response and chronicity of the disease. To date, there are no curative strategies, largely due to the limited understanding of the intrinsic effects of each treatment. Objectives The objective of the study was to evaluate the histological changes promoted by triple combination cream, with or without complementary treatment with microneedling and oral tranexamic acid, in the treatment of melasma. Methods A factorial, randomised, controlled and evaluator-blinded clinical trial was performed involving 64 women with facial melasma, divided in four groups, who underwent 60 days of treatment with triple combination cream alone (control group) or combined with two monthly microneedling sessions (microneedling group), TA 250 mg twice daily (tranexamic acid group), or both tranexamic acid group and microneedling group. The participants underwent biopsy of the area with melasma at inclusion (D1) and D60. The primary outcomes were the variation (D1 × D60) between the variables: Thickness of the epidermis and stratum corneum, stratum corneum compaction and solar elastosis; melanin density in the epidermis and upper dermis; proportion between the extension of the nonintact and intact basement membrane zone; mast cell count in the upper dermis; melanocyte count in the basal layer, pendulum melanocyte count and melanocyte area; immunostaining density of vascular endothelial growth factor; stem cell factor and keratinocyte growth factor. Results One participant in the TG discontinued tranexamic acid due persistent headache; and herpes simplex occurred in three patients after microneedling. The groups showed a 24% (CI95%: 17-35%; P < 0.01) reduction in epidermal melanin density. There was no change in dermal melanin density or the area of melanocytes after treatment. There was an overall 25% (CI95%: 7-42%; P < 0.01) reduction in the number of pendulum melanocytes, especially in the microneedling and tranexamic acid group, that presented a 41% (CI95%: 7-73%; P < 0.01) reduction. The extension of the nonintact basal membrane relative to the intact basal membrane decreased after treatment, especially in microneedling group and microneedling and tranexamic acid group. There was an increase of 13% (CI95%: 5-21%; P = 0.02) in epidermal thickness and 6% (CI95%: 0-22%; P = 0.04) thinning of the stratum corneum in the groups. All groups showed stratum corneum compaction. Solar elastosis improved only in the microneedling group and microneedling and tranexamic acid group. Vascular endothelial growth factor immunostaining increased 14% (CI95%: 4-24%; P = 0.03) in the groups; and stem cell factor increased only in microneedling group. There was no change in the number of mast cells, CD34 and keratinocyte growth factor immunostaining. Limitations The site of biopsy may not represent all of the facial melasma and the immunohistochemical sensitivity of the cytokines does not have a stoichiometric relationship with proteins. Conclusion A greater thickness of the epidermis is associated with melasma bleaching. Dermal melanin seems to have no impact on melasma prognosis. Damage to the skin barrier and stimulus of angiogenesis should be avoided in the treatment of melasma. Microneedling complements the topical treatment of melasma by improving patterns of skin photoaging. Oral tranexamic acid complements the topical treatment of melasma by inhibiting the stem cell factor.
Topics: Humans; Female; Tranexamic Acid; Fibroblast Growth Factor 7; Melanins; Vascular Endothelial Growth Factor A; Stem Cell Factor; Melanosis; Treatment Outcome
PubMed: 35389028
DOI: 10.25259/IJDVL_126_2021 -
International Journal of Cosmetic... Apr 2006People of skin of colour comprise the majority of the world's population and Asian subjects comprise more than half of the total population of the earth. Even so, the...
