Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single-cell RNA sequencing, we uncovered both direct and indirect paths by which resident SG progenitors ordinarily differentiate into sebocytes, including transit through a Krt5+PPARγ+ transitional basal cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair-follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR2 signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.

This review presents several aspects of the innovative concept of sebaceous immunobiology, which summarizes the numerous activities of the sebaceous gland including its classical physiological and pathophysiological tasks, namely sebum production and the development of seborrhea and acne. Sebaceous lipids, which represent 90% of the skin surface lipids in adolescents and adults, are markedly involved in the skin barrier function and perifollicular and dermal innate immune processes, leading to inflammatory skin diseases. Innovative experimental techniques using stem cell and sebocyte models have clarified the roles of distinct stem cells in sebaceous gland physiology and sebocyte function control mechanisms. The sebaceous gland represents an integral part of the pilosebaceous unit and its status is connected to hair follicle morphogenesis. Interestingly, professional inflammatory cells contribute to sebocyte differentiation and homeostasis, whereas the regulation of sebaceous gland function by immune cells is antigen-independent. Inflammation is involved in the very earliest differentiation changes of the pilosebaceous unit in acne. Sebocytes behave as potent immune regulators, integrating into the innate immune responses of the skin. Expressing inflammatory mediators, sebocytes also contribute to the polarization of cutaneous T cells towards the Th17 phenotype. In addition, the immune response of the perifollicular infiltrate depends on factors produced by the sebaceous glands, mostly sebaceous lipids. Human sebocytes in vitro express functional pattern recognition receptors, which are likely to interact with bacteria in acne pathogenesis. Sex steroids, peroxisome proliferator-activated receptor ligands, neuropeptides, endocannabinoids and a selective apoptotic process contribute to a complex regulation of sebocyte-induced immunological reaction in numerous acquired and congenital skin diseases, including hair diseases and atopic dermatitis.

UNASSIGNED: Sebocytes are the main cells involved in the pathogenesis of acne by producing lipids and inflammatory cytokines. Although palmitic acid (PA) has been suggested to induce an inflammatory reaction, its effect on sebocytes remains to be elucidated.
UNASSIGNED: In the present study, we investigated whether PA promotes inflammasome-mediated inflammation of sebocytes both in vivo and in vitro.
UNASSIGNED: We intradermally injected PA into the mice ears. And, we treated cultured human sebocytes with PA. Inflammasome-mediated inflammation was verified by immunohistochemistry, Western blot and ELISA.
UNASSIGNED: PA-treated mice developed an inflammatory response associated with increased interleukin (IL)-1β expression in the sebaceous glands. When PA was added to cultured human sebocytes, caspase-1 activation and IL-1β secretion were significantly enhanced. In addition, NLRP3 knockdown attenuated IL-1β production by sebocytes stimulated with PA. PA-mediated inflammasome activation required reactive oxygen species.
UNASSIGNED: These findings indicate that PA activates the NLRP3 inflammasome before induction of an inflammatory response in sebocytes. Thus, PA may play a role in the inflammation of acne.

UNASSIGNED: Increased sebum secretion is considered the main causative factor in the pathogenesis of acne. There is an unmet pharmacological need for a novel drug that can control sebum production with a favorable adverse effect profile.
UNASSIGNED: To investigate the effect of azidothymidine on lipid synthesis in sebocytes and to identify the underlying mechanism of the inhibitory effect of azidothymidine on insulinlike growth factor (IGF)-1-induced lipid synthesis in sebocytes.
UNASSIGNED: Immortalized human sebocytes were used for the analysis. Thin-layer chromatography (TLC) and Oil Red O staining were performed to evaluate lipid synthesis in the sebocytes. The differentiation, lipid synthesis, mitochondrial biogenesis, and mitophagy in sebocytes were investigated.
UNASSIGNED: TLC and Oil Red O staining revealed that azidothymidine reduced IGF-1 induced lipid synthesis in the immortalized human sebocytes. Azidothