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Everts HBEndogenous retinoids in the hair follicle and sebaceous gland. Biochim Biophys Acta 1821:222-229
Abstract
Vitamin A and its derivatives (retinoids) are critically important in the development and maintenance of multiple epithelial tissues, including skin, hair, and sebaceous glands, as shown by the detrimental effects of either vitamin A deficiency or toxicity. Thus, precise levels of retinoic acid (RA, active metabolite) are needed. These precise levels of RA are achieved by regulating several steps in the conversion of dietary vitamin A (retinol) to RA and RA catabolism. This review discusses the localization of RA synthesis to specific sites within the hair follicle and sebaceous gland, including their stem cells, during both homeostasis and disease states. It also discusses what is known about the specific roles of RA within the hair follicle and sebaceous gland. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.
... These expression patterns suggested that HGF and MSP may regulate the hair follicle cycle and maintain hair growth to some extent. A recent review summarised the role of endogenous retinoids in the hair follicle and revealed that retinoids were critically important in the development and maintenance of the hair follicle [46]. Four retinoids, including LRAT, RDH16, SDR9C7 and SDR16C6, were differentially expressed among different stages (Table 4). ...
... Four retinoids, including LRAT, RDH16, SDR9C7 and SDR16C6, were differentially expressed among different stages (Table 4). LRAT, RDH16 and SDR9C7 were reported to be associated with cellular retinol metabolism in the skin [46]–[48]. They may play important roles in different developmental events during cashmere goat hair follicle cycling. ...
Cashmere goat (Capra hircus) hair follicle development and cycling can be divided into three stages: anagen, catagen and telogen. To elucidate the genes involved in hair follicle development and cycling in cashmere goats, transcriptome profiling of skin was carried out by analysing samples from three hair follicle developmental stages using RNA-Seq. The RNA-Seq analysis generated 8487344, 8142514 and 7345335 clean reads in anagen, catagen and telogen stages, respectively, which provided abundant data for further analysis. A total of 1332 differentially expressed genes (DEGs) were identified, providing evidence that the development of hair follicles among the three distinct stages changed considerably. A total of 683 genes with significant differential expression were detected between anagen and catagen, 530 DEGs were identified between anagen and telogen, and 119 DEGs were identified between catagen and telogen. A large number of DEGs were predominantly related to cellular process, cell & cell part, binding, biological regulation and metabolic process among the different stages of hair follicle development. In addition, the Wnt, Shh, TGF-β and Notch signaling pathways may be involved in hair follicle development and the identified DEGs may play important roles in these signaling pathways. These results will expand our understanding of the complex molecular mechanisms of hair follicle development and cycling in cashmere goats and provide a foundation for future studies.
... Vitamin A and its derivatives (retinoids) are important for development and maintenance of multiple epithelial tissues including skin, hair, and sebaceous glands, as severe, adverse effects are seen in vitamin A deficiency or excess (Everts, 2012; Smith and Thiboutot, 2008; Zouboulis, 2006). Vitamin A is stored in the liver and extra-hepatic tissues as retinyl esters (O'Byrne et al., 2005). ...
... Retinoic acid (RA) synthesis occurs locally in or near cells that utilize it. Precise spatial and temporal levels of RA in skin are achieved by regulating key steps in cellular vitamin A metabolism: storage as retinyl esters, RA synthesis, and RA degradation (Everts, 2012). Retinol is transported into the cell via the protein called Stimulated by RA6 (STRA6) and binds cellular retinol binding protein 1 (RBP1, aka CRBP). ...
C57BL/6 mice develop dermatitis and scarring alopecia resembling human cicatricial alopecias (CAs), particularly the central centrifugal CA (CCCA) type. To evaluate the role of retinoids in CA, the expression of retinoid metabolism components were examined in these mice with mild, moderate, or severe CA compared with hair cycle-matched mice with no disease. Two feeding studies were conducted with dams fed either NIH 31 diet (study 1) or AIN93G diet (study 2). Adult mice were fed AIN93M diet with 4 (recommended), 28, or 56 IU vitamin A g(-1) diet. Feeding the AIN93M diet to adults increased CA frequency over NIH 31 fed mice. Increased follicular dystrophy was seen in study 1 and increased dermal scars in study 2 in mice fed the 28 IU diet. These results indicate that retinoid metabolism is altered in CA in C57BL/6J mice that require precise levels of dietary vitamin A. Human patients with CCCA, pseudopelade (end-stage scarring), and controls with no alopecia were also studied. Many retinoid metabolism proteins were increased in mild CCCA, but were undetectable in pseudopelade. Studies to determine whether these dietary alterations in retinoid metabolism seen in C57BL/6J mice are also involved in different types of human CA are needed.Journal of Investigative Dermatology advance online publication, 25 October 2012; doi:10.1038/jid.2012.393.
... RA synthesis occurs locally in or near the cells where it will ultimately be used. Precise spatial and temporal levels of RA in the skin are achieved by regulating several key steps in cellular vitamin A metabolism: storage as retinyl esters, RA synthesis, and RA degradation (Everts, 2012). Briefly, vitamin A circulates as retinol bound to retinol binding protein (RBP4). ...
Alopecia areata (AA) is an autoimmune disease that attacks anagen hair follicles. Gene array in graft-induced C3H/HeJ mice revealed that genes involved in retinoic acid (RA) synthesis were increased, whereas RA degradation genes were decreased in AA compared with sham controls. This was confirmed by immunohistochemistry in biopsies from patients with AA and both mouse and rat AA models. RA levels were also increased in C3H/HeJ mice with AA. C3H/HeJ mice were fed a purified diet containing one of the four levels of dietary vitamin A or an unpurified diet 2 weeks before grafting and disease progression followed. High vitamin A accelerated AA, whereas mice that were not fed vitamin A had more severe disease by the end of the study. More hair follicles were in anagen in mice fed high vitamin A. Both the number and localization of granzyme B-positive cells were altered by vitamin A. IFNγ was also the lowest and IL13 highest in mice fed high vitamin A. Other cytokines were reduced and chemokines increased as the disease progressed, but no additional effects of vitamin A were seen. Combined, these results suggest that vitamin A regulates both the hair cycle and immune response to alter the progression of AA.Journal of Investigative Dermatology advance online publication, 27 September 2012; doi:10.1038/jid.2012.344.
The X-linked histone demethylase, UTX ( KDM6A ), is a master regulator of gene enhancers, though its role in self-renewing epithelia like the skin is not well understood. Here, we find that UTX is a key regulator of skin differentiation via the regulation of retinoic acid (RA) signaling, an essential metabolic pathway in both skin homeostasis, as well as in the treatment of an array of skin conditions ranging from cancer and acne to aging. Through deletion of Utx in the skin, we demonstrate direct regulation of both retinoid metabolic genes such as Crabp2 , as well as key genes involved in epidermal stem cell fate and differentiation (i.e., Cdh1 , Grhl3 , Ctnnb1 ). Spatial analyses show that UTX loss dysregulates epidermal, sebaceous, and hair follicle differentiation programs. Strikingly, this only occurs in homozygous females, demonstrating that UTX’s Y-linked paralog, UTY ( Kdm6c ), can compensate in males. Further, we observe genome-wide losses of H3K27 acetylation (H3K27ac) with minimal changes in H3K27 trimethylation (H3K27me3), revealing that UTX functions primarily noncatalytically to promote skin homeostasis. Together, the elucidation of these links between epigenetics, metabolic signaling, and epithelial differentiation offers new insights into how epigenetic modulation may allow for fine-tuning of key signaling pathways to treat disease.
All-trans retinoic acid (ATRA), the active form of retinoids, is a potent anti-aging and anti-inflammatory agent with pleiotropic effects on various skin conditions. In the interfollicular epidermis, tissue turnover is maintained by heterogeneous epidermal stem cell populations located at the basal layer. Mouse tail skin contains slow- and fast-cycling epidermal stem cell populations. The reduction of fast-cycling epidermal regions after ATRA application was first documented in 1987; however, stem cell-level changes remained largely unexplored. This study demonstrates that ATRA treatment leads to reversible changes which decrease the fast-cycling epidermal compartment while expanding the slow-cycling one. ATRA biases both slow- and fast-cycling epidermal stem cell populations toward differentiation, with the remaining Slc1a3-CreER+ fast-cycling clones in the basal layers biasing to the slow-cycling lineage. Similar changes in slow- and fast-cycling epidermal stem cell populations are also evident in human primary cultures in vitro. These findings shed light on the role of retinoic acid signaling in regulating the balance of epidermal stem cell heterogeneity and lineages.
The growing demand is driving the growth of the herbal cosmetics industry globally and attracting the attention of nature to priceless gifts. Herbal skin care products are created by combining a variety of herbal active ingredients with a cosmetic base to nourish and cure certain skin conditions. As the main component of sunlight, ultraviolet radiation is crucial for causing skin damage. They cause a variety of skin conditions, such as rashes, sunburn, erythema, and skin cancer. Since ancient times, natural substances have been used in traditional medicines as well as in healing practices across numerous cultures. They have been used in topical creams, lotions, and preparations. Clinical and laboratory studies conducted over the last 20 years have revealed the advantages of a variety of natural substances for skin care. The morphological and physiological characteristics of the skin are constantly changing. It has been shown that bioactive substances such as polyphenols strengthen the endogenous antioxidant system of the skin, preventing a number of skin issues.
Scope
Hair loss is a common problem that can negatively impact individuals' psychological well‐being. Androgenetic alopecia (AGA) is one of the most prevalent types of nonscarring hair loss. This review summarizes the existing evidence on the relationship between AGA and various micronutrients, including vitamin B, vitamin D, vitamin A, vitamin C, iron, selenium, zinc, manganese, and copper.
Methods
A literature search was conducted to identify relevant articles published between 1993 and 2023. The search identified 49 relevant articles.
Results
The findings suggest that deficiencies or imbalances in these micronutrients may contribute to the pathogenesis of AGA and represent modifiable risk factors for hair loss prevention and treatment. Vitamin B, vitamin D, iron, and zinc appear to play critical roles in hair growth and maintenance. Deficiencies in these micronutrients have been associated with increased risk of AGA, while supplementation with these nutrients has shown potential benefits in improving hair growth and preventing hair loss. However, the current evidence is not entirely consistent, with some studies reporting no significant associations.
Conclusion
Deficiencies or imbalances in specific vitamins and minerals, especially vitamin B, vitamin D, Fe, Se, and Zn are involved in the pathogenesis of AGA and may represent modifiable risk factors for the treatment and prevention of this condition.
Background
Depletion or permanent quiescence of the hair follicle stem cell (HFSC) pool underlies pathogenesis in androgenetic alopecia (AGA). Reactivation of quiescent HFSCs is considered an efficient treatment strategy for hair loss. The retinoic acid (RA) is critical to ensure stem cell homeostasis and function. However, little is known about whether RA regulates HFSC homeostasis. We aimed to investigate the impact of RA on HFSC homeostasis and the underlying mechanisms, in order to provide new potential targets for medical therapies of AGA.
Methods
Microdissected hair follicles from the occipital and frontal scalp in AGA were obtained for RNA sequencing analysis and test. The C57BL/6 mice model in telogen was established to investigate the effect of exogenous RA. Miniaturized hair follicles from frontal scalp were incubated with or without RA in hair follicle organ culture to test the effects on hair shaft elongation, hair cycling and HFSC activities. A strategy to characterize the effect of RA on HFSC in primary culture was developed to identify novel mechanisms that control HFSC activation. A clinical study was performed to test the efficacy of RA treatment in AGA patients.
Results
RA signalling was inhibited in the course of AGA pathogenesis along with HFSC dysfunction. Hair regeneration was retarded in AGA miniaturized hair follicles with RA deficiency, but they tended to recover after treatment with RA. In addition, RA treatment during the telogen phase facilitated HFSC anagen entry and accelerated hair growth. Mechanistically, RA promoted hair growth by stimulating stem cells via Wnt/β‐catenin signalling and accelerating the transition from a dormant to an activated state. Furthermore, a clinical study suggested that RA has obvious advantages in the early intervention of AGA by reactivating HFSCs.
Conclusions
Our study provides insights into the reactivation of HFSCs in AGA and provides potential targets for medical therapies.
Purpose: This study examined the effect of a hair essence containing α-tocopheryl acetate, retinyl palmitate, and phytantriol (TRP-hair essence) on damaged hair and hair quality characteristics such as hair volume and gloss.Methods: The TRP-hair essence containing 0.01% (w/w) each of α-tocopheryl acetate (vitamin E), retinyl palmitate (vitamin A), and phytantriol was prepared. The effect of the TRP-hair essence on damaged hair was analyzed using a scanning electron microscope; its impact on hair volume and gloss was confirmed using a high-resolution digital camera. Furthermore, a sensory evaluation was used to determine satisfaction after using the TRP-hair essence.Results: The cuticle of the hair that had been damaged because of chemical treatment improved by 19.8% ( p <0.05) following only a single round of the TRP-hair essence treatment. Hair volume and gloss significantly increased immediately and 24 hours after using the TRP-hair essence ( p <0.05). There was substantial satisfaction in terms of the sensory evaluation of directly using the TRP-hair essence on human hair.Conclusion: Using the TRP-hair essence effectively recovered the damaged hair and improved its quality characteristics such as hair volume and gloss, resulting in high satisfaction with use.
Background:
Retinoid signaling is an important regulator of the epidermis and skin appendages. Therefore, synthetic retinoids have been developed for therapeutic use for skin disorders such as psoriasis and acne.
