Sebaceous Gland Differentiation Research Articles

The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation.

The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in mouse homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.

The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation

The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in mouse homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.

Autophagy-Mediated Cellular Remodeling during Terminal Differentiation of Keratinocytes in the Epidermis and Skin Appendages.

The epidermis of the skin and skin appendages, such as nails, hair and sebaceous glands, depend on a balance of cell proliferation and terminal differentiation in order to fulfill their functions at the interface of the body and the environment. The differentiation of epithelial cells of the skin, commonly referred to as keratinocytes, involves major remodeling processes that generate metabolically inactive cell remnants serving as building blocks of the epidermal stratum corneum, nail plates and hair shafts. Only sebaceous gland differentiation results in cell disintegration and holocrine secretion. A series of studies performed in the past decade have revealed that the lysosome-dependent intracellular degradation mechanism of autophagy is active during keratinocyte differentiation, and the blockade of autophagy significantly alters the properties of the differentiation products. Here, we present a model for the autophagy-mediated degradation of organelles and cytosolic proteins as an important contributor to cellular remodeling in keratinocyte differentiation. The roles of autophagy are discussed in comparison to alternative intracellular degradation mechanisms and in the context of programmed cell death as an integral end point of epithelial differentiation.

Comparison of acne vulgaris patients and healthy controls in terms of autistic features and 2D:4D ratio

Objective In the pathogenesis of acne vulgaris; androgen hormones are mentioned as an important factor for affecting sebaceous gland differentiation. Intrauterine exposure to androgen hormones is associated with autism and autistic features. An important indicator of androgen exposure is the 2D:4D ratio. In this study, we aimed to compare acne vulgaris patients with healthy controls in terms of autistic features and 2D:4D ratio. Method The study was carried out in the outpatient unit of the Department of Dermatology and Venereology, Atatürk Training and Research Hospital, Ankara Yıldırım Beyazıt University School of Medicine. 104 patients aged between 18-40 years old diagnosed with acne vulgaris and 123 healthy controls were included in the study. The sociodemographic data form was completed by the researcher and 2D:4D ratios were measured. Autistic features were measured with the Autism Spectrum Quotient. Informed consent was obtained from all participants. Results In the analysis, 2D:4D ratios were found to be significantly lower in male gender than female gender. Both hands analyzed separately for 2D:4D ratio. There were no significant differences between the two groups in terms of 2D:4D ratios. In addition, in terms of mean 2D:4D ratios, no significant difference was found both the whole sample and the male and female gender between patient and control group. There was no significant difference between patient and control group in terms of autism spectrum quotient scores when evaluated the whole sample and male and female separately. Conclusion As a result of this study; new data on the relationship between acne and 2D:4D ratios, which are rarely associated with previous studies, have been obtained. The relationship between acne and autistic features, which were not previously examined, was assessed with this study. According to our knowledge, this is the first study to evaluate the relationship between acne and autistic features.

Primary lung sebaceous carcinoma successfully treated with radiotherapy and pembrolizumab: A case report

Sebaceous carcinoma is a rare cutaneous malignant tumor, usually occurring on the eyelids, head, neck, and trunk. There have been few reports about sebaceous carcinoma with primary lung cancer, for which optimal therapy has not yet been established. A 70-year-old man presented with a mass in the left iliac bone and tumor of the lower left lung. The morphological characteristics of the iliac bone biopsy pathology and immunostaining results showed sebaceous gland differentiation. After systemic examination, we diagnosed a primary lung sebaceous carcinoma with intrapulmonary and bone metastases. PD-L1 was positive in 1%-24% of tumor cells, and microsatellites were stable. We detected protein kinase B (AKT1) mutations using the Oncomine Dx target test. Palliative radiotherapy (RT) of a total of 45 Gy was provided in 15 fractions to the left iliac region, which resulted in a 25% reduction in the tumor size. Subsequently, four courses of first-line pembrolizumab led to a 30% reduction in the total tumor count. RT and pembrolizumab may be treatment options for certain rare primary sebaceous carcinomas of the lungs. A synergistic effect from RT and subsequent administration of immune checkpoint inhibitors may have contributed to tumor reduction.

Effects of testosterone on skin structure and factors related to androgen conversion and binding in Hetian sheep.

