Sebaceous gland: Milestones of 30-year modelling research dedicated to the "brain of the skin".

In 2018, Schneider and Zouboulis analysed the available tools for studying sebaceous gland pathophysiology in vitro. Since then, the interest in this field remains unbroken, as demonstrated by recent reviews on sebaceous gland physiology, endocrinology and neurobiology, the role of sebaceous glands beyond acne, and several original works on different areas of sebaceous gland function, including sebaceous lipogenesis. Landmark developments in the first part of the 30-year modelling research dedicated to the sebaceous gland, which is considered by several scientists as the brain of the skin, were the short-term culture of human sebaceous glands, the culture of human sebaceous gland cells and the development of immortalized sebaceous gland cell lines exhibiting characteristics of normal sebocytes. On the other hand, current developments represent the establishment of sebaceous gland spheroids, the 3D-SeboSkin model of viable skin explants ex vivo, the combination of culture-expanded epidermal stem cells of mice and adult humans to form de novo hair follicles and sebaceous glands, when they are transplanted into excisional wounds in mice, and 3D-printed scaffolds coated with decellularized matrix of adipose-derived mesenchymal stromal cells and SZ95 sebocytes. These novel tools may become useful platforms for better understanding of cellular and molecular mechanisms governing sebocyte biology and sebaceous gland homeostasis, such as the changes in sebum synthesis and composition, the infundibular differentiation and the influence of the innate immunity and the cutaneous microbiome and for identifying potential therapeutic targets of skin diseases affecting the sebaceous glands.

Why do humans get acne? A hypothesis.

Acne is a disease unique to humans and is associated with sebaceous glands that are found at high density on the scalp, forehead and face. Despite being a near universal problem in adolescence, the reason why such troublesome sebaceous glands exist at all is not well understood. Some interesting theories have been postulated including roles for skin maintenance, immunological function and perhaps even pheromones, but pre-pubertal skin which has sebaceous glands that are largely inactive, is healthy. Dystocia, obstructed labour, is unique to humans and no other animal has as much trouble giving birth. This is thought to reflect the relatively large human foetal head and proportionally small maternal pelvis. Noting the high density of sebaceous glands on the face, chest and back; these are exactly the same structures that pose the greatest obstruction during childbirth. Sebaceous glands develop after the fourth month of gestation and are large and well-developed at birth. Sebum production is also relatively high at birth. Having extra lubrication at these sites would help make the baby more slippery for birth conferring a selective advantage to successful delivery, as does the presence of the vernix caseosa, a white creamy substance, unique to humans that coats new-born infants. It is proposed that the sebaceous glands that cause acne are present on the face and forehead as they confer a selective advantage by 'lubricating' the widest parts of the new born baby to ease the passage of childbirth. Later in life, sebaceous glands may be inappropriately and pathologically primed, driven by a combination of hormones, diet and lifestyle to create acne.

Caveolin-1 as a possible target in the treatment for acne.

Expression of caveolin-1 (Cav-1) is an important pathophysiological factor in acne. Cav-1 strongly interacts with such well-recognized etiopathogenic factors such as hyperseborrhea, follicular hyperkeratinization and pathogenicity of Cutibacterium acnes. Cav-1 is a strong negative regulator of transforming growth factor beta (TGF-ß) expression. It acts as a critical determinant of autophagy, which is significantly induced in acne lesions through C. acnes and by absorption of fatty acids. Cav-1 also demonstrates different correlations with the development of innate immunity. We propose that normalization of Cav-1 expression can serve as a target in anti-acne therapy.

Seborrheic dermatitis-Looking beyond Malassezia.

Seborrhoeic Dermatitis (SD) is a very common chronic and/or relapsing inflammatory skin disorder whose pathophysiology remains poorly understood. Yeast of the genus Malassezia has long been regarded as a main predisposing factor, even though causal relationship has not been firmly established. Additional predisposing factors have been described, including sebaceous activity, host immunity (especially HIV infection), epidermal barrier integrity, skin microbiota, endocrine and neurologic factors, and environmental influences. Genetic studies in humans and mouse models-with particularly interesting insights from examining the Mpzl3 knockout mice and their SD-like skin phenotype, and patients carrying a ZNF750 mutation-highlight defects in host immunity, epidermal barrier and sebaceous activity. After synthesizing key evidence from the literature, we propose that intrinsic host factors, such as changes in the amount or composition of sebum and/or defective epidermal barrier, rather than Malassezia, may form the basis of SD pathobiology. We argue that these intrinsic changes provide favourable conditions for the commensal Malassezia to over-colonize and elicit host inflammatory response. Aberrant host immune activity or failure to clear skin microbes may bypass the initial epidermal or sebaceous abnormalities. We delineate specific future clinical investigations, complemented by studies in suitable SD animal models, that dissect the roles of different epidermal compartments and immune components as well as their crosstalk and interactions with the skin microbiota during the process of SD. This research perspective beyond the conventional Malassezia-centric view of SD pathogenesis is expected to enable the development of better therapeutic interventions for the management of recurrent SD.