Aims:
In previous studies, we showed how the photostable retinoid EC23 induces neuronal differentiation in stem cell-like cell populations, and here, we aim to investigate its ability to influence epidermal and hair follicle growth.
Methods:
EC23 influence on skin biology was investigated initially in cultures of monolayer keratinocytes and three-dimentional in vitro models of skin, and finally in in vivo studies of mice back skin.
Results:
EC23 induces keratinocyte hyperproliferation in vitro and in vivo, and when applied to mouse skin increases the number of involucrin-positive suprabasal cell layers. These phenotypic changes are similar in skin treated with the natural retinoid all-trans retinoic acid (ATRA); however, EC23 is more potent; a tenfold lower dose of EC23 is sufficient to induce epidermal thickening, and resulting hyperproliferation is sustained for a longer time period after first dose. EC23 treatment resulted in a disorganized stratum corneum, reduced cell surface lipids and compromised barrier, similar to ATRA treatment. However, EC23 induces a rapid telogen to anagen transition and hair re-growth in 6-week-old mice with synchronously resting back skin follicles. The impact of EC23 on the hair cycle was surprising as similar results have not been seen with ATRA.
Conclusions:
These data suggest that synthetic retinoid EC23 is a useful tool in exploring the turnover and differentiation of cells and has a potent effect on skin physiology.
Hair loss is a widespread concern in dermatology clinics, affecting both men’s and women’s quality of life. Hair loss can have many different causes, which are critical to identify in order to provide appropriate treatment. Hair loss can happen due to many variables, such as genetic factors or predisposition, vitamin and mineral deficiencies, skin problems, hair growth disorders, poor diet, hormonal problems, certain internal diseases, drug use, stress and depression, cosmetic factors, childbirth, and the chemotherapy process. Treatment for hair loss varies depending on the type of alopecia, deficiency, or excess of structures such as vitamins and minerals, and also on hair and skin structure.
The Mediterranean diet is characterized by low amounts of saturated fat, animal protein, and high amounts of unsaturated fat, fiber, polyphenols, and antioxidants. The main nutrients found in the Mediterranean Diet are rich in antioxidant, anti-inflammatory components. It also has an important place in hair loss treatment, since recently treatment strategies have included polyphenols and unsaturated oils more and more frequently. The goal of this work was to review published articles examining alopecia and its types, the many micronutrients that affect alopecia, and the role of the Mediterranean diet in alopecia. The literature shows that little is known about hair loss, nutritional factors, and diet, and that the data collected are conflicting. Given these differences, research into the function of diet and nutrition in the treatment of baldness is a dynamic and growing topic.
Particulate matter 2.5 (PM2.5), an atmospheric pollutant with an aerodynamic diameter of <2.5 μm, can cause serious human health problems, including skin damage. Since sebocytes are involved in the regulation of skin homeostasis, it is necessary to study the effects of PM2.5 on sebocytes. We examined the role of PM2.5 via the identification of differentially expressed genes, functional enrichment and canonical pathway analysis, upstream regulator analysis, and disease and biological function analysis through mRNA sequencing. Xenobiotic and lipid metabolism, inflammation, oxidative stress, and cell barrier damage-related pathways were enriched; additionally, PM2.5 altered steroid hormone biosynthesis and retinol metabolism-related pathways. Consequently, PM2.5 increased lipid synthesis, lipid peroxidation, inflammatory cytokine expression, and oxidative stress and altered the lipid composition and expression of factors that affect cell barriers. Furthermore, PM2.5 altered the activity of sterol regulatory element binding proteins, mitogen-activated protein kinases, transforming growth factor beta-SMAD, and forkhead box O3-mediated pathways. We also suggest that the alterations in retinol and estrogen metabolism by PM2.5 are related to the damage. These results were validated using the HairSkin® model. Thus, our results provide evidence of the harmful effects of PM2.5 on sebocytes as well as new targets for alleviating the skin damage it causes.
O livro enfatiza fatores que regem a vida humana do início ao fim e que podem ser muito diferentes entre indivíduos e populações: 1) caracteres genéticos herdados diretamente de nossos pais e indiretamente de nossos ancestrais, os quais permanecem relativamente estáveis ao longo da vida; 2) fatores ambientais (alimentação, condição e estilo de vida) até certo ponto controláveis, sendo a alimentação o mais importante. A primeira parte do livro trata da definição e da conceituação do processo de envelhecimento e seus efeitos na saúde. Seguem-se a apresentação e a discussão de mecanismos que promovem degradação molecular e celular responsáveis por distúrbios metabólicos que podem resultar em doenças crônico-degenerativas. A maior parte do texto é dedicada à apresentação de alimentos e compostos bioativos que agem combatendo o envelhecimento precoce e retardando doenças da idade. Por fim, faz-se uma discussão sobre conceitos de dietas saudáveis com sugestões para pesquisas, visando melhorar o perfil alimentar do brasileiro.
Objective:
Scalp hair is among the most exposed parts of the human body, yet the impact of visible and UV light on hair lipids, an important structural component of hair, is poorly researched. We have used lipidomics, a broad-based approach to measure lipids in samples, which has hitherto not been applied to UV-exposed hair in the published literature, and could allow for a wider understanding of how UV light impacts on specific hair lipids.
Methods:
Mixed blonde Caucasian hair switches were divided into two groups of five, with half of the hair switches exposed to UV and visible light mimicking normal daytime exposure and half left unexposed. LC-MS lipidomics was used to profile the lipids in the hair samples.
Results:
A total of 791 lipids and 32 lipid classes with tentative identifications were detected in the hair samples. Nineteen lipid classes and 397 lipids differed between UV treated and non-treated hair. The main lipid classes that differed were vitamin A fatty acid esters, sterol esters, several ceramides, mono-, di-, and triglycerides, phosphatidylethanolamines (all decreased in UV-exposed hair) and bismonoacylglycerolphosphates, acylcarnitines, and acylglycines (all increased in UV-exposed hair). Most detected lipids were decreased in UV-exposed hair, supporting earlier work that has found that UV-exposure causes oxidation of lipids which would result in a decrease in most lipid classes.
Conclusion:
Light exposure to hair has a widespread impact on the hair lipidome. This study also adds to the emerging literature on the hair lipidome, broadening the range of lipid classes reported in hair.
Vitamin A is a fat-soluble micronutrient necessary for the growth of healthy skin and hair. However, both too little and too much vitamin A has deleterious effects. Retinoic acid and retinal are the main active metabolites of vitamin A. Retinoic acid dose-dependently regulates hair follicle stem cells, influencing the functioning of the hair cycle, wound healing, and melanocyte stem cells. Retinoic acid also influences melanocyte differentiation and proliferation in a dose-dependent and temporal manner. Levels of retinoids decline when exposed to ultraviolet irradiation in the skin. Retinal is necessary for the phototransduction cascade that initiates melanogenesis but the source of that retinal is currently unknown. This review discusses new research on retinoids and their effects on the skin and hair.
Background
The giant panda ( Ailuropoda melanoleuca ) is a threatened species endemic to China. Alopecia, characterized by thinning and broken hair, mostly occurs in breeding males. Alopecia significantly affects the health and public image of the giant panda and the cause of alopecia is unclear.
Results
Here, we researched gene expression profiles of four alopecia giant pandas and seven healthy giant pandas. All pandas were approximately ten years old and their blood samples collected during the breeding season. A total of 458 up-regulated DEGs and 211 down-regulated DEGs were identified. KEGG pathway enrichment identified that upregulated genes were enriched in the Notch signaling pathway and downregulated genes were enriched in ribosome, oxidative phosphorylation, and thermogenesis pathways. We obtained 28 hair growth-related DEGs, and identified three hub genes NOTCH1 , SMAD3 , and TGFB1 in PPI analysis. Five hair growth-related signaling pathways were identified with abnormal expression, these were Notch, Wnt, TGF-β, Mapk, and PI3K-Akt. The overexpression of NOTCH1 delays inner root sheath differentiation and results in hair shaft abnormalities. The delayed hair regression was associated with a significant decrease in the expression levels of TGFB1.
Conclusions
Our data confirmed the abnormal expression of several hair-related genes and pathways and identified alopecia candidate genes in the giant panda. Results of this study provide theoretical basis for the establishment of prevention and treatment strategies for giant pandas with alopecia.
The goal of the study. Evaluating of the effectiveness of treatment of men with a diagnosis «Seborrheic dermatitis of the scalp» by the system using of retinol palmitate. Material and methods. 36 patients every day for 2 months received overnight per os 200000 ME of retinol palmitate, and in the comparison group (39 people) antiseborrheic shampoos have been used. The dynamics of severity of skin oiliness, pruritis, erythema, peeling, infiltration, excoriations has been evaluated in points. Before and after the treatment a histological and morphometric study of biopsy material from the affected areas has been carried.The terms of relapses have been set. Results. Retinol palmitate treatment efficiency - 91.7%, antiseborrheic shampoos - 84.6%. Along with the regression of symptoms of the disease in both groups after retinol palmitate treatment significantly declined oiliness of skin; the sizes of sebaceous glands acini and the presence of differentiated sebocytes, the squares of lymphocytic-macrophage clusters in the dermis, the number of keratinocytes with vacuolated cytoplasm have been reduced. Relapses of the disease during a year occured more rare - in 21 patients out of 32 (in the comparison group- in 25 out of 31) and at a later date (in the first 3 months in 2 patients out of 32, in comparison group in 10 out of 31). Identified effects were due to the action of retinol palmitate on the morphogenesis of the sebaceous glands.
In recent years, interest in the health effects of natural antioxidants has increased due to their safety and applicability in cosmetic formulation. Nevertheless, efficacy of natural antioxidants in vivo is less documented than their prooxidant properties in vivo. Plant extracts rich in vitamins, flavonoids, and phenolic compounds can induce oxidative damage by reacting with various biomolecules while also providing antioxidant properties. Because the biological activities of natural antioxidants differ, their effectiveness for slowing the aging process remains unclear. This review article focuses on the use of natural antioxidants in skincare and the possible mechanisms underlying their desired effect, along with recent applications in skincare formulation and their limitations.
Retinoic acid (RA) is one of the factors crucial for cell growth, differentiation, and embryogenesis; it interacts with the retinoic acid receptor and retinoic acid X receptor to eventually regulate target gene expression in chordates. RA is transformed from retinaldehyde via oxidization by retinaldehyde dehydrogenase (RALDH), which belongs to the family of oxidoreductases. Several chemicals, including disulphiram, diethylaminobenzaldehyde, and SB-210661, can effectively inhibit RALDH activity, potentially causing reproductive and developmental toxicity. The modes of action can be sequentially explained based on the molecular initiating event toward key events, and finally the adverse outcomes. Adverse outcome pathway (AOP) is a conceptual and theoretical framework that describes the sequential chain of casually liked events at different biological levels from molecular events to adverse effects. In the present review, we discussed a recently registered AOP (AOP297; inhibition of retinaldehyde dehydrogenase leads to population decline) to explain and support the weight of evidence for RALDH inhibition-related developmental toxicity using the existing knowledge.
Topical 17-beta-estradiol (E2) regulates the hair cycle, hair shaft differentiation, and sebum production. Vitamin A also regulate sebum production. Vitamin A metabolism proteins localized to the pilosebaceous unit (PSU; hair follicle and sebaceous gland); and were regulated by E2 in other tissues. This study tests the hypothesis that E2 also regulates vitamin A metabolism in the PSU. First, aromatase and estrogen receptors localized to similar sites as retinoid metabolism proteins during mid-anagen. Next, female and male wax stripped C57BL/6J mice were topically treated with E2, the estrogen receptor antagonist ICI 182,780 (ICI), letrozole, E2 plus letrozole, or vehicle control (acetone) during mid-anagen. E2 or one of its inhibitors regulated most of the vitamin A metabolism genes and proteins examined in a sex dependent manner. Most components were higher in females and reduced with ICI in females. ICI reductions occurred in the premedulla, sebaceous gland, and epidermis. Reduced E2 also reduced RA receptors in the sebaceous gland and bulge in females. However, reduced E2 increased the number of retinal dehydrogenase 2 positive hair follicle associated dermal dendritic cells in males. These results suggest that estrogen regulates vitamin A metabolism in the skin. Interactions between E2 and vitamin A have implications in acne treatment, hair loss, and skin immunity.
The hair follicle dermal papilla is critical for hair generation and de novo regeneration. When cultured in vitro, dermal papilla cells from different species demonstrate two distinguishable growth patterns under the conventional culture condition: a self-aggregative three dimensional spheroidal (3D) cell pattern and a two dimensional (2D) monolayer cell pattern, correlating with different hair inducing properties. Whether the loss of self-aggregative behavior relates to species-specific differences or the improper culture condition remains unclear. Can the fixed 2D patterned dermal papilla cells recover the self-aggregative behavior and 3D pattern also remains undetected. Here, we successfully constructed the two growth patterns using sika deer (Cervus nippon) dermal papilla cells and proved it was the culture condition that determined the dermal papilla growth pattern. The two growth patterns could transit mutually as the culture condition was exchanged. The fixed 2D patterned sika deer dermal papilla cells could recover the self-aggregative behavior and transit back to 3D pattern, accompanied by the restoration of hair inducing capability when the culture condition was changed. In addition, the global gene expressions during the transition from 2D pattern to 3D pattern were compared to detect the potential regulating genes and pathways involved in the recovery of 3D pattern and hair inducing capability.