The effects of androgens on human skin mainly include the regulation of growth and differentiation of hair follicles and sebaceous glands. Androgens may have some physiological roles in sheep skin that are similar to those of humans, but further confirmation is needed. Therefore, Hetian sheep were chosen in this study as an animal model to explore the effects of testosterone on skin structure and factors related to androgen conversion and binding in Hetian sheep. The sheep were treated with different concentrations of testosterone for 42days. Skin tissue sections were prepared and then subjected to hematoxylin-eosin, Sacpic, Masson's trichrome, and Oil Red O staining to observe changes in skin morphology. Changes in the content of blood-related factors were also detected using ELISA kits. The skin tissue distribution of androgen receptor was explored by immunohistochemistry and immunofluorescence assays. The results showed that testosterone significantly increases the sebaceous gland area and stimulates the formation of new sebaceous glands. Further exploration revealed that testosterone promotes the proliferation of sebaceous gland juvenile cells. However, testosterone was found to have no significant effect on hair follicle density and hair follicle structure. Testosterone increased dihydrotestosterone levels but decreased 5α-reductase 1 and 5α-reductase 2 levels. The androgen receptors were distributed in the hair follicles, sebaceous glands, and some major skin appendages of Hetian sheep. This study suggests that androgens can be effective in regulating sebum production in sheep. This study will help advance research efforts to further explore the molecular and cellular mechanisms by which androgens modify sheep follicles and sebaceous glands.

Embigin is a fibronectin receptor that affects sebaceous gland differentiation and metabolism.

Stem cell renewal and differentiation are regulated by interactions with the niche. Although multiple cell populations have been identified in distinct anatomical compartments, little is known about niche-specific molecular factors. Using skin as a model system and combining single-cell RNA-seq data analysis, immunofluorescence, and transgenic mouse models, we show that the transmembrane protein embigin is specifically expressed in the sebaceous gland and that the number of embigin-expressing cells is negatively regulated by Wnt. The loss of embigin promotes exit from the progenitor compartment and progression toward differentiation, and also compromises lipid metabolism. Embigin modulates sebaceous niche architecture by affecting extracellular matrix organization and basolateral targeting of monocarboxylate transport. We discover through ligand screening that embigin is a direct fibronectin receptor, binding to the N-terminal fibronectin domain without impairing integrin function. Our results solve the long-standing question of how embigin regulates cell adhesion and demonstrate a mechanism that couples adhesion and metabolism.

Serum level of substance P and stress in acne-vulgaris patients

ObjectiveThe aim of the study was to evaluate the relationship between stress and serum concentration of substance P (SP) in acne-vulgaris patients.BackgroundAcne vulgaris is a multifactorial disorder of the pilosebaceous unit. The clinical picture can vary significantly, from mild comedonal acne to fulminant systemic disease. Although all age groups may be affected by its many variants, the peak incidence is during adolescence. Various studies have proved that neuropeptides affect the activity of the pilosebaceous unit by stimulating proliferation and differentiation of sebaceous glands, lipid synthesis, and induction of neutral endopeptidase expression in sebaceous cells, especially SP.Patients and methodsA case–control study included 40 patients with acne vulgaris and 40 age-matched and sex-matched controls. Emotional stress was analyzed with the use of Social Readjustment Rating Scale, whereas the methods of coping with stress were assessed with the Coping Inventory for Stressful Situation questionnaire, followed by taking blood samples to assess SP serum levels using the enzyme-linked immunosorbent-assay method.ResultsSP was significantly higher in the acne-patient group versus the control group (P < 0.05). A statistically significant difference was observed between acne patients and control groups regarding the Social Readjustment Rating Scale (P < 0.05).ConclusionThere was a statistically significant relation between stress scale and serum SP level in acne vulgaris.

Eruptive Necrotizing Infundibular Crystalline Folliculitis: An Expression of an Abortive Sebaceous Follicular Repair Pathway Linked to Committed Infundibular Stem Cells?