People of skin of colour comprise the majority of the world's population and Asian subjects comprise more than half of the total population of the earth. Even so, the literature on the characteristics of the subjects with skin of colour is limited. Several groups over the past decades have attempted to decipher the underlying differences in skin structure and function in different ethnic skin types. However, most of these studies have been of small scale and in some studies interindividual differences in skin quality overwhelm any racial differences. There has been a recent call for more studies to address genetic together with phenotypic differences among different racial groups and in this respect several large-scale studies have been conducted recently. The most obvious ethnic skin difference relates to skin colour which is dominated by the presence of melanin. The photoprotection derived from this polymer influences the rate of the skin aging changes between the different racial groups. However, all racial groups are eventually subjected to the photoaging process. Generally Caucasians have an earlier onset and greater skin wrinkling and sagging signs than other skin types and in general increased pigmentary problems are seen in skin of colour although one large study reported that East Asians living in the U.S.A. had the least pigment spots. Induction of a hyperpigmentary response is thought to be through signaling by the protease-activated receptor-2 which together with its activating protease is increased in the epidermis of subjects with skin of colour. Changes in skin biophysical properties with age demonstrate that the more darkly pigmented subjects retaining younger skin properties compared with the more lightly pigmented groups. However, despite having a more compact stratum corneum (SC) there are conflicting reports on barrier function in these subjects. Nevertheless, upon a chemical or mechanical challenge the SC barrier function is reported to be stronger in subjects with darker skin despite having the reported lowest ceramide levels. One has to remember that barrier function relates to the total architecture of the SC and not just its lipid levels. Asian skin is reported to possess a similar basal transepidermal water loss (TEWL) to Caucasian skin and similar ceramide levels but upon mechanical challenge it has the weakest barrier function. Differences in intercellular cohesion are obviously apparent. In contrast reduced SC natural moisturizing factor levels have been reported compared with Caucasian and African American skin. These differences will contribute to differences in desquamation but few data are available. One recent study has shown reduced epidermal Cathepsin L2 levels in darker skin types which if also occurs in the SC could contribute to the known skin ashing problems these subjects experience. In very general terms as the desquamatory enzymes are extruded with the lamellar granules subjects with lowered SC lipid levels are expected to have lowered desquamatory enzyme levels. Increased pores size, sebum secretion and skin surface microflora occur in Negroid subjects. Equally increased mast cell granule size occurs in these subjects. The frequency of skin sensitivity is quite similar across different racial groups but the stimuli for its induction shows subtle differences. Nevertheless, several studies indicate that Asian skin maybe more sensitive to exogenous chemicals probably due to a thinner SC and higher eccrine gland density. In conclusion, we know more of the biophysical and somatosensory characteristics of ethnic skin types but clearly, there is still more to learn and especially about the inherent underlying biological differences in ethnic skin types.
PubMed: 18492142
DOI: 10.1111/j.1467-2494.2006.00302.x -
The Journal of Investigative Dermatology Sep 2008Aquaporin-3 (AQP3) is a membrane transporter of water and glycerol expressed in plasma membranes in the basal layer keratinocytes of epidermis in normal skin. AQP3... (Review)
Review
Aquaporin-3 (AQP3) is a membrane transporter of water and glycerol expressed in plasma membranes in the basal layer keratinocytes of epidermis in normal skin. AQP3 expression in human skin is increased in response to skin stress in diseases such as atopic eczema, to various agents such as retinoic acid, and in skin carcinomas. AQP3-knockout mice have reduced stratum corneum water content and elasticity compared with wild-type mice, as well as impaired wound healing and epidermal biosynthesis. Reduced AQP3-dependent glycerol transport in AQP3-deficient epidermis appears to be responsible for these phenotype findings, as evidenced by reduced glycerol content in epidermis and stratum corneum in AQP3-knockout mice, and correction of the phenotype abnormalities by glycerol replacement. Recent data implicate AQP3 as an important determinant in epidermal proliferation and skin tumorigenesis, in which AQP3-knockout mice are resistant to tumor formation by a mechanism that may involve reduced cell glycerol content and ATP energy for biosynthesis. AQP3 is thus a key player in epidermal biology and a potential target for drug development.
Topics: Animals; Aquaporin 3; Biological Transport; Cell Transformation, Neoplastic; Epidermis; Glycerol; Humans; Mice; Mice, Knockout; Water; Wound Healing
PubMed: 18548108
DOI: 10.1038/jid.2008.70 -
Clinical, Cosmetic and Investigational... 2022The purpose of this study was to explore the expression of TNF-α and NF-κB/p65 in Lichen planus skin lesions and their correlation with the pathogenesis of Lichen planus.
PURPOSE
The purpose of this study was to explore the expression of TNF-α and NF-κB/p65 in Lichen planus skin lesions and their correlation with the pathogenesis of Lichen planus.
PATIENTS AND METHODS
The case group consisted of 30 individuals diagnosed with LP based on clinical and histopathologic examination. The control group consisted of 10 individuals from an Orthopedic Department with normal skin. TNF-α and NF-κB/p65 expression in skin tissue samples was detected by immunohistochemistry.
RESULTS
The immunohistochemical results showed that TNF-α and NF-κB/p65 expression levels were significantly higher in LP skin lesions than normal skin tissues (P ≤ 0.05). Positive TNF-α staining mainly occurred in the cytoplasm of keratinocytes of the stratum granulosum, stratum spinosum, and stratum basale in the epidermis and lymphocytes in the superficial dermis. Positive NF-κB/p65 staining mainly occurred in the nucleus and cytoplasm of keratinocytes of the stratum spinosum and stratum basale in the epidermis and lymphocytes in the superficial dermis.
CONCLUSION
TNF-α and NF-κB/p65 are overexpressed in cutaneous LP. The two are positively correlated in LP, suggesting that they both play essential roles in the pathogenesis of LP.
PubMed: 35941857
DOI: 10.2147/CCID.S372662