Retinoids have numerous applications in inflammatory, dyskeratotic, and oncohematology diseases. Retinoids have now reached the fourth generation, progressively reducing toxicity whilst increasing their efficacy. Trifarotene is a new fourth-generation retinoid with a selective action on RAR-γ. In this review, we reported the trials—both concluded and in progress—including the use of trifarotene in dermatological diseases. Studies were identified by searching electronic databases (MEDLINE, EMBASE, PubMed, Cochrane, Trials.gov) from 2012 to today and reference lists of respective articles. Only articles published in English language were included. Randomized trials evaluating trifarotene tolerability, safety, and efficacy in congenital ichthyosis and acne have demonstrated great results and mild side effects, leading to the approval by the FDA of trifarotene for the treatment of lamellar ichthyosis in 2014, and of acne vulgaris in October 2019. No high-quality randomized clinical trials have evaluated the treatment of primary cutaneous lymphomas with trifarotene. Finally, we are hypothesizing future perspectives in the treatment of non-melanoma skin cancers, fungal infections, photoaging, and hand-foot skin reactions with trifarotene.
Hair follicles cycle through periods of growth (anagen), regression (catagen), rest (telogen), and release (exogen). Telogen is further divided into refractory and competent telogen based on expression of bone morphogenetic protein 4 (BMP4) and wingless-related MMTV integration site 7A (WNT7A). During refractory telogen hair follicle stem cells (HFSC) are inhibited. Retinoic acid synthesis proteins localized to the hair follicle and this localization pattern changed throughout the hair cycle. In addition, excess retinyl esters arrested hair follicles in telogen. The purpose of this study was to further define these hair cycle changes. BMP4 and WNT7A expression was also used to distinguish refractory from competent telogen in C57BL/6J mice fed different levels of retinyl esters from two previous studies. These two studies produced opposite results; and differed in the amount of retinyl esters the dams consumed and the age of the mice when the different diet began. There were a greater percentage of hair follicles in refractory telogen both when mice were bred on an unpurified diet containing copious levels of retinyl esters (study 1) and consumed excess levels of retinyl esters starting at 12 weeks of age, as well as when mice were bred on a purified diet containing adequate levels of retinyl esters (study 2) and remained on this diet at 6 weeks of age. WNT7A expression was consistent with these results. Next, the localization of vitamin A metabolism proteins in the two stages of telogen was examined. Keratin 6 (KRT6) and cellular retinoic acid binding protein 2 (CRABP2) localized almost exclusively to refractory telogen hair follicles in study 1. However, KRT6 and CRABP2 localized to both competent and refractory telogen hair follicles in mice fed adequate and high levels of retinyl esters in study 2. In mice bred and fed an unpurified diet retinol dehydrogenase SDR16C5, retinal dehydrogenase 2 (ALDH1A2), and cytochrome p450 26B1 (CYP26B1), enzymes and proteins involved in RA metabolism, localized to BMP4 positive refractory telogen hair follicles. This suggests that vitamin A may contribute to the inhibition of HFSC during refractory telogen in a dose dependent manner.
Animal studies as early as the 1920s suggested that vitamin A deficiency leads to squamous cell metaplasia in numerous epithelial tissues including the skin. However, humans usually die from vitamin A deficiency before cancers have time to develop. A recent long-term cohort study found that high dietary vitamin A reduced the risk of cutaneous squamous cell carcinoma (cSCC). cSCC is a form of nonmelanoma skin cancer that primarily occurs from excess exposure to ultraviolet light B (UVB). These cancers are expensive to treat and can lead to metastasis and death. Oral synthetic retinoids prevent the reoccurrence of cSCC, but side effects limit their use in chemoprevention. Several proteins involved in vitamin A metabolism and signaling are altered in cSCC, which may lead to retinoid resistance. The expression of vitamin A metabolism proteins may also have prognostic value. This article reviews what is known about natural and synthetic retinoids and their metabolism in cSCC.
Androgens have an intense consequence on the human scalp and body hair. Scalp hair sprouts fundamentally in awol of androgens whereas the body hair hike is vulnerable to the activity of androgens. Androgenetic alopecia (AGA) invoked as males emulate Alopecia due to the cause of the dynamic reduction of scalp hair. Androgens are medium of terminus growth of hair although the body. Local and system androgens convert the extensive terminal follicles into lesser vellus like structure. The out start of this type of alopecia is intensely irregular and the reason behind this existence of enough circulating steroidal hormones androgens and due to genetic predisposition. Effective treatments are available in the market as well as under clinical and preclinical testing. Many herbal formulations are also available but not FDA approved. Different conventional and NDDS formulations are already available in the market. To avoid various systemic side effects of both Finasteride and Minoxidil, topical formulations and natural products (nutrients, minerals, vitamins) now a days are being widely used to treat Androgenic alopecia. CAM (complementary and alternative medicine) provides the option to elect favorable, low-risk, adjuvant and alternative therapies. Herein, we offer a widespread review of topical marketed formulations, natural products, and CAM treatment options for AGA.
Graphic Abstract
Retinol dehydrogenases catalyze the rate-limiting step in the biosynthesis of retinoic acid, a bioactive lipid molecule that regulates the expression of hundreds of genes by binding to nuclear transcription factors, the retinoic acid receptors. Several enzymes exhibit retinol dehydrogenase activities in vitro; however, their physiological relevance for retinoic acid biosynthesis in vivo remains unclear. Here, we present evidence that two murine epidermal retinol dehydrogenases, short-chain dehydrogenase/reductase family 16C member 5 (SDR16C5) and SDR16C6, contribute to retinoic acid biosynthesis in living cells and are also essential for the oxidation of retinol to retinaldehyde in vivo Mice with targeted knockout of the more catalytically active SDR16C6 enzyme have no obvious phenotype, possibly due to functional redundancy, because Sdr16c5 and Sdr16c6 exhibit an overlapping expression pattern during later developmental stages and in adulthood. Mice that lack both enzymes are viable and fertile, but display accelerated hair growth after shaving and also enlarged meibomian glands, consistent with a nearly 80% reduction in the retinol dehydrogenase activities of skin membrane fractions from the Sdr16c5/Sdr16c6 double-knockout mice. The up-regulation of hair-follicle stem cell genes is consistent with reduced retinoic acid signaling in the skin of the double-knockout mice. These results indicate that the retinol dehydrogenase activities of murine SDR16C5 and SDR16C6 enzymes are not critical for survival, but are responsible for most of the retinol dehydrogenase activity in skin, essential for the regulation of the hair-follicle cycle, and required for the maintenance of both sebaceous and meibomian glands.
Vitamin A deficiency increases susceptibility to skin
infection. However, the mechanisms by which
vitamin A regulates skin immunity remain unclear.
Here, we show that resistin-like molecule a (RELMa),
a small secreted cysteine-rich protein, is expressed
by epidermal keratinocytes and sebocytes and
serves as an antimicrobial protein that is required
for vitamin-A-dependent resistance to skin infection.
RELMa was induced by microbiota colonization of
the murine skin, was bactericidal in vitro, and was
protected against bacterial infection of the skin
in vivo. RELMa expression required dietary vitamin
A and was induced by the therapeutic vitamin A
analog isotretinoin, which protected against skin
infection in a RELMa-dependent manner. The RELM
family member Resistin was expressed in human
skin, was induced by vitamin A analogs, and killed
skin bacteria, indicating a conserved function for
RELM proteins in skin innate immunity. Our findings
provide insight into how vitamin A promotes resistance
to skin infection.
Background
Sebaceous glands (SGs) are appendages of mammalian skin that produce a mixture of lipids known as sebum. Acne vulgaris is an exceptionally common skin condition, characterized by elevated sebum production, altered sebum composition, and the formation of infundibular cysts, called comedones. Comedo‐associated SGs are atrophic, suggesting that comedo formation involves abnormal differentiation of progenitor cells that generate the SG and infundibulum: the ‘comedo switch’. Understanding the biological processes that govern SG homeostasis promises to highlight potential aetiological mechanisms underlying acne and other SG‐associated skin disorders.
Results
In this review, we discuss the clinical data, genetic mouse models and in vitro research that have highlighted major hormones, paracrine factors, transcription factors and signalling pathways that control SG homeostasis. These include, but are not limited to androgens, progestogens and oestrogens; retinoids; receptor tyrosine kinases such as ErbB family receptors, fibroblast growth factor receptor 2 and insulin/insulin‐like growth factor 1 receptors; peroxisome proliferator‐activated receptor γ; aryl hydrocarbon receptor; and the Wnt signalling pathway. Where possible, the cellular and molecular mechanisms by which these regulatory factors control SG biology are indicated, along with considerations as to how they might contribute to acne pathogenesis.
Conclusions
Future research should seek to establish the relative importance, and causative relationships, of altered sebum production, sebum composition, inflammation and abnormal differentiation of sebaceous progenitors to the process of comedo formation in acne. Such an understanding will allow for therapeutic targeting of regulatory factors that control SG homeostasis, with the aim of treating acne.
Background
Alopecia areata (AA) is multifactorial disease mostly autoimmune affecting anagen hair follicles. Many researchers hypothesize that adequate retinoic acid (RA) levels are important for proper hair follicle behavior. Previous animal studies revealed increase in RA synthesis proteins and decrease in RA degradation proteins in AA patients when compared with controls.
Objective
To evaluate cellular retinol‐binding protein‐1 expression in lesional skin of alopecia areata in comparison with controls, in an attempt to know its role in the pathogenesis of alopecia areata .
Methods
Immunohistochemical expression of cellular retinol‐binding protein‐1 CRBP1 was evaluated in skin biopsies taken from lesions of alopecia areata in 30 patients and 10 normal biopsy specimens taken from skin of healthy controls (HC) who were within the same age and sex.
Results
CRBP1 expression was significantly increased in lesional alopecia areata skin in comparison with normal skin of controls (P < 0.001*). Significant positive correlation was found between expression of CRBP‐1 and percentage of hair loss in the scalp (SALT score; r = 0.840, P = <0.001).
Conclusion
These results may enhance the idea of the possible role of CRBP1 in the pathogenesis of AA, and ensuring the importance of its level in AA treatment.
People commonly inquire about vitamin and mineral supplementation and diet as a means to prevent or manage dermatological diseases and, in particular, hair loss. Answering these queries is frequently challenging, given the enormous and conflicting evidence that exists on this subject. There are several reasons to suspect a role for micronutrients in non-scarring alopecia. Micronutrients are major elements in the normal hair follicle cycle, playing a role in cellular turnover, a frequent occurrence in the matrix cells in the follicle bulb that are rapidly dividing. Management of alopecia is an essential aspect of clinical dermatology given the prevalence of hair loss and its significant impact on patients’ quality of life. The role of nutrition and diet in treating hair loss represents a dynamic and growing area of inquiry. In this review we summarize the role of vitamins and minerals, such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, iron, selenium, and zinc, in non-scarring alopecia. A broad literature search of PubMed and Google Scholar was performed in July 2018 to compile published articles that study the relationship between vitamins and minerals, and hair loss. Micronutrients such as vitamins and minerals play an important, but not entirely clear role in normal hair follicle development and immune cell function. Deficiency of such micronutrients may represent a modifiable risk factor associated with the development, prevention, and treatment of alopecia. Given the role of vitamins and minerals in the hair cycle and immune defense mechanism, large double-blind placebo-controlled trials are required to determine the effect of specific micronutrient supplementation on hair growth in those with both micronutrient deficiency and non-scarring alopecia to establish any association between hair loss and such micronutrient deficiency.
Plain Language Summary: Plain language summary available for this article.
Purpose: To assess the effects of marginal vitamin A deficiency (MVAD) on rat meibomian gland morphology as well as retinoic acid receptor (RAR) and retinoid X receptor (RXR) amounts and localization.
Methods: Eight adult female rats were randomized into MVAD and vitamin A normal (VAN) groups, and fed vitamin A-deficient and normal control diets, respectively, for 3 weeks before mating. At postnatal week 4 (P4w), eight newborn animals in both groups were euthanized, respectively. Then, serum retinol levels were analyzed. Meibomian glands from P4w animals were further assessed upon hematoxylin and eosin staining. RAR and RXR gene and protein expression amounts were detected by real time polymerase chain reaction (qRT-PCR), immunofluorescence and western blotting, respectively.
Results: Secretory cell nuclei had reduced areas, while the multilayered squamous epithelium of the ductule was overtly thinner in MVAD rats compared with VAN animals. RXR−α showed highest mRNA amounts among all RA receptors; compared with control values, RXR−α showed overtly decreased mRNA amounts in animals with MVAD. In addition, compared with normal rats, MVAD rats had starkly lower RXR-α and RXR-γ expression levels. Furthermore, only the RXR-α protein was detected in the nucleus of cells forming the multilayered squamous epithelium of the ductule in VAN rats.
Conclusion: RARs and RXRs may be involved in the regulation of meibomian gland function. RXR-α and 9-cis RA signaling affects meibomian gland function, and the mechanisms of retinoids on secretory cells and the ductule epithelium may differ.
Fluconazole-induced alopecia is a significant problem for patients receiving long-term therapy. We evaluated the hair-cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms. Plasma and tissue levels of retinoic acid were not found causal. Human patients with alopecia attributed to fluconazole also underwent detailed assessment and in both our murine model and human cohort fluconazole induced telogen effluvium. Future work further examining the mechanism of fluconazole-induced alopecia should be undertaken.
Background/ Objectives
Isotretinoin is a synthetic vitamin A agent that affects all of the pathogenic factors that suppress sebum production and play a role in the formation of acne. It is frequently used in the treatment of moderate‐severe acne vulgaris. However, there are some mucocutaneous and systemic side effects that limit the use of isotretinoin. In this study, we aimed to determine the effect of isotretinoin on hair growth parameters.