Inactivation of autophagy leads to changes in sebaceous gland morphology and function.

We have reported recently that inactivation of the essential autophagy-related gene 7 (Atg7) in keratinocytes has little or no impact on morphology and function of the epidermal barrier in experimental animals. When these mice aged, mutant males, (Atg7 ΔKC), developed an oily coat. As the keratin 14 promoter driven cre/LoxP system inactivates floxed Atg7 in all keratin 14 (K14) expressing cells, including sebocytes, we investigated whether the oily hair phenotype was the consequence of changes in function of the skin sebaceous glands. Using an antibody to the GFP-LC3 fusion protein, autophagosomes were detected at the border of sebocyte disintegration in control but not in mutant animals, suggesting that autophagy was (a) active in normal sebaceous glands and (b) was inactivated in the mutant mice. Detailed analysis established that dorsal sebaceous glands were about twice as large in all Atg7 ΔKC mice compared to those of controls (Atg7 F/F), and their rate of sebocyte proliferation was increased. In addition, male mutant mice yielded twice as much lipid per unit hair as age-matched controls. Analysis of sebum lipids by thin layer chromatography revealed a 40% reduction in the proportion of free fatty acids (FFA) and cholesterol, and a 5-fold increase in the proportion of fatty acid methyl esters (FAME). In addition, the most common diester wax species (58-60 carbon atoms) were increased, while shorter species (54-55 carbon atoms) were under-represented in mutant sebum. Our data show that autophagy contributes to sebaceous gland function and to the control of sebum composition.

Update on Frontal Fibrosing Alopecia. / Actualización en alopecia frontal fibrosante.

Frontal fibrosing alopecia (FFA) is an increasingly common acquired primary scarring alopecia, first described by Kossard in 1994. Clinically it is characterized by frontotemporal hairline recession, frequently accompanied by eyebrow loss. FFA was initially thought to have a hormonal origin as it was first described in postmenopausal women and premenopausal women with a history of hysterectomy or early menopause. This origin, however, has been questioned in recent years due to the publication of cases in men and premenopausal women. Although FFA has a highly characteristic clincal pattern, it is histologically similar to lichen planopilaris, and is currently believed to be a clinical variant of this condition. No clinical trials to date have investigated the efficacy of treatments for FFA. Numerous drugs, however, have been assessed in observational studies, and the best results to date have been reported for 5-αreductase inhibitors and intralesional corticosteroids, followed by antimalarials and calcineurin inhibitors. In this article, we review the latest data on the etiology, pathogenesis, clinical presentation, diagnosis, and treatment of FFA.

Red face revisited: Disorders of hair growth and the pilosebaceous unit.

This paper reviews the recent literature on the diseases of the hair and pilosebaceous unit that may cause a red face. We discuss the epidemiology, clinicals, pathogenesis, and therapy of lichen planopilaris with its variants, discoid lupus erythematosus, folliculitis decalvans, dissecting folliculitis, acne keloidalis nuchae, pseudofolliculitis barbae, tinea capitis, tinea barbae, folliculitis of diverse causative factors and inflammatory follicular keratotic syndromes, ulerythema ophryogenes, atrophoderma vermiculatum, keratosis follicularis spinulosa decalvans, and folliculitis spinulosa decalvans.

Estudio de patrones de implantación pilosa frontal en la mujer española caucásica / Study of Frontal Hairline Patterns in Spanish Caucasian Women