:Necrotizing infundibular crystalline folliculitis is a rare entity, which is a distinctive clinical and histopathological entity. Eruptive yellow waxy umbilicated folliculocentric plugs clinically correspond to pale crystalline filaments embedded in an amorphous sebum-rich material. Remarkably, only the superficial infundibular ostia remain, and the distended cavity is devoid of a follicular or sebaceous gland remnant. The pathogenesis of this enigmatic event remains to be established. The emergence of necrotizing infundibular crystalline folliculitis (NICF) as a paradoxical side effect of antitumor inhibitors epidermal growth factor receptor vascular endothelial growth factor and more recently programmed death-1 represents the expression of altered molecular pathways that underpin the pathogenesis of NICF. To explore these pathways, it is necessary to explore the hierarchy of follicular stem cells, particularly the potential role of committed infundibular stem cells that play a key role in wound healing. Committed infundibular stem cells are closely linked to the sebaceous gland stem cell axis, and this has relevance in the process of homeostatic repair of sebaceous follicles in the wake of folliculitis. The unscheduled modulation of this infundibular homeostatic sebaceous repair axis by epidermal growth factor receptor vascular endothelial growth factor, and programmed death-1 may lead to an aberrant outcome with metaplasia of infundibular keratinocytes to sebocytes. In the absence of sebaceous gland differentiation, these metaplastic infundibular sebocyte cells would lead to the consumption and loss of the infundibulum as a result of holocrine sebum production. This conceptual pathogenic pathway for NICF is constructed by incorporating recent advances in the fields of follicular stem cells, wound repair, follicular homeostasis, regulatory T cells, and molecular pathways linked to the biologicals inducing NICF.

Correlation Between Stress Scale and Serum Substance P Level in Acne Vulgaris.

IntroductionAcne vulgaris is a chronic inflammatory disease of pilosebaceous follicles with polymorphic lesions, consisting of comedones, papules, pustules and nodules with varying degrees of severity. Stress is one of the triggers of acne vulgaris. Peripheral nerves release substance P in response to stress. Substance P causes proliferation and differentiation of sebaceous glands and increases lipid synthesis in sebocytes.PurposeTo determine the correlation between stress scale and serum substance P level in acne vulgaris.Patients and MethodsThis study was an observational analytic study with a cross-sectional design involving 30 patients with acne vulgaris and 30 controls. History taking, dermatological examination and the Holmes−Rahe stress scale questionnaire were performed with each patient to evaluate stress scale, followed by taking blood samples to assess substance P serum levels using the ELISA test. The collected data were analyzed using the Spearman correlation test.ResultsIn both groups, the majority of subjects were 23–27 years old (36.7%) and most of them were female (76.7%). The majority in the acne vulgaris group had low scores on the stress scale, represented by 17 patients (56.7%). The main cause of stress in the acne vulgaris group was a major change in sleeping habits (66.7%). In the acne vulgaris group, the highest mean value of serum substance P level in high stress scale group was 168.2 pg/mL. There was a positive correlation between stress scale and serum substance P level in acne vulgaris with moderate strength and this was statistically significant (r = 0.446; p = 0.014). Meanwhile, stress scale and serum substance P level in controls were not correlated and this was not statistically significant (r = −0.090; p = 0.636).ConclusionThere was a correlation between stress scale and serum substance P level in acne vulgaris.

Recent advances in understanding and managing acne.

Multidisciplinary investigations into the pathogenesis of acne have significantly progressed over the past three years. Studies of the etiology of acne from the perspectives, for example, of sebaceous gland biology, sebum, genetics, keratinization, differentiation, hair cycles, immunology, bacteriology, and wound healing have elucidated its pathogenesis. This has led to the development of new therapies and paved the way for advanced studies that will enable the further evolution of acne treatment.

Indications and Use of Isotretinoin in Facial Plastic Surgery.

Isotretinoin is a first generation retinoid with pleiotropic effects on keratinocyte differentiation, proliferation, and activity of sebaceous glands. For years, there has been intense debate on whether the use of isotretinoin combined with cosmetic or surgical procedures is safe and potentially more efficient than either therapy alone. Due to delays in wound healing and keloid formation, conservative recommendations were not to combine isotretinoin with any plastic surgery or local treatment at 6 to 12 months after discontinuation of the drug. However, there is increasing evidence that a combination approach is not only safe, but may also provide excellent cosmetic outcomes in acne scars, sebaceous gland hyperplasia, and thick-skinned patients undergoing facial plastic surgery. In particular, low-dose regimens of isotretinoin may offer advantages over standard dosage treatments because of better tolerability and safety in long-term use adjunct with surgical interventions. In this article, the authors aim to summarize the current evidence on the use of isotretinoin in facial plastic surgery and to share their experience from selected patients.