Material and Methods
Isotretinoin treatment at 0.5 mg/kg per day dose was started to patients with moderate‐severe acne vulgaris, and hair growth parameters were evaluated before treatment and after 3 months of treatment. Parameters were measured by Fotofinder dermatoscopy device using the TrichoScan Professional program.
Results
In the TrichoScan analysis, the total hair count, hair density, percentage of anagen and telogen hair, density, count, and ratio of vellus and terminal hairs in the 0.73 area were calculated. As a result, there were differences in some values between the first analysis and the second analysis. However, these differences were not statistically significant.
Conclusion
Our study was based on the mucocutaneous side effects of isotretinoin which are telogen effluvium and thinning hair. Our results support that the drug does not alter hair growth parameters in the short term and when very high doses are not used.
Hair loss is multifactorial. Antiandrogens are inconsistent in clinical results. Instead of fighting hair loss, we focus on strengthening the hair roots and promoting better hair growth. The article lists non-androgenic causes, enlists foods to be added and avoided for good hair growth, and provides scientific evidence for role of nutrients in hair loss management. New process of autophagy conceals clinical detection of low nutrient levels through lab tests. It is experimentally proven that DHT causes accumulation of ROS which in turn releases TGF ß1 leading to miniaturization, and this action can be successfully blocked by the use of antioxidants. Changing food preferences and decreasing nutritive value of the foods make it necessary to have supplements. Too many supplements consumed together reduce the absorption and efficiency of one another. Therefore, a low-dose once in 3 days cyclical vitamin therapy has been proposed. Nutritional correction ensures wellness, good health, and good hair growth without the fear of side effects.
Recognised for its key role in lactation, it is less well‐appreciated that the neurohormone prolactin (PRL) is actually one of the most pleiotropic hormones known. Not only does PRL exert both tropic and trophic effects in a wide range of tissues, but it is also expressed in human skin and hair follicles and regulates multiple complex cutaneous functions, including keratin expression and hair growth. Despite several clinical indications that PRL may also play a role in sebaceous gland SG biology, the effects of PRL on SG have received little attention. In this Viewpoint essay, we argue that PRL may be a sebotrop(h)ic hormone and could represent a novel therapeutic target in human dermatoses affecting the SG. We provide preliminary evidence in support of this hypothesis (based on findings in human skin organ culture) and chart the major open questions in SG research from a PRL perspective. We close by delineating how these questions can be experimentally addressed so as to identify new therapeutic strategies that are either sebogenic and sebostatic, for example in the management of acne and cutaneous aging.
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Alopecia areata (AA) is an autoimmune disease characterized by non-cicatricial hair loss. No definitive therapy currently exists for AA. To compared the efficacy and safety of the mometasone furoate 0.1% cream alone with the mometasone furoate 0.1% cream plus adapalene 0.1% gel in treatment of AA. Twenty patients with AA and with mean age of 27.4 ± 9.2 years were enrolled. Patches with a diameter of < 5 cm were treated with mometasone furate 0.1% cream (M), and patches with a diameter of ≥5 cm were treated with mometasone furate 0.1% cream plus adapalene 0.1% gel (M + D) for a period of 12 weeks. Hair regrowth was evaluated using a Re-growth score (RGS). Mean RGSs of M + D group were higher than M group for 4th week (2.60 vs. 1.45); 8th week (3.85 vs. 2.40) and 12th week (4.40 vs. 3.30). Mean percentages of hair re-growth in M + D group were statistically higher than M group for 4th (50.2% vs. 23.5%), 8th (78.5% vs. 50.7%), and 12th week (90.5% vs. 71%). Study revealed the efficacy and safety of adapalene and mometasone furoate combination in AA. Adapalene can be used as a new therapeutic modality in AA.
All-trans-retinoic acid (RA) is a bioactive derivative of vitamin A that serves as an activating ligand for nuclear transcription factors, retinoic acid receptors. RA biosynthesis is initiated by the enzymes that oxidize retinol to retinaldehyde. It is well established that retinol dehydrogenase 10 (RDH10, SDR16C4), which belongs to the 16C family of the short chain dehydrogenase/reductase (SDR) superfamily of proteins, is the major enzyme responsible for the oxidation of retinol to retinaldehyde for RA biosynthesis during embryogenesis. However, several lines of evidence point towards the existence of additional retinol dehydrogenases that contribute to RA biosynthesis in vivo. In close proximity to RDH10 gene on human chromosome 8 are located two genes that are phylogenetically related to RDH10. The predicted protein products of these genes, retinol dehydrogenase epidermal 2 (RDHE2, SDR16C5) and retinol dehydrogenase epidermal 2-similar (RDHE2S, SDR16C6), share 59% and 56% sequence similarity with RDH10, respectively. Previously, we showed that the single ortholog of the human RDHE2 and RDHE2S in frogs, Xenopus laevis rdhe2, oxidizes retinol to retinaldehyde and is essential for frog embryonic development. In this study, we explored the potential of each of the two human proteins to contribute to RA biosynthesis. The results of this study demonstrate that human RDHE2 exhibits a relatively low but reproducible activity when expressed in either HepG2 or HEK293 cells. Expression of the native RDHE2 is downregulated in the presence of elevated levels of RA. On the other hand, the protein encoded by the human RDHE2S gene is unstable when expressed in HEK293 cells. RDHE2S protein produced in Sf9 cells is stable but has no detectable catalytic activity towards retinol. We conclude that the human RDHE2S does not contribute to RA biosynthesis, whereas the low-activity RA-sensitive human RDHE2 may have a role in adjusting the cellular levels of RA in accord with specific physiological conditions.
Aging is an accelerating and escalating phenomenon and reality worldwide. According to the World Health Organization, over 2 billion people will be aged 60 years and older by 2050. Aging changes every aspect of human life and influences all medical disciplines. Geriatrics and gerontology are gaining growing significance in daily practice. The pathogenesis of hair aging remains largely unknown and is now under intensive investigation. Progeria/progeroid syndromes or silver/white hair syndromes are good natural models for the study of hair aging in vivo. Aging appears to exert no effect on the number, expression, and distribution of hair follicle stem cell markers, although melanocyte stem cells are obviously affected. Chronic persistent low-grade inflammation is an essential hallmark of the aging process, so-called inflammaging, while ultraviolet irradiation, skin microbes, and stress are among the most important etiologies for inducing a proinflammatory state in skin and hair follicles. Inflammation also plays a crucial role in the pathogenesis of different hair diseases, especially alopecia areata, folliculitis decalvans, lichen planopilaris, and telogen effluvium. Antioxidants, phytoestrogens, and retinoids have been demonstrated to possess anti-aging effects on hair follicles. Antioxidation takes center stage in current anti-aging strategies, in which polyphenols are the most extensively studied and promising agents. There is preliminary evidence for beneficial effects of certain nutraceuticals such as trace elements and polyamines in the anti-aging of hair. However, the optimal dosage and application route remains to be determined. Further extensive well-controlled clinical studies are required to confirm the effects of antioxidants in the prevention, interruption, and reversal of hair aging.
The sequence of events and mechanisms leading to the development of the primary acne lesion, the comedone, is revisited. Recent knowledge obtained both from lineage tracing experiments in the mouse and the pilosebaceous response to xenobiotics in humans provides robust models for further understanding key biological events at the cellular roots of comedogenesis. The focus is set on the LRIG1+ sebaceous stem cells in the isthmus of the pilosebaceous duct. The master switch that transforms a normally functioning sebaceous gland into a microcomedone and the hierarchy of factors involved in this process are reviewed. The key strategic target in acne care appears to be the naïve pilosebaceous follicle that is not involved yet in the acne cycle. The prevention of the comedone switch implies that the key switching factors are adequately controlled in the long term. © 2015 S. Karger AG, Basel.
Retinoids function as important regulatory signaling molecules during development, acting in cellular growth and differentiation both during embryogenesis and in the adult animal. In 1953, Fell and Mellanby first found that excess vitamin A can induce transdifferentiation of chick embryonic epidermis to a mucous epithelium (Fell, H.B.; Mellanby, E. Metaplasia produced in cultures of chick ectoderm by high vitamin A. J. Physiol. 1953, 119, 470–488). However, the molecular mechanism of this transdifferentiation process was unknown for a long time. Recent studies demonstrated that Gbx1, a divergent homeobox gene, is one of the target genes of all-trans retinoic acid (ATRA) for this transdifferentiation. Furthermore, it was found that ATRA can induce the epidermal transdifferentiation into a mucosal epithelium in mammalian embryonic skin, as well as in chick embryonic skin. In the mammalian embryonic skin, the co-expression of Tgm2 and Gbx1 in the epidermis and an increase in TGF-β2 expression elicited by ATRA in the dermis are required for the mucosal transdifferentiation, which occurs through epithelial-mesenchymal interaction. Not only does retinoic acid (RA) play an important role in mucosal transdifferentiation, periderm desquamation, and barrier formation in the developing mammalian skin, but it is also involved in hair follicle downgrowth and bending by its effect on the Wnt/β-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families.
Retinoic acid (RA) is essential during embryogenesis and for tissue homeostasis, whereas excess RA is well known as a teratogen.
In humans, excess RA is associated with hair loss. In the present study, we demonstrate that specific levels of RA, regulated
by Cyp26b1, one of the RA-degrading enzymes, are required for hair follicle (hf) morphogenesis. Mice with embryonic ablation of Cyp26b1 (Cyp26b1−/−) have excessive endogenous RA, resulting in arrest of hf growth at the hair germ stage. The altered hf development is rescued
by grafting the mutant skin on immunodeficient mice. Our results show that normalization of RA levels is associated with reinitiation
of hf development. Conditional deficiency of Cyp26b1 in the dermis (En1Cre;Cyp26b1f/−) results in decreased hair follicle density and specific effect on hair type, indicating that RA levels also influence
regulators of hair bending. Our results support the model of RA-dependent dermal signals regulating hf downgrowth and bending.
To elucidate target gene pathways of RA, we performed microarray and RNA-Seq profiling of genes differentially expressed in
Cyp26b1−/− skin and En1Cre;Cyp26b1f/− tissues. We show specific effects on the Wnt-catenin pathway and on members of the Runx, Fox, and Sox transcription factor
families, indicating that RA modulates pathways and factors implicated in hf downgrowth and bending. Our results establish
that proper RA distribution is essential for morphogenesis, development, and differentiation of hfs.
BackgroundATP-binding cassette (ABC) transporters are involved in the active transport of an extremely diverse range of substrates across biological membranes. These transporters are commonly implicated in the development of multidrug resistance and are also involved in numerous physiological and homeostatic processes, including lipid transport, cell migration and differentiation.Objectives
To close the knowledge gap in the expression of ABC transporters in the human hair follicle (HF).Methods
Quantitative polymerase chain reaction (qPCR) of ABC genes and immunofluorescence microscopy analysis of cryosections of human HFs.ResultsBy qPCR analysis, numerous members of the ABC transporter superfamily, such as ABCB1, ABCG2 and ABCA12, were found to be transcribed in full-length human scalp HFs. Immunofluorescence microscopy demonstrated that the intrafollicular protein expression of different xenobiotic ABC transporters (ABCB1, ABCC1, ABCC4, ABCG2) varies greatly, with ABCG2 expression restricted primarily to the epithelial stem cell region of the outer root sheath (bulge), whereas expression of ABCB1, ABCC1 and ABCC4 was more widespread. Lipid transporters ABCA1, ABCA12 and ABCA4 were almost uniformly expressed throughout the HF epithelium. Functional ABCB1/G2 activity was demonstrated by exclusion of the substrate dye, Hoechst 33342. In the bulge, this was reversed by ABCB1 and ABCG2 inhibition.Conclusions
These data encourage further investigation of ABC transporters as potentially important regulators of HF epithelial biology. Clinically, pharmacological modulation of the activity of selected intrafollicular ABC transporters may permit novel therapeutic interventions, such as protecting HF stem cells from chemotherapy-induced damage, counteracting cholesterol-associated hypertrichosis, and manipulating the intrafollicular prostaglandin balance in androgenetic alopecia.
Alopecia areata (AA) is an autoimmune hair loss disease caused by a cell-mediated immune attack of the lower portion of the cycling hair follicle. Feeding mice 3-7 times the recommended level of dietary vitamin A accelerated the progression of AA in the graft-induced C3H/HeJ mouse model of AA. In this study, we also found that dietary vitamin A, in a dose dependent manner, activated the hair follicle stem cells (SCs) to induce the development and growth phase of the hair cycle (anagen), which may have made the hair follicle more susceptible to autoimmune attack. Our purpose here is to determine the mechanism by which dietary vitamin A regulates the hair cycle. We found that vitamin A in a dose-dependent manner increased nuclear localized beta-catenin (CTNNB1; a marker of canonical wingless-type Mouse Mammary Tumor Virus integration site family (WNT) signaling) and levels of WNT7A within the hair follicle bulge in these C3H/HeJ mice. These findings suggest that feeding mice high levels of dietary vitamin A increases WNT signaling to activate hair follicle SCs.
Introduction:
Alopecia is a common concern encountered in the medical practice. Treatment approach varies according to the type and severity of alopecia. However, available treatment options have limited efficacy and several adverse effects. Presently, there are different treatment options being studied to overcome these limitations. Additionally, cellular pathways involved in the pathophysiology of alopecia are further being clarified to potentially target pathogenic molecules.
Areas covered:
We searched the literature for recently published articles discussing new treatment options as well as mechanisms involved in alopecia. We discuss the use of stem cells, growth factors, cellular pathways and robotic hair transplant, among other emerging therapies used for alopecia.
Expert opinion:
Future looks very promising and new effective treatments such as janus kinase inhibitors could possibly be available for alopecia areata. The stem-cell technology is advancing and companies involved in hair follicle neogenesis are starting clinical trials on patients with androgenetic alopecia.
Diacylglycerol O-acyltransferase 1 (DGAT1) plays an important role in synthesizing lipids, and inhibitors of DGAT1 have been investigated as potential treatments for diabetes and metabolic diseases. DGAT1 knockout (-/-) mice are resistant to obesity, have increased sensitivity to insulin, and exhibit sebaceous gland atrophy and alopecia. Prolonged pharmacological inhibition of DGAT1 with AZD7687 in mice results in the same skin phenotype, including sebaceous gland atrophy and alopecia, as seen in the skin of DGAT1 (-/-) mice. AZD7687-mediated effects on the skin were dose- and time-dependent and reversible. They occurred only at substantial levels of continuous DGAT1 inhibition. Prolonged treatment of dogs with AZD7687 also resulted in sebaceous gland atrophy but did not result in the more adverse skin changes of hair loss and skin lesions. Our findings highlight a significant risk of generating the same lesions that were seen in mouse skin during clinical development of DGAT1 inhibitors in humans and also reveal a species difference in the effects on the skin, indicating that the mouse may be an especially sensitive species. Therefore, although human therapeutic doses may not have the same influence on skin morphology as seen in mice, monitoring of skin changes will be essential in clinical trials with DGAT1 inhibitors.
In this report, we describe an auto-regulatory loop in human keratinocytes, whereby all-trans retinoic acid (retinoic acid) regulates its own biosynthesis from all-trans retinol (retinol) through regulation of retinol esterification. Retinol esterification activity was low in normal proliferating
human keratinocytes, cultured in retinoid-free media. Treatment of keratinocytes with retinoic acid induced retinol esterifying
activity (8-fold). Induction of retinol esterifying activity was blocked by either actinomycin D or cycloheximide. Based on
substrate specificity and inhibitor sensitivity, lecithin:retinol acyltransferase (LRAT) was identified as the retinoic acid-inducible
retinol esterifying enzyme. Induction of LRAT by retinoic acid reduced conversion of retinol to retinoic acid by 50%. This
reduction in retinoic acid synthesis resulted from sequestration of retinol as retinyl esters, since inhibition of LRAT restored
retinoic acid synthesis to control levels. In normal human skin, undifferentiated keratinocytes, in the lowest cell layer,
esterified retinol 4 times greater, than differentiating keratinocytes, in upper cell layers, reflecting an induced state,
under conditions of retinol sufficiency. Regulation of LRAT activity by retinoic acid provides a novel mechanism through which
retinoic acid can regulate its own level by controlling availability of retinol for conversion to retinoic acid. In human
skin in vivo, retinyl esters synthesized in basal keratinocytes could undergo hydrolysis during differentiation and thus serve as a source
of retinol for keratinocytes in upper layers of skin.
We previously reported that mice with skin-specific deletion of stearoyl-CoA desaturase-1 (Scd1) recapitulated the skin phenotype and hypermetabolism observed in mice with a whole-body deletion of Scd1. In this study, we first performed a diet-induced obesity experiment at thermoneutral temperature (33°C) and found that skin-specific Scd1 knockout (SKO) mice still remain resistant to obesity. To elucidate the metabolic changes in the skin that contribute to the obesity resistance and skin phenotype, we performed microarray analysis of skin gene expression in male SKO and control mice fed a standard rodent diet. We identified an extraordinary number of differentially expressed genes that support the previously documented histological observations of sebaceous gland hypoplasia, inflammation and epidermal hyperplasia in SKO mice. Additionally, transcript levels were reduced in skin of SKO mice for genes involved in fatty acid synthesis, elongation and desaturation, which may be attributed to decreased abundance of key transcription factors including SREBP1c, ChREBP and LXRα. Conversely, genes involved in cholesterol synthesis were increased, suggesting an imbalance between skin fatty acid and cholesterol synthesis. Unexpectedly, we observed a robust elevation in skin retinol, retinoic acid and retinoic acid-induced genes in SKO mice. Furthermore, SEB-1 sebocytes treated with retinol and SCD inhibitor also display an elevation in retinoic acid-induced genes. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining retinol homeostasis and point to disturbed retinol metabolism as a novel contributor to the Scd1 deficiency-induced skin phenotype.
When the skin is damaged, a variety of cell types must migrate, proliferate, and differentiate to reform a functional barrier to the external environment. Recent studies have shown that progenitor cells residing in hair follicles (HFs) are able to contribute to this re-epithelialization of wounds in vivo. However, the influence of the hair cycle on wound healing has not previously been addressed. Here, we have exploited spontaneous postnatal hair-cycle synchronicity in mice to systematically examine the influence of the different hair-cycle stages on murine skin wound healing. We report significant acceleration of healing during the anagen phase of HF cycling in vivo, associated with alterations in epithelial, endothelial, and inflammatory cell types. Intriguingly, gene profiling data reveal a clear correlation between the transcription of genes beneficial for wound healing and those upregulated during the anagen phase of the hair cycle in unwounded skin. These findings, which demonstrate a previously unappreciated association between HF cycling and wound healing, reveal numerous molecular correlates for further investigation.
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Mammalian epidermis consists of three self-renewing compartments: the hair follicle, the sebaceous gland, and the interfollicular
epidermis. We generated knock-in alleles of murine Lgr6, a close relative of the Lgr5 stem cell gene. Lgr6 was expressed in the earliest embryonic hair placodes. In adult hair follicles, Lgr6+ cells resided in a previously uncharacterized
region directly above the follicle bulge. They expressed none of the known bulge stem cell markers. Prenatal Lgr6+ cells established
the hair follicle, sebaceous gland, and interfollicular epidermis. Postnatally, Lgr6+ cells generated sebaceous gland and
interfollicular epidermis, whereas contribution to hair lineages gradually diminished with age. Adult Lgr6+ cells executed
long-term wound repair, including the formation of new hair follicles. We conclude that Lgr6 marks the most primitive epidermal
stem cell.
Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors.
The specific tissue changes which follow the deprivation of fat-soluble vitamin A in albino white rats and in the human concerns epithelial tissues. This effect is the substitution of stratified keratinizing epithelium for normal epithelium in various parts of the respiratory tract, alimentary tract, eyes, and paraocular glands and the genitourinary tract. We have described the morphological sequences which clearly show that the replacement of epithelium arises from focal proliferation of cells arising from the original epithelium and not by differentiation or change of preexisting cells. Young rats respond to the deficiency more promptly than adults. Growth activity of epithelium is not diminished. On the contrary, there is convincing evidence that it is greatly augmented. In a few of our animals the behavior of the replacing epithelium in respect to numbers of mitotic figures and response on the part of connective tissue and blood vessels suggests the acquisition of neoplastic properties. While the epitheliums which are the seats of these changes are largely of covering types, glandular epithelium is involved, specifically in the paraocular glands and salivary glands. It is highly probable also that the epithelium of gland ducts, respiratory mucosa, and genitourinary tract have secretory functions so that we conclude that the deficiency results in loss of specific (chemical) functions of the epitheliums concerned, while the power of growth becomes augmented. Explanation for the substitution of a chemically inactive (nonsecretory) epithelium, common in type for all locations, remains a matter of speculation. We can only speculate also in regard to the absence of change in the epithelium of such organ as the liver, parenchyma of the kidney, stomach, and intestines. The significance of the order or sequence in which different organs exhibit this change has not been determined. In general the respiratory mucosa in nares, trachea, and bronchi respond first, then the salivary glands, eye, genitourinary tract, then paraocular glands and pancreas, although as has been noted there are exceptions to this order. Our studies show that the mitochondrial apparatus is not primarily affected. Study of individual cells indicates that the first morphological evidence of avitaminosis will be found in the nucleus. We have not devoted sufficient study to be certain, but an increase of chromatin and in some instances in size of nucleoli are early morphological manifestations. Other important effects of fat-soluble A deficiency are atrophy of glandular organs, emaciation, localized edema of testes, submaxillary gland, and connective tissue structures of the lungs and focal myocardial lesions. From our own limited experience with rats fed on a water-soluble B deficient diet and from work by Cramer, Drew, and Mottram, the loss of fat in water-soluble B deficiency is as great, if not greater than in vitamin A deuciency, so that tor tne present we assume that this is not a specific manifestation of any one avitaminosis. The same applies to glandular atrophy. Both of these effects probably concern the nutrition as a whole and may be ascribed to inanition. The occurrence of transient edema in testes and salivary gland coinciding with a period of maximum atrophic change, suggests the hypothesis that this edema is the result of failure of epithelium to utilize transported material, which leads further to the hypothesis that the capillaries of these organs are differentiated in regard to permeability to the respective materials utilized by the cells. It would seem that in the case of the testis we have a unique instance of complete atrophy producible at will without impairment of circulation and supporting tissues. This phenomenon may possibly be followed with advantage in the study of the mechanism of edema. Vascularization of the cornea, as we have shown it to be independent of infection, must be a physiological response to the increased demands of the rapidly growing epithelium which has replaced the corneal epithelium. We have assumed throughout this work that the diet on which we kept our animals was deficient in respect to a single substance or group of substances having similar physiological properties, designated by the term fat-soluble vitamin A. Whether or not more than one so called vitamin or accessory substance was missing in the diet we employed does not affect the theoretical importance of the morphological results. Work by Evans and Bishop would indicate that other factors affecting fertility in addition to the so called antixerophthalmic or vitamin A factor may have been missing. Our own experience leads us to believe the specific effects we have described upon epithelial tissues were in all probability due to withdrawal of a single factor. We have shown how these effects, that is the replacement of uterine epithelium by keratinizing epithelium can account for sterility in the female. Whether or not the atrophy of the testis is due to the same factor remains to be proved, but presumptive evidence is strong that this is the case. The study of the reverse changes that follow in the rapid amelioration when the rats are restored to an adequate diet has been begun and will be reported later. We have shown that the substitution of keratinizing epithelium in all locations is not secondary to infections, and presumably is a primary effect of the withdrawal of factors essential for the chemical activities or maintenance of differentiation of the epitheliums concerned. It is, of course, possible that the phenomenon is produced in a roundabout way in that it may be secondary to the effects of the avitaminosis upon the metabolism of tissue-sustaining substances. This possibility is supported by the cessation of growth of the skeleton and teeth, although we know that other avitaminoses produce retardation of growth.
Lrig1 is a marker of human interfollicular epidermal stem cells and helps maintain stem cell quiescence. We show that, in mouse epidermis, Lrig1 defines the hair follicle junctional zone adjacent to the sebaceous glands and infundibulum. Lrig1 is a Myc target gene; loss of Lrig1 increases the proliferative capacity of stem cells in culture and results in epidermal hyperproliferation in vivo. Lrig1-expressing cells can give rise to all of the adult epidermal lineages in skin reconstitution assays. However, during homeostasis and on retinoic acid stimulation, they are bipotent, contributing to the sebaceous gland and interfollicular epidermis. beta-catenin activation increases the size of the junctional zone compartment, and loss of Lrig1 causes a selective increase in beta-catenin-induced ectopic hair follicle formation in the interfollicular epidermis. Our results suggest that Lrig1-positive cells constitute a previously unidentified reservoir of adult mouse interfollicular epidermal stem cells.
Increased fibroblast growth factor receptor-2 (FGFR2) signaling has been proposed to be involved in acne pathogenesis and explains acne lesions in Apert syndrome and unilateral acneiform nevus associated with gain-of-function point mutations of FGFR2. If, indeed, increased FGFR2 signaling plays a major pathogenic role in follicular hyperkeratinization and sebaceous gland hypertrophy in acne, effective anti-acne drugs may attenuate increased FGFR2 signaling. The purpose of this article is to elucidate the hypothesis that known anti-acne agents may operate by downregulation of increased FGFR2 signaling. Anti-androgens suppress FGF-ligand expression, benzoyl peroxide induces FGFR2 downregulation by lysosomal receptor degradation, azelaic acid inhibits mitochondrial ATP formation required for receptor tyrosine kinase phosphorylation, tetracyclines inhibit the expression, and activity of FGFR2b downstream matrix metalloproteinases, and retinoids attenuate the FGFR2 pathway at several regulatory levels of the signal transduction cascade critical for cell cycle control, cell proliferation, differentiation, and lipogenesis. Erythromycin, a P-450 inhibitor, may interfere with FGFR2 signaling by its inhibitory effect on retinoid catabolism. The gain-of-function mutations of FGFR2 in Apert syndrome and unilateral acneiform nevus, and the proposed synergistic inhibitory interactions of anti-acne agents at various levels of the FGFR2-signaling cascade underline the role of FGFR2 signaling in the pathogenesis of acne.
Primary cicatricial or scarring alopecias (CA) are a group of inflammatory hair disorders of unknown pathogenesis characterized by the permanent destruction of the hair follicle. The current treatment options are ineffective in controlling disease progression largely because the molecular basis for CA is not understood. Microarray analysis of the lymphocytic CA, Lichen planopilaris (LPP), compared to normal scalp biopsies identified decreased expression of genes required for lipid metabolism and peroxisome biogenesis. Immunohistochemical analysis showed progressive loss of peroxisomes, proinflammatory lipid accumulation, and infiltration of inflammatory cells followed by destruction of the pilosebaceous unit. The expression of peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor that regulates these processes, is significantly decreased in LPP. Specific agonists of PPARgamma are effective in inducing peroxisomal and lipid metabolic gene expression in human keratinocytes. Finally, targeted deletion of PPARgamma in follicular stem cells in mice causes a skin and hair phenotype that emulates scarring alopecia. These studies suggest that PPARgamma is crucial for healthy pilosebaceous units and it is the loss of this function that triggers the pathogenesis of LPP. We propose that PPARgamma-targeted therapy may represent a new strategy in the treatment of these disorders.