Introducción: Las medidas de la línea de implantación pilosa frontal de la mujer española caucásica no han sido descritas, y tampoco si existe relación entre estas medidas y los niveles hormonales androgénicos, producción sebácea e hidratación. Material y métodos: Estudio observacional, prospectivo, descriptivo y analítico en 103 mujeres sanas españolas caucásicas premenopáusicas, pertenecientes a la plantilla sanitaria de nuestro hospital a las que se les midió la línea de implantación pilosa frontal, los niveles de sebo y la hidratación de la capa córnea, y en 50 voluntarias de este grupo se determinaron, además, los niveles hormonales androgénicos 3-5 días después de terminar la menstruación. Resultados: La edad media de nuestras pacientes fue de 29,7 años. El pico de viuda se objetivó en el 94,17% de las pacientes. Las dimensiones medias del pico de viuda en nuestro grupo fueron de 1,01cm de alto y 2,13cm de ancho. Los niveles medios hormonales fueron los que habitualmente consideramos como normales en el laboratorio de nuestro hospital, excepto la 17-hidroxi-progesterona, que alcanzó valores medios de 1,39ng/ml (rango: 0,6-5,9; N: 0,15-1,10). El PSA fue de 0,04ng/ml (rango: 0,02-0,08; N: 0,00-0,02). Conclusiones: Las medidas de las líneas de implantación pilosa frontal de la mujer caucásica española han sido distintas de las descritas para la mujer americana. El conocimiento de este patrón de distribución de la línea de implantación pilosa frontal normal puede ayudar en el caso de que la paciente con una alopecia androgenética femenina de patrón masculino, una alopecia frontal fibrosante u otra cicatricial ya estable desee corregir quirúrgicamente su problema mediante trasplante capilar (AU)

Background: Anterior hairline measurements and their possible relationship with androgen levels, sebum production, and skin hydration have not been reported in white Spanish women. Material and methods: This was a prospective descriptive and analytical observational study conducted on 103 healthy premenopausal white Spanish women recruited from the health staff of Hospital Universitario Virgen Macarena in Seville, Spain. Measurements were made of anterior hairline implantation, sebum levels, and the degree of hydration of the stratum corneum. Androgen levels were also determined in 50 volunteers from this group 3 to 5 days after the end of the menstrual cycle. Results: The mean age of the women was 29.7 years. A widow’s peak was observed in 94.17% of the group. The mean dimensions of the widow’s peak were a height of 1.01 cm and width of 2.13 cm. The mean hormone levels were within normal limits for our hospital’s laboratory with the exception of 17-hydroxyprogesterone, with a mean level of 1.39 ng/mL (range, 0.6-5.9 ng/mL; normal limits, 0.15-1.10 ng/mL). The mean prostate specific antigen level was 0.04 ng/mL (range 0.02-0.08 ng/mL; normal limits, 0.00-0.02 ng/mL). Conclusions: The hairline measurements of the white Spanish women in this study differ from those reported in American women. Knowledge of this normal pattern of anterior hairline implantation can be important in the evaluation of women with female androgenetic alopecia with male pattern, frontal fibrosing alopecia, or other established scarring alopecia seeking a surgical solution by hair transplantation (AU)

Imaging of sebaceous glands of human skin by three-dimensional ultrasound microscopy and its relation to elasticity.

High frequency ultrasound imaging has realized high resolution in vivo imaging of the biological tissues at a microscopic level. Human skin structure, especially sebaceous glands at the deep part of the dermis, was observed by three-dimensional ultrasound microscopy with the central frequency of 120 MHz. The visco-elasticity and surface sebum level of the observed region were measured by established testing devices. Both sebaceous glands density and surface sebum level were higher in cheek than those in forearm. The viscosity of forearm was lower than that of cheek. These results suggest that sebaceous glands may act as cushions of the skin besides their classical role of secreting sebum and some hormones. High frequency ultrasound imaging contributes to the evaluation of human skin aging.

[The sebaceous gland]. / Die Talgdrüse.

The development and function of the sebaceous gland in the fetal and neonatal periods appear to be regulated by maternal androgens and by endogenous steroid synthesis, as well as by other morphogens. The most apparent function of the glands is to excrete sebum. A strong increase in sebum excretion occurs a few hours after birth; this peaks during the first week and slowly subsides thereafter. A new rise takes place at about age 9 years with adrenarche and continues up to age 17 years, when the adult level is reached. The sebaceous gland is a target organ but also an important formation site of hormones, and especially of active androgens. Hormonal activity is based on an hormone (ligand)-receptor interaction, whereas sebocytes express a wide spectrum of hormone receptors. Androgens are well known for their effects on sebum excretion, whereas terminal sebocyte differentiation is assisted by peroxisome proliferator-activated receptor ligands. Estrogens, glucocorticoids, and prolactin also influence sebaceous gland function. In addition, stress-sensing cutaneous signals lead to the production and release of corticotrophin-releasing hormone from dermal nerves and sebocytes with subsequent dose-dependent regulation of sebaceous nonpolar lipids. Among other lipid fractions, sebaceous glands have been shown to synthesize considerable amounts of free fatty acids without exogenous influence. Atopic dermatitis, seborrheic dermatitis, psoriasis and acne vulgaris are some of the disease on which pathogenesis and severity sebaceous lipids may or are surely involved.