Evolution of the MC5R gene in placental mammals with evidence for its inactivation in multiple lineages that lack sebaceous glands

MC5R is one of five melanocortin receptor genes found in placental mammals. MC5R plays an important role in energy homeostasis and is also expressed in the terminal differentiation of sebaceous glands. Among placental mammals there are multiple lineages that either lack or have degenerative sebaceous glands including Cetacea (whales, dolphins, and porpoises), Hippopotamidae (hippopotamuses), Sirenia (manatees and dugongs), Proboscidea (elephants), Rhinocerotidae (rhinos), and Heterocephalus glaber (naked mole rat). Given the loss or diminution of sebaceous glands in these taxa, we procured MC5R sequences from publicly available genomes and transcriptomes, supplemented by a newly generated sequence for Choeropsis liberiensis (pygmy hippopotamus), to determine if this gene remains intact or is inactivated in association with loss/reduction of sebaceous glands. Our data set includes complete MC5R sequences for 114 placental mammal species including two individuals of Mammuthus primigenius (woolly mammoth) from Oimyakon and Wrangel Island. Complete loss or inactivation of the MC5R gene occurs in multiple placental lineages that have lost sebaceous glands (Cetacea, West Indian manatee, African elephant, white rhinoceros) or are characterized by unusual skin (pangolins, aardvarks). Both M. primigenius individuals share inactivating mutations with the African elephant even though sebaceous glands have been reported in the former. MC5R remains intact in hippopotamuses and the naked mole rat, although slightly elevated dN/dS ratios in these lineages allow for the possibility that the accumulation of inactivating mutations in MC5R may lag behind the relaxation of purifying selection. For Cetacea and Hippopotamidae, the absence of shared inactivating mutations in two different skin genes (MC5R, PSORS1C2) is consistent with the hypothesis that semi-aquatic lifestyles were acquired independently in these clades following divergence from a common ancestor.

448 Involvement of catecholamine in the differentiation of sebaceous glands in vitro

448 Involvement of catecholamine in the differentiation of sebaceous glands in vitro

Five Years Data of Clinical and Histopathological Characteristics of Skin Adnexal Tumors in Dr. Hasan Sadikin General Hospital Bandung

Background : Skin adnexal tumors arise from skin adnexal differentiation. Very limited number of study has been performed on their clinical and histopathological characteristics in Dr. Hasan Sadikin General Hospital. The objectives of this study was to identify the clinical and histopathological characteristic of skin adnexal tumors during the period of 2009 to 2013. Methods : AA descriptive study performed on 79 medical records of patients with skin adnexal tumors at the Department of Anatomic Pathology in Dr. Hasan Sadikin General Hospital Bandung from 2009 to 2013. Data were collected during the period of September to October 2014. The inclusion criteria were medical records containing information on skin adnexal tumors confirmed by histopathological examination results, patient characteristics (age and gender), and the tumor characteristics (size, location, malignancy, type, and histopathological origin). Collected data were processed using computer and presented in tables. Results : This study showed that tumors occured during productive age with male to female ratio was 1.2:1. Most skin adnexal tumors were ≤5 cm in size and were distributed in the head-neck region. Most of the tumors were benign and arised from hair follicle differentiation with pilomatricoma type while the malignant tumors commonly arised from sebaceous gland differentiation with sebaceous carcinoma type. Conclusions : Most skin adnexal tumors occur in productive age with no gender prediclation. They are small in size and are distributed in the cephalic region. Most are benign tumors arising from hair follicle differentiation with some malignant tumors arising from sebaceous gland differentiation. [AMJ.2016;3(4):514–9] DOI: 10.15850/amj.v3n4.933

Morphogenesis of eyelid meibomian gland

AbstractPurpose Dysfunction of Meibomian gland is the primary cause of dry eye. The purpose of our study is to understand embryogenesis for a better understanding of the pathophysiology of these diseases.Methods Eyelids were obtained from 22 fetuses formalin fixated of 10‐34 weeks gestational age (GA) with approval of Ethics Committee. These 88 eyelids were processed with sections 5µm thick and analyzed by light microscopy after staining with hematoxylin‐phloxine‐saffron and PAS reaction. For each sample, different morphological criteria were investigated: evaluation of glandular bud, sebaceous gland differentiation, arborization of the gland, opening of excretory duct.Results Histological analysis revealed that up to 13 weeks of GA, the fetal lid consists of fine vascular structures in a loose mesenchyme, under a very thin epithelium. At 14 weeks of GA, a first process of the excretory duct is individualized as a cell invagination extending from the eyelid margin. Sebaceous cell differentiation is identified at 15 weeks of GA. The excretory canal keeps its maturation to appear as a small cellular cord, unique and full around 16 weeks of GA, glands begin its buds arborization at 19 weeks of GA. This channel gradually widens and expands, appearing always blocked by a plug of squamous cells and keratin cuticle at 22 weeks of GA. The plugging lasts until 34 weeks of GA.Conclusion Glandular structures involved in tear secretion appear in fetus around fourteen weeks of gestation. The Meibomian glands extend its maturation after birth. Further studies will allow a better understanding of the physiopathology of dry eye.

Rare presentation of radicular cyst with sebaceous differentiation

Sebaceous glands in the oral mucosa are said to be a normal variation, but the presence of the sebaceous gland in the jaw is extremely rare. Sebaceous gland differentiation in dentigerous cysts and in keratocystic odontogenic tumor (earlier odontogenic keratocysts) has been reported, but it has never been reported in any radicular cyst. We presented a case of a radicular cyst in an 18-year-old male with sebaceous gland differentiation.

Scaling dermatosis in three dogs associated with abnormal sebaceous gland differentiation

Abnormal sebaceous gland differentiation, so-called 'sebaceous gland dysplasia', is a rare condition described in the dog and the cat. Although little is known about this condition, it is thought that a genetic defect causes abnormal sebaceous gland development. Clinically, this condition occurs in young cats and dogs and is characterized by variable degrees of adherent scale, hair casts, poor coat quality and hypotrichosis. Here, we describe the clinical presentation and treatment of three adult dogs with abnormal sebaceous gland differentiation. Three adult dogs presented with a keratinization defect characterized by progressive scaling, hair casts, dull, dry, brittle hair coat and hypotrichosis beginning in puppyhood to early adulthood. Multiple 6 mm punch skin biopsy samples were obtained from each dog. Treatments included various topical keratomodulatory agents, oral essential fatty acids and oral vitamin A. Histologically, all sebaceous glands were small and composed of a mixture of irregularly clustered basal reserve cells and mature sebocytes. With therapy, two of the dogs showed moderate to marked clinical improvement in scaling, hair casts and hair coat quality. Although rare, 'sebaceous gland dysplasia' should be considered in cases where a primary keratinization defect is suspected. Given that abnormal sebaceous differentiation is a structural defect of the skin, treatment must be maintained and is aimed at ameliorating the clinical signs rather than curing the disease.

C-MYC-Induced Sebaceous Gland Differentiation Is Controlled by an Androgen Receptor/p53 Axis

SummaryAlthough the sebaceous gland (SG) plays an important role in skin function, the mechanisms regulating SG differentiation and carcinoma formation are poorly understood. We previously reported that c-MYC overexpression stimulates SG differentiation. We now demonstrate roles for the androgen receptor (AR) and p53. MYC-induced SG differentiation was reduced in mice lacking a functional AR. High levels of MYC triggered a p53-dependent DNA damage response, leading to accumulation of proliferative SG progenitors and inhibition of AR signaling. Conversely, testosterone treatment or p53 deletion activated AR signaling and restored MYC-induced differentiation. Poorly differentiated human sebaceous carcinomas exhibited high p53 and low AR expression. Thus, the consequences of overactivating MYC in the SG depend on whether AR or p53 is activated, as they form a regulatory axis controlling proliferation and differentiation.

TGFβ signaling regulates lipogenesis in human sebaceous glands cells

BackgroundSebaceous glands are components of the skin essential for its normal lubrication by the production of sebum. This contributes to skin health and more importantly is crucial for the skin barrier function. A mechanistic understanding of sebaceous gland cells growth and differentiation has lagged behind that for keratinocytes, partly because of a lack of an in vitro model that can be used for experimental manipulation.MethodsWe have developed an in vitro culture model to isolate and grow primary human sebocytes without transformation that display functional characteristics of sebocytes. We used this novel method to probe the effect of Transforming Growth Factor β (TGFβ) signaling on sebocyte differentiation, by examining the expression of genes involved in lipogenesis upon treatment with TGFβ1. We also repressed TGFβ signaling through knockdown of the TGFβ Receptor II to address if the effect of TGFβ activation is mediated via canonical Smad signal transduction.ResultsWe find that activation of the TGFβ signaling pathway is necessary and sufficient for maintaining sebocytes in an undifferentiated state. The presence of TGFβ ligand triggered decreased expression in genes required for the production of characteristics sebaceous lipids and for sebocyte differentiation such as FADS2 and PPARγ, thereby decreasing lipid accumulation through the TGFβ RII-Smad2 dependent pathway.ConclusionTGFβ signaling plays an essential role in sebaceous gland regulation by maintaining sebocytes in an undifferentiated state. This data was generated using a novel method for human sebocyte culture, which is likely to prove generally useful in investigations of sebaceous gland growth and differentiation. These findings open a new paradigm in human skin biology with important implications for skin therapies.