Retinoic acid (RA) is a potent signaling molecule that is essential for many biological processes, and its levels are tightly regulated by mechanisms that are only partially understood. The synthesis of RA from its precursor retinol (vitamin A) is an important regulatory mechanism. Therefore, the esterification of retinol with fatty acyl moieties to generate retinyl esters, the main storage form of retinol, may also regulate RA levels. Here we show that the neutral lipid synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) functions as the major acyl-CoA:retinol acyltransferase (ARAT) in murine skin. When dietary retinol is abundant, DGAT1 deficiency results in elevated levels of RA in skin and cyclical hair loss; both are prevented by dietary retinol deprivation. Further, DGAT1-deficient skin exhibits enhanced sensitivity to topically administered retinol. Deletion of the enzyme specifically in the epidermis causes alopecia, indicating that the regulation of RA homeostasis by DGAT1 is autonomous in the epidermis. These findings show that DGAT1 functions as an ARAT in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity. Our findings may have implications for human skin or hair disorders treated with agents that modulate RA signaling.
Journal of Investigative Dermatology advance online publication, 6 November 2008; doi:10.1038/jid.2008.338.
In mouse hair follicles, a group of quiescent cells in the bulge is believed to have stem cell activity. Lgr5, a marker of intestinal stem cells, is expressed in actively cycling cells in the bulge and secondary germ of telogen hair follicles and in the lower outer root sheath of anagen hair follicles. Here we show that Lgr5(+) cells comprise an actively proliferating and multipotent stem cell population able to give rise to new hair follicles and maintain all cell lineages of the hair follicle over long periods of time. Lgr5(+) progeny repopulate other stem cell compartments in the hair follicle, supporting the existence of a stem or progenitor cell hierarchy. By marking Lgr5(+) cells during trafficking through the lower outer root sheath, we show that these cells retain stem cell properties and contribute to hair follicle growth during the next anagen. Expression analysis suggests involvement of autocrine Hedgehog signaling in maintaining the Lgr5(+) stem cell population.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that modulate target gene expression in response to natural fatty acid ligands and synthetic agonists. It is noteworthy that all trans-retinoic acid (atRA) has recently been reported to act as a ligand for PPARbeta/delta, to activate its transcriptional activity, and, in contrast to the "classic" function of atRA, to stimulate cell proliferation (Schug et al., 2007). Here, we report that in contrast to synthetic PPARbeta/delta agonists, atRA failed to induce the transcriptional activity of PPARbeta/delta using different types of reporter gene assays. Likewise, atRA did not affect the expression of the bona fide PPARbeta/delta target genes ADRP and ANGPTL4 but strongly increased expression of the retinoic acid target gene CYP26A under the identical experimental conditions. Consistent with these observations, atRA did not compete with established PPARbeta/delta agonists in a ligand binding assay, and atRA did not enable the interaction of PPARbeta/delta with a coactivator peptide in a time-resolved fluorescence resonance energy transfer assay in vitro. These results are in sharp contrast to the effect of established PPARbeta/delta agonists in both in vitro assays. Taken as a whole, these data strongly suggest that atRA does not function as a ligand of PPARbeta/delta in any of the experimental systems tested and that the previously reported atRA effects are more likely to reflect an uncharacterized and less direct mechanism.
Although there is strong evidence that ligand activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta induces terminal differentiation and attenuates cell growth, some studies suggest that PPARbeta/delta actually enhances cell proliferation. For example, it was suggested recently that retinoic acid (RA) is a ligand for PPARbeta/delta and potentiates cell proliferation by activating PPARbeta/delta. The present study examined the effect of ligand activation of PPARbeta/delta on cell proliferation, cell cycle kinetics, and target gene expression in human HaCaT keratinocytes using two highly specific PPARbeta/delta ligands [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy acetic acid (GW0742) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516)] and RA. Both PPARbeta/delta ligands and RA inhibited cell proliferation of HaCaT keratinocytes. GW0742 and GW501516 increased expression of known PPARbeta/delta target genes, whereas RA did not; RA increased the expression of known retinoic acid receptor/retinoid X receptor target genes, whereas GW0742 did not affect these genes. GW0742, GW501516, and RA did not modulate the expression of 3-phosphoinositide-dependent protein kinase or alter protein kinase B phosphorylation. GW0742 and RA increased annexin V staining as quantitatively determined by flow cytometry. The effects of GW0742 and RA were also examined in wild-type and PPARbeta/delta-null primary mouse keratinocytes to determine the specific role of PPARbeta/delta in modulating cell growth. Although inhibition of keratinocyte proliferation by GW0742 was PPARbeta/delta-dependent, inhibition of cell proliferation by RA occurred in both genotypes. Results from these studies demonstrate that ligand activation of PPARbeta/delta inhibits keratinocyte proliferation through PPARbeta/delta-dependent mechanisms. In contrast, the observed inhibition of cell proliferation in mouse and human keratinocytes by RA is mediated by PPARbeta/delta-independent mechanisms and is inconsistent with the notion that RA potentiates cell proliferation by activating PPARbeta/delta.
The CRABP-I and CRABP-II proteins are high affinity cytoplasmic retinoic acid-binding proteins. In undifferentiated F9 teratocarcinoma stem cells, only the CRABP-I protein is expressed at detectable levels. We have previously shown that overexpression of the CRABP-I protein in stably transfected F9 stem cell lines results in a lower sensitivity to a given external concentration of retinoic acid relative to that of untransfected F9 cells; in contrast, reduced CRABP-I expression in CRABP-I cDNA anti-sense transfected lines is associated with increased sensitivity of these lines to retinoic acid. These three types of cell lines were cultured in the presence of 50 nM [3H]retinoic acid, and the metabolism of retinoic acid was followed over the next 24 h. The results demonstrate that CRABP-I has the ability to alter both the levels and types of RA metabolites produced in the cytoplasm of differentiating embryonic stem cells. Moreover, the level of CRABP-I determines the rate of RA metabolism to 4-oxo-RA such that the higher the CRABP-I level, the faster the metabolism of [3H]retinoic acid. This is the first reported connection between the level of CRABP-I expression and intracellular RA metabolism.
The factors that determine the axial orientation and phenotypes of skin appendages were analyzed by studying the effect of retinoic acid (RA) on embryonic chicken skin explant cultures. With RA uniformly distributed in the culture media, the feather buds became smaller, were disoriented or were transformed into scale-like structures in a concentration-dependent manner (from 0.05 –2.5 μM). With RA distributed as a gradient created by a RA-soaked anion exchange bead, a radial zone of inhibition with a rim of disoriented buds was observed. The new axis of the disoriented buds appeared to be determined by a combination of the original feather axis determining force and a new axial force pointing centrifugally away from the RA source. This observed result can be simulated with a computer model using a vectorial sum of different feather axial determination forces. The size of the inhibited zone is linearly correlated to the RA concentration and may be used to quantify the morphogenetic activity of retinoids. These effects are specific to developmental stages (Hamburg and Hamilton stage 31–34).
Both all-trans and 13-cis RA have morphogenetic activity. Retinol has no effect and retinal has a small inhibitory effect but neither phenotypic transformation nor axial disorientation were observed. The antero-posterior gradient of homeoprotein XlHbox 1 in feather buds became diffusive after RA treatment. RA dissolves dermal condensations and the distribution of N-CAM is altered from an anterior localized pattern to a diffusive presence in the bud cores. Endogenous retinoids in developing skins show developmental stage-dependent changes both quantitatively and qualitatively. The results suggest that RA either is or can modulate the endogenous morphogen(s) that determine the orientation and phenotype of skin appendages, and that this morphogenetic pathway involves Hox genes and adhesion molecules.
Treatment with retinoic acid (RA) is known to produce complex teratogenic effects in vertebrates, and its presence in the developing embryo as an endogenous substance has led to the suggestion that RA might be a natural morphogenetic agent. Although our understanding of the molecular mechanism of RA action has improved considerably with the identification of nuclear receptors for RA (RARs) and RA-responsive genes, the exact relationship between the proposed morphogenetic activity of RA and its teratogenic effects remains to be characterized. Here, we show that a RA response element (RARE) present in the RAR beta gene can direct specific spatial and temporal expression of an hsplacZ transgene during mouse embryogenesis. In the early embryo, the transgene is expressed in a specific anterior-posterior domain that is completely obliterated by treatment of pregnant mice with teratogenic doses of RA. The expression of the transgene becomes more restricted as organogenesis progresses and mimics closely the reported expression of the RAR beta gene. These results suggest that, in vivo, some of the morphogenetic effects of RA could be mediated through localized transcriptional activity controlled by the various RARs. The specific pattern of expression of the RAREhsplacZ transgene does not correlate with the proposed sites of action of RA as defined by its teratogenic effects but does support a role for RA in early anterior-posterior patterning along the body axis.
This review describes the various types of sebaceous glands, their locations, and where possible their different functions. All sebaceous glands are similar in structure and secrete sebum by a holocrine process. However, the nature of this secretion and the regulation of the secretory process seem to differ among the various types of glands. Methods for measuring sebum secretion and assessing sebaceous gland activity are also described. The area of major interest during the last 20 years has undoubtedly been the mechanisms that control sebaceous gland function. Most studies have focused on the endocrine control and in particular on the role of androgens and pituitary hormones, although evidence suggests that nonendocrine factors may also be important. However, many questions remain and during the next few years attention will certainly be given to the role of retinoids and their mode of action in the treatment of acne.
Based on the published literature, the assessment of nonclinical and clinical data on retinol indicates absence of any systemic effects after topical or cosmetic use. Hypervitaminosis A that may be produced by the ingestion of excessive amounts of retinol or retinyl esters has never been associated with topical application. In rabbits treated with retinyl palmitate at about three times a prospective human dose level, no systemic toxicity was observed. Retinol, retinyl esters, and retinaldehyde are devoid of sensitization potential and no evidence of phototoxicity or photoallergy has been obtained. Although retinoids may be degraded to some extent by sunlight, their biological activity appears to be largely retained. In fact, topical retinoids have been shown to improve the conditions of photodamaged and photoaged skin. Topical retinol is absorbed into the epidermis and extensively metabolized, particularly by keratinocytes. Studies in human volunteers provided no evidence that topically applied retinol or retinoid metabolites are percutaneously absorbed, inducing any detectable changes in their constitutive plasma levels. In the absence of systemic exposure, topical application of the retinoids is not associated with birth defects that have been related to excessive oral intakes. Retinol and its metabolites are not only nongeno-toxic but also exert antimutagenic activity. Likewise, retinol and retinoids have antiproliferative and differentiation-inducing effects that are used effectively in the treatment of human cancer. Retinol is considered to be a safe cosmetic ingredient in the present practices of use and concentration.
Retinoic acid derivatives (retinoids) exert their pleiotropic effects on cell development through specific nuclear receptors, the retinoic acid receptors and retinoid X receptors. Despite recent progress in understanding the cellular and molecular mechanisms of retinoid activity, it is unknown which of the retinoid receptor pathways are involved in the specific processes of sebocyte growth and development. In this study, we investigated the roles of specific retinoid receptors in sebocyte growth and differentiation, by testing the effects of selective retinoic acid receptor and retinoid X receptor ligands at concentrations between 10-10 M and 10-6 M in a primary rat preputial cell monolayer culture system. Cell growth was determined by number of cells and colonies, and cell differentiation by analysis of lipid-forming colonies. All-trans retinoic acid and selective retinoic acid receptor agonists (CD271 = adapalene, an RAR-, agonist; CD2043 = retinoic acid receptor pan-agonist; and CD336 = Am580, an RAR- agonist) caused significant decreases in numbers of cells, colonies, and lipid-forming colonies, but with an exception at high doses of all-trans retinoic acid (10-6 M), with which only a small number of colonies grew but they became twice as differentiated as controls (42.2 4.0% vs 22.6 2.7%, mean  SEM, lipid-forming colonies, p < 0.01). Furthermore, the RAR-, antagonist CD2665 antagonized the suppressive effects of all-trans retinoic acid, adapalene, and CD2043 on both cell growth and differentiation. In contrast, the retinoid X receptor agonist CD2809 increased cell growth slightly and lipid-forming colonies dramatically in a clear dose-related manner to a maximum of 73.7% 6.7% at 10-6 M (p < 0.001). Our data suggest that retinoic acid receptors and retinoid X receptors differ in their roles in sebocyte growth and differentiation: (i) retinoic acid receptors, especially the and/or subtypes, mediate both the antiproliferative and antidifferentiative effects of retinoids; (ii) retinoid X receptors mediate prominent differentiative and weak proliferative effects; (iii) the antiproliferative and antidifferentiative effects of all-trans retinoic acid are probably mediated by retinoic acid receptors, whereas its differentiative effect at high dose may be mediated by retinoid X receptors via all-trans retinoic acid metabolism to 9-cis retinoic acid, the natural ligand of retinoid X receptors.Keywords: retinoic acid, retinoic acid receptor, retinoid X receptor
Increasing evidence suggests that the retinoid-X receptors (RXR-· ,-· ,-·) play a crucial role in regulating the transcriptional
activity of several steroid hormone receptors, including the receptors for retinoic acid (RAR-· ,-· ,-·), 1,25-dihydroxyvitamin
D3 and thyroid hormone. We investigated the localization of the different types of RXR-· ,-· ,-· and RAR-· ,-· ,-· proteins
in frozen sections of normal human skin (n = 12) in situ, applying recently raised corresponding specific monoclonal antibodies and an immunohistochemical technique that we established
for the detection of these nuclear receptors. Our findings indicate that RXR-· ,-· ,-· and RAR-· ,-· ,-· proteins can be detected
by immunohistochemistry in normal human skin. In contrast to RXR-· ,-· ,-· as well as RAR-· and RAR-· proteins that were consistently
detected in cell layers of the viable epidermis, RAR-· was only focally demonstrated in single epidermal cells in three out
of 12 biopsies analysed. Immunohistochemical labelling of RAR-· ,-· ,-· and RXR-· ,-· ,-· proteins in epidermal nuclei was
also pronounced in the stratum granulosum, suggesting a function of RXR and RAR proteins in the transition from proliferation
to differatiation in epidermal keratinocytes. Expression of RXRs and RARs in hair follicles, sebaceous glands and endothelial
cell points to a biological function from these nuclear receptors to hair growth as well as to the physiology of sebaceous
glands and endothelial cells.