FoxO1 - the key for the pathogenesis and therapy of acne?

Five main factors play a pivotal role in the pathogenesis of acne: androgen dependence, follicular retention hyperkeratosis, increased sebaceous lipogenesis, increased colonization with P. acnes, and inflammatory events. This paper offers a solution for the pathogenesis of acne and explains all major pathogenic factors at the genomic level by a relative deficiency of the nuclear transcription factor FoxO1. Nuclear FoxO1 suppresses androgen receptor, other important nuclear receptors and key genes of cell proliferation, lipid biosynthesis and inflammatory cytokines. Elevated growth factors during puberty and persistent growth factor signals due to Western life style stimulate the export of FoxO1 out of the nucleus into the cytoplasm via activation of the phos-phoinositide-3-kinase (PI3K)/Akt pathway. By this mechanism, genes and nuclear receptors involved in acne are derepressed leading to increased androgen receptor-mediated signal transduction, increased cell proliferation of androgen-dependent cells, induction of sebaceous lipogenesis and upregulation of Toll-like-receptor-2-dependent inflammatory cytokines. All known acne-inducing factors exert their action by reduction of nuclear FoxO1 levels. In contrast, retinoids, antibiotics and dietary intervention will increase the nuclear content of FoxO1, thereby normalizing increased transcription of genes involved in acne. Various receptor-mediated growth factor signals are integrated at the level of PI3K/Akt activation which finally results in nuclear FoxO1 deficiency.

New insights into adolescent acne.

Interest in sebaceous gland functioning and its diseases is increasing. This article provides a summarized update of the current knowledge of the pathophysiology of acne vulgaris and the new treatment concepts that have emerged in recent years. Recent literature is reviewed regarding teenage acne, focusing on pathogenesis, associations, controversies and considerations in therapy to further help practitioners stay current on the issues regarding this topic. Current research is expected to provide new and improved treatments in the near future.

The sebocyte culture: a model to study the pathophysiology of the sebaceous gland in sebostasis, seborrhoea and acne.

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.

Frontiers in sebaceous gland biology and pathology.

The development of experimental models for the in vitro study of human sebaceous gland turned down the theory of a phylogenetic relict and led to the identification of several, unknown or disregarded functions of this organ. Such functions are the production of foetal vernix caseosa, the influence of three-dimensional organization of the skin surface lipids and the integrity of skin barrier and the influence on follicular differentiation. In addition, the sebaceous gland contributes to the transport of fat-soluble antioxidants from and to the skin surface, the natural photoprotection, the pro- and antiinflammatory skin properties and to the innate antimicrobial activity of the skin. It is mainly responsible for skin's independent endocrine function, the hormonally induced skin ageing process, the steroidogenic function of the skin as well as its thermoregulatory and repelling properties and for selective control of the hormonal and xenobiotical actions of the skin. Interestingly, sebocytes, at least in vitro, preserve characteristics of stem-like cells despite their programming for terminal differentiation. This review reports on various sebaceous gland functions, which are currently under investigation, including its role on the hypothalamus-pituitary-adrenal-like axis of the skin, the impact of acetylcholine on sebocyte biology, the activity of ectopeptidases as new targets to regulate sebocyte function, the effects of vitamin D on human sebocytes, the expression of retinoid metabolizing cytochrome P450 enzymes and the possible role of sebum as vehicle of fragrances. These multiple homeostatic functions award the sebaceous gland the role 'brain of the skin' and the most important cutaneous endocrine gland.

Thematic review series: skin lipids. Sebaceous gland lipids: friend or foe?

Sebaceous glands are intriguing glands that are found throughout the human body except on the palms of the hands and soles of the feet. The true function of these glands has yet to be determined, but there are several theories, including antioxidant effects, antibacterial effects, and transport of pheromones. Sebaceous glands produce lipids that are involved in the pathogenesis of one of the most prevalent diseases of adolescence, acne. Although the majority of lipids produced by the sebaceous gland are also produced in other areas of the body, there are two that are characteristic of the sebaceous gland, wax esters and squalene. This review seeks to present an update on the physiology of the sebaceous glands, with particular emphasis on the production of sebaceous lipids.

[Sebaceous glands and acne].

New studys on the sebaceous glands in recent years have facilitated the further understanding and treatment of acne vulgaris. This article summarizes the advancements in the relationship between sebaceous glands and acne, with focus on androgen metabolism in skin, abnormal lipids secretion, and immunology of sebaceous gland cells.