Retinoic acid (RA) has marked effects on mouse upper-lip skin morphogenesis, leading to the development of glomerular gland instead of hair vibrissa follicle, but does not apparently change the dorsal pelage hair developmental program. In order to test the hypothesis that an up-regulation of the β retinoic acid nuclear receptor (RARβ) may be implicated in the alteration of the dermal-epidermal interactions which occur during cutaneous appendage development, RA-treated and untreated skin explants, controls as well as heterotopic recombinants, were made among nasal, upper-lip, and dorsal mouse embryonic tissues. They were analyzed by in situ hybridization with RARβ 35S-labeled probe after 48 hr of in vitro culture as well as by identification of the morphological phenotype of cutaneous appendages after 6 additional days of culture on the chick chorioallantoic membrane. The results show that only mesenchyme from the facial region can express the RARβ gene either normally or after RA treatment, depending on its nasal or upper-lip origin. However, the RARβ up-regulation is unrelated to hair glandular metaplasia, which depends both on a glandular bias of the upper-lip epidermis and on the weakening of hair follicle-inducing dermal properties. The latter occurs in both the upper-lip and dorsal dermis as a consequence of RA treatment.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that modulate target gene expression in response to natural fatty acid ligands and synthetic agonists. It is noteworthy that all trans-retinoic acid (atRA) has recently been reported to act as a ligand for PPARbeta/delta, to activate its transcriptional activity, and, in contrast to the "classic" function of atRA, to stimulate cell proliferation (Schug et al., 2007). Here, we report that in contrast to synthetic PPARbeta/delta agonists, atRA failed to induce the transcriptional activity of PPARbeta/delta using different types of reporter gene assays. Likewise, atRA did not affect the expression of the bona fide PPARbeta/delta target genes ADRP and ANGPTL4 but strongly increased expression of the retinoic acid target gene CYP26A under the identical experimental conditions. Consistent with these observations, atRA did not compete with established PPARbeta/delta agonists in a ligand binding assay, and atRA did not enable the interaction of PPARbeta/delta with a coactivator peptide in a time-resolved fluorescence resonance energy transfer assay in vitro. These results are in sharp contrast to the effect of established PPARbeta/delta agonists in both in vitro assays. Taken as a whole, these data strongly suggest that atRA does not function as a ligand of PPARbeta/delta in any of the experimental systems tested and that the previously reported atRA effects are more likely to reflect an uncharacterized and less direct mechanism.
All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes. Epithelial differentiation and its relationship to cancer, and embryogenesis have typified intense areas of interest into atRA function. Recently, however, interest in atRA action in the nervous system, the immune system, energy balance and obesity has increased considerably, especially concerning postnatal function. atRA action depends on atRA biosynthesis: defects in retinoid-dependent processes increasingly relate to defects in atRA biogenesis. Considerable evidence indicates that physiological atRA biosynthesis occurs via a regulated process, consisting of a complex interaction of retinoid binding-proteins and retinoid recognizing enzymes. An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. Each of these enzymes associates with explicit biological processes mediated by atRA. Redundancy occurs, but seems limited. Cumulative data support a model of interactions among these enzymes with retinoid binding-proteins, with feedback regulation and/or control by atRA via modulating gene expression of multiple participants. The ratio apo-CRBP1/holo-CRBP1 participates by influencing retinol flux into and out of storage as retinyl esters, thereby modulating substrate to support atRA biosynthesis. atRA biosynthesis requires the presence of both an RDH and an RALDH: conversely, absence of one isozyme of either step does not indicate lack of atRA biosynthesis at the site. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.
Retinoic acid (RA) is the active metabolite of vitamin A (retinol) that controls growth and development. The first step of RA synthesis is controlled by enzymes of the alcohol dehydrogenase (ADH) and retinol dehydrogenase (RDH) families that catalyze oxidation of retinol to retinaldehyde. The second step of RA synthesis is controlled by members of the aldehyde dehydrogenase (ALDH) family also known as retinaldehyde dehydrogenase (RALDH) that further oxidize retinaldehyde to produce RA. RA functions as a ligand for DNA-binding RA receptors that directly regulate transcription of specific target genes. Elucidation of the vitamin A metabolic pathway and investigation of the endogenous function of vitamin A metabolites has been greatly improved by development of mouse ADH, RDH, and RALDH loss-of-function models. ADH knockouts have demonstrated a postnatal role for this enzyme family in clearance of excess retinol to prevent vitamin A toxicity and in generation of RA for postnatal survival during vitamin A deficiency. A point mutation in Rdh10 generated by ethylnitrosourea has demonstrated that RDH10 generates much of the retinaldehyde needed for RA synthesis during embryonic development. Raldh1, Raldh2, and Raldh3 knockouts have demonstrated that RALDH1, RALDH2, and RALDH3 generate most of the RA needed during embryogenesis. These mouse models serve as instrumental tools for providing new insight into retinoid function. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.
Recent breakthroughs in the generation of induced pluripotent stem cells (iPSCs) have provided a novel renewable source of cells with embryonic stem cell-like properties, which may potentially be used for gene therapy and tissue engineering. Although iPSCs have been differentiated into various cell types, iPSC-derived keratinocytes have not yet been obtained. In this study, we report the in vitro differentiation of mouse iPSCs into a keratinocyte lineage through sequential applications of retinoic acid and bone-morphogenetic protein-4 and growth on collagen IV-coated plates. We show that iPSCs can be differentiated into functional keratinocytes capable of regenerating a fully differentiated epidermis, hair follicles, and sebaceous glands in an in vivo environment. Keratinocytes derived from iPSCs displayed characteristics similar to those of primary keratinocytes with respect to gene and protein expression, as well as their ability to differentiate in vitro and to reconstitute normal skin and its appendages in an in vivo assay. At present, no effective therapeutic treatments are available for many genetic skin diseases. The development of methods for the efficient differentiation of iPSCs into a keratinocyte lineage will enable us to determine whether genetically corrected autologous iPSCs can be used to generate a permanent corrective therapy for these diseases.
Multipotent adult stem cells have many potential therapeutic applications. Our recent findings suggest that hair follicles are a promising source of easily accessible multipotent stem cells. Stem cells in the hair follicle area express the neural stem cell marker nestin, suggesting that hair-follicle stem cells and neural stem cells have common features. Nestin-expressing hair follicle stem cells can form neurons and other cell types, and thus adult hair follicle stem cells could have important therapeutic applications, particularly for neurologic diseases. Transplanted hair follicle stem cells promote the functional recovery of injured peripheral nerve and spinal cord. Recent findings suggest that direct transplantation of hair-follicle stem cells without culture can promote nerve repair, which makes them potentially clinically practical. Human hair follicle stem cells as well as mouse hair follicle stem cells promote nerve repair and can be applied to test the hypothesis that human hair follicle stem cells can provide a readily available source of neurologically therapeutic stem cells. The use of hair follicle stem cells for nerve regeneration overcomes critical problems of embryonic stem cells or induced pluripotent stem cells in that the hair follicle stem cells are multipotent, readily accessible, non-oncogenic, and are not associated with ethical issues.
The vitamin D receptor (VDR) typically binds DNA in a heterodimer complex with the retinoid X receptor (RXR) to direct repeat sequences separated by three base pairs, or vitamin D response elements (VDREs). A modified yeast one-hybrid screen was utilized to search for partner proteins capable of associating with the VDR on a repressor VDRE. Screening of a HeLa cell cDNA library revealed that retinoic acid receptor gamma 2 (RARgamma2) could specifically interact with VDREs, either in the presence or absence of the VDR. Importantly, the A-domain of RARgamma2 appeared to be crucial for this interaction as evidenced by the inability of RARgamma1 to affect reporter gene activity. Transfection data in COS-7 cells revealed the combination of both receptor ligands strongly attenuated transcriptional activation from an enhancer VDRE when RARgamma2 was co-transfected into these cells with the VDR. Furthermore, a VDR/RARgamma2 complex was detected in the mobility shift assay from nuclear extracts of transfected cells. Thus, the data highlight the novel ability of RARgamma2 to interact with VDREs and impact vitamin D activity, which would allow for additional fine-tuning of a transcriptional response depending on ligand availability and expression profile of these nuclear receptors in a given cell type.
Recent studies on stem cells in the adult hair follicle (HF) have uncovered a veritable menagerie of exceptionally diverse and dynamic keratinocytes with stem cell properties located in distinct regions of the HF. Although endowed with specific functions during normal hair follicle maintenance, the majority of these cells can act as multipotent stem cells in stress situations, such as physical injury, which argues for an unanticipated degree of plasticity of these cells. This review provides an overview of the different epithelial stem cell populations, identified in the mouse HF, and their relationships with one another, and envisions possible cellular mechanisms underlying normal HF maintenance and skin regeneration.
Mammalian epidermis is maintained by self-renewal of stem cells and terminal differentiation of their progeny. New data reveal a diversity amongst stem cells that was previously unrecognized. Different stem cell populations have different locations and differ in whether they are quiescent or actively cycling. During normal epidermal homeostasis, each stem cell population feeds a restricted number of differentiated lineages. However, in response to injury or genetic manipulation the different pools of stem cells demonstrate multi-lineage differentiation ability. While it is well established that Wnt signalling promotes hair follicle (HF) differentiation, new observations suggest a role for EGF receptor signalling in promoting differentiation of interfollicular epidermis. NFATc1 maintains quiescence in the HF, while Lrig1 exerts the same function in the junctional zone. The stage is now set for exploring the relationship between the different epidermal stem cell populations and between quiescence and lineage selection.
Skin plays an important part in the protection against oxidative stressors, such as ultraviolet radiation, ozone, and chemicals. This study was based on the observation that upper facial stratum corneum contained significantly higher levels of the antioxidant alpha-tocopherol than corresponding layers of arm stratum corneum. We hypothesized that the underlying mechanism involves sebaceous gland secretion of vitamin E. To test this, we examined in eight human volunteers: (i) stratum corneum levels and distribution profiles of vitamin E in sites with a different sebaceous gland density (arm versus cheek); (ii) whether vitamin E is a significant constituent of human sebum; and (iii) if there is a correlation between levels of vitamin E and squalene, a marker of sebum secretion, in skin surface lipids. Using standardized techniques for stratum corneum tape stripping and sebum collection, followed by high-performance liquid chromatography analysis of tocopherols and squalene, we found that: (i) the ratio of cheek versus upper arm alpha-tocopherol levels was 20 : 1 for the upper stratum corneum and decreased gradually with stratum corneum depth; (ii) vitamin E (alpha- and gamma-tocopherol forms) is a significant constituent of human sebum and is continuously secreted at cheek and forehead sites during a test period of 135 min; and (iii) vitamin E correlates well with levels of cosecreted squalene (r2 = 0.86, p < 0.001). In conclusion, sebaceous gland secretion is a relevant physiologic pathway for the delivery of vitamin E to upper layers of facial skin. This mechanism may serve to protect skin surface lipids and the upper stratum corneum from harmful oxidation.
The initiation stage of mouse skin carcinogenesis involves the induction of mutations in keratinocyte stem cells (KSC), which confers a selective growth advantage allowing clonal expansion during tumor promotion. Targeted disruption of signal transducer and activator of transcription 3 (Stat3) in bulge region KSCs was achieved by treating K15.CrePR1 x Stat3(fl/fl) mice with RU486. Deletion of Stat3 prior to skin tumor initiation with 7,12-dimethylbenz(a)anthracene significantly increased the number of apoptotic KSCs and decreased the frequency of Ha-ras codon 61 A(182)-->T transversion mutations in this cell population compared with wild-type littermates. Targeted disruption of Stat3 in bulge region KSCs at the time of initiation also dramatically reduced the number of skin tumors (by approximately 80%) produced following promotion with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. These results show that Stat3 is required for the survival of bulge region KSCs during tumor initiation. Furthermore, these data provide direct evidence that bulge region KSCs are the primary targets for the initiation of skin tumors in this model system.
The Global Alliance to Improve Outcomes in Acne published recommendations for the management of acne as a supplement to the Journal of the American Academy of Dermatology in 2003. The recommendations incorporated evidence-based strategies when possible and the collective clinical experience of the group when evidence was lacking. This update reviews new information about acne pathophysiology and treatment-such as lasers and light therapy-and relevant topics where published data were sparse in 2003 but are now available including combination therapy, revision of acne scarring, and maintenance therapy. The update also includes a new way of looking at acne as a chronic disease, a discussion of the changing role of antibiotics in acne management as a result of concerns about microbial resistance, and factors that affect adherence to acne treatments. Summary statements and recommendations are provided throughout the update along with an indication of the level of evidence that currently supports each finding. As in the original supplement, the authors have based recommendations on published evidence as much as possible.
Hair is a primary characteristic of mammals, and exerts a wide range of functions including thermoregulation, physical protection, sensory activity, and social interactions. The hair shaft consists of terminally differentiated keratinocytes that are produced by the hair follicle. Hair follicle development takes place during fetal skin development and relies on tightly regulated ectodermal-mesodermal interactions. After birth, mature and actively growing hair follicles eventually become anchored in the subcutis, and periodically regenerate by spontaneously undergoing repetitive cycles of growth (anagen), apoptosis-driven regression (catagen), and relative quiescence (telogen). Our molecular understanding of hair follicle biology relies heavily on mouse mutants with abnormalities in hair structure, growth, and/or pigmentation. These mice have allowed novel insights into important general molecular and cellular processes beyond skin and hair biology, ranging from organ induction, morphogenesis and regeneration, to pigment and stem cell biology, cell proliferation, migration and apoptosis. In this review, we present basic concepts of hair follicle biology and summarize important recent advances in the field.
All-trans retinoic acid (RA) levels are controlled by enzymes of the vitamin A metabolism (RDH16, RalDH2, and LRAT) and RA catabolism (CYP26 and CYP2S1). Here, the mRNA expression of these enzymes was investigated in human keratinocytes at different Ca(2+)concentrations and after exposure to RA and CYP26 inhibitors. Cellular differentiation (high Ca(2+)) increased the expression of LRAT, RDH16 and RalDH2, and decreased CYP26B1. RA (1 microM) induced CYP26A1, CYP26B1, CYP2S1, CRABPII and LRAT mRNA. The CYP26 inhibitor talarozole altered CYP26A1 and LRAT mRNA expression in a similar way as RA, increased the cellular accumulation of [(3)H]RA, and induced a punctate CRABPII staining, also observed after siRNA knock-down of CYP26B1 (but not after RA exposure). Furthermore, CYP26B1 siRNA increased the accumulation of [(3)H]RA and the CRABPII mRNA, suggesting an augmented retinoid signalling. Thus CYP26B1 appears essential for RA catabolism under physiological conditions, whereas CYP26A1 might play a greater role during RA excess.
Sebocytes are sebum-producing cells that form the sebaceous glands. We investigated the role of sebocytes as target cells for vitamin D metabolites and the existence of an enzymatic machinery for the local synthesis and metabolism of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3), calcitriol], the biologically active vitamin D metabolite, in these cell types. Expression of vitamin D receptor (VDR), vitamin D-25-hydroxylase (25 OHase), 25-hydroxyvitamin D-1alpha-hydroxylase (1 alphaOHase), and 1,25-dihydroxyvitamin D-24-hydroxylase (24 OHase) was detected in SZ95 sebocytes in vitro using real time quantitative polymerase chain reaction. Splice variants of 1alphaOHase were identified by nested touchdown polymerase chain reaction. We demonstrated that incubation of SZ95 sebocytes with 1,25(OH)(2)D(3) resulted in a cell culture condition-, time-, and dose-dependent modulation of cell proliferation, cell cycle regulation, lipid content and interleukin-6/interleukin-8 secretion in vitro. RNA expression of VDR and 24 OHase was upregulated along with vitamin D analogue treatment. Although several other splice variants of 1alphaOHase were detected, our findings indicate that the full length product represents the major 1 alphaOHase gene product in SZ95 cells. In conclusion, SZ95 sebocytes express VDR and the enzymatic machinery to synthesize and metabolize biologically active vitamin D analogues. Sebocytes represent target cells for biologically active metabolites. Our findings indicate that the vitamin D endocrine system is of high importance for sebocyte function and physiology. We conclude that sebaceous glands represent potential targets for therapy with vitamin D analogues or for pharmacological modulation of 1,25(OH)(2)D(3) synthesis/metabolism.
Primary cicatricial alopecias (PCA) represent uncommon inflammatory disorders that result in permanent loss of scalp hair. Cutaneous autoimmunity, most prominently chronic cutaneous lupus erythematosus (CCLE), can result in this kind of scarring hair loss. The cosmetic disfigurement caused by PCA and the very unsatisfactory therapeutic options available to date all demand a better understanding of the obscure pathobiology of PCA so as to define new therapeutic targets and strategies. Hair follicle (HF) cycling and regeneration are abolished in PCA due to irreversible, epithelial hair follicle stem cell (eHFSC) damage, triggered by major, yet unclear pro-inflammatory events (e.g. type I interferon-associated cytotoxic inflammation, loss of HF immune privilege, loss of immunosuppressive "no danger" signals). Therefore, immuno-protection of eHFSC and restitution of their immune privilege are attractive future therapeutic strategies in PCA. Chronic cutaneous lupus erythematosus-associated PCA may serve as a model system for other diseases where epithelial stem cells undergo immuno-destruction.
Retinoic acid (RA) signalling is essential for epidermal differentiation; however, the mechanisms by which it acts are largely unexplored. Partitioning of RA between different nuclear receptors is regulated by RA-binding proteins. We show that cellular RA-binding proteins CRABP1 and CRABP2 and the fatty acid-binding protein FABP5 are dynamically expressed during skin development and in adult tissue. CRABP1 is expressed in embryonic dermis and in the stroma of skin tumours, but confined to the hair follicle dermal papilla in normal postnatal skin. CRABP2 and FABP5 are expressed in the differentiating cells of sebaceous gland, interfollicular epidermis and hair follicles, with FABP5 being a prominent marker of sebaceous glands and anagen follicle bulbs. All three proteins are upregulated in response to RA treatment or Notch activation and are negatively regulated by Wnt/beta-catenin signalling. Ectopic follicles induced by beta-catenin arise from areas of the sebaceous gland that have lost CRABP2 and FABP5; conversely, inhibition of hair follicle formation by N-terminally truncated Lef1 results in upregulation of CRABP2 and FABP5. Our findings demonstrate that there is dynamic regulation of RA signalling in different regions of the skin and provide evidence for interactions between the RA, beta-catenin and Notch pathways.
Acne is the most common skin disease which affects millions of people worldwide. Seborrhea and sebostasis are major cosmetic problems but also lead occasionally to diseases. This article summarizes the data of newest research of sebostasis, seborrhoea and acne made possible through the development of human and animal sebocyte culture models.
Experiments were conducted to determine the sequence and reliability of appearance of key signs of vitamin A deficiency. Rapid and essentially synchronous vitamin A deficiency was induced by the withdrawal of retinoic acid from mature (190–210 g) stringently vitamin A-deficient male rats reared by feeding early growth plateau (60–70 g) vitamin A-deprived rats diets first supplemented with and then lacking in 2 µg retinoic acid per gram diet in repeating 18 day:10 day supplementation: deprivation cycles. Growth was depressed within 1 to 2 days of the withdrawal of retinoic acid whether animals were force-fed or were fed ad libitum. Similar patterns were obtained when animals were fed 5 or 10 µg retinoic acid per gram diet. Appetite was depressed (1–2 days) whether animals were fed 18% casein diets, or were given 10% dextrose drinking solutions only. Decreased food intake was not due to impaired taste function or to poor palatability of the deficient diet. Bilateral electrolytic lesions in the ventromedial nucleus of the hypothalamus or anterior prepyriform cortex failed to prevent or to delay loss of appetite. Supplementation with antibiotics decreased body weight losses in the late stages of deficiency and increased survival time. Other signs of deficiency (days until onset following retinoate withdrawal; percent incidence) were: decreased intestinal goblet cell numbers (2–3; 80), decreased pilocarpine induced salivation (6–8; 80), tracheal metaplasia (6–8; 80), transient periocular porphyria (6–8; 60), altered salivary gland morphology (9–10; 80), decreased stomach emptying in force-fed animals (12; 70), twisting (12; 5) and leg crippling (12; 5). We conclude that the sequence of appearance of individual signs of deficiency following the induction of synchronous vitamin A deficiency is highly reproducible, and that the more general use of synchronously deficient animals would materially assist studies of cause-effect relationships in vitamin A deficiency.
All-trans retinoic acid (RA) has previously been shown to modulate the transcriptional properties of the retinoic acid receptor (RAR) and retinoid X receptor (RXR). The inability of all-trans RA to bind to RXR suggests that it may be metabolized to a more active high affinity ligand. We report here an experimental approach that has identified 9-cis RA as an RXR ligand. It is up to 40-fold more potent than all-trans RA in transfection assays and binds with high affinity. The production of 9-cis RA in cultured cells and the identification of this molecule in liver and kidney demonstrates the existence of this molecule in living organisms. The discovery of this novel hormone points to the key role retinoid metabolism may have in generating new signaling pathways.
Esterification of retinol (vitamin A alcohol) with long-chain fatty acids by lecithin-retinol acyltransferase (LRAT) is an important step in both the absorption and storage of vitamin A. Retinol in cells is bound by either cellular retinol binding protein (CRBP), present in most tissues including liver, or cellular retinol binding protein type II [CRBP(II)], present in the absorptive cell of the small intestine. Here we investigated whether retinol must dissociate from these carrier proteins in order to serve as a substrate for LRAT by comparing Michaelis constants for esterification of retinol presented either free or bound. Esterification of free retinol by both liver and intestinal LRAT resulted in Km values (0.63 and 0.44 microM, respectively) similar to those obtained for esterification of retinol-CRBP (0.20 and 0.78 microM, respectively) and esterification of retinol-CRBP(II) (0.24 and 0.32 microM, respectively). Because Kd values for retinol-CRBP and retinol-CRBP(II) are 10(-8)-10-(-10) M, these similar Km values indicated prior dissociation is not required and that direct binding protein-enzyme interaction must occur. Evidence for such interaction was obtained when apo-CRBP proved to be a potent competitive inhibitor of LRAT, with a KI (0.21 microM) lower than the Km for CRBP-retinol (0.78 microM). Apo-CRBP(II), in contrast, was a poor competitor for esterification of retinol bound to CRBP(II). Apo-CRBP reacted with 4 mM p-(chloromercuri)benzenesulfonic acid lost retinol binding ability but retained the ability to inhibit LRAT, confirming that the inhibition could not be explained by a reduction in the concentration of free retinol.(ABSTRACT TRUNCATED AT 250 WORDS)
A randomized, double-blind, multicentre study was performed to compare the efficacy of acitretin (50 mg/day) with hydroxychloroquine (400 mg/day) in 28 and 30 patients, respectively, suffering from cutaneous lupus erythematosus (LE). The study was carried out over an 8-week period. Improvement of facial LE lesions after treatment with acitretin and hydroxychloroquine was assessed using several clinical parameters. In the acitretin group there was marked improvement or clearing of erythema in 10/24 patients (42%), of infiltration in 15/24 (63%) and of scaling/hyperkeratosis in 12/20 (60%). In the hydroxychloroquine group there was complete clearing or marked improvement of erythema in 17/25 patients (68%), of infiltration in 17/25 (68%) and of scaling/hyperkeratosis in 15/23 (65%). Overall improvement occurred in 13/28 patients (46%) treated with acitretin and in 15/30 patients (50%) with hydroxychloroquine. The incidence of side-effects was higher in the acitretin group, and necessitated discontinuation of treatment in four patients. The present results demonstrate that both acitretin and hydroxychloroquine provide effective treatment in approximately 50% of cases of cutaneous LE.
The aim of this study was to determine the effects of 13-cis-RA, all-trans-RA, and acitretin on the proliferation, lipid synthesis, and keratin expression of human sebocytes in vitro and to elucidate possible mechanisms of retinoid action on sebaceous glands at the cellular level. It was found that 13-cis-RA and all-trans-RA decreased sebocyte proliferation in a dose- and time-dependent manner, with a 13-cis-RA-IC50 of 10(-5) M (after 7 d) and 10(-6) M (after 14 d) and an all-trans-RA-IC50 of 10(-7) M (after 14 d; no IC50 after 7 d). Acitretin inhibited sebocyte proliferation only at 10(-5) M. Furthermore, 13-cis-RA was the most potent inhibitor of acetate incorporation into lipids, which indicated lipid synthesis (48.2% reduction), followed by all-trans-RA (-38.6%), and by acitretin (-27.5%). All retinoids tested markedly decreased the synthesis of triglycerides, wax/stearyl esters, and free fatty acids in cultured sebocytes, whereas squalene synthesis remained uninfluenced and cholesterol synthesis slightly increased. On the other hand, keratin 5 was down-regulated, keratin 17 was up-regulated, and the expression of keratin 13 was virtually unaffected by all retinoids tested. Keratins 6 and 16 were down-regulated by 13-cis-RA and by all-trans-RA, keratin 14 was down-regulated by 13-cis-RA only, and keratin 19 was up-regulated by all-trans-RA. These investigations indicate that 13-cis-RA and, to a lesser extent, all-trans-RA are potent inhibitors of both cell proliferation and lipid synthesis in human sebocytes in vitro, whereas acitretin only decreases lipogenesis in this model. In addition, retinoids may modify the differentiation of sebocytes in vitro by modulating keratin expression. Models of cultured human sebocytes are useful tools for further investigations on the sebaceous gland and its activity at the cellular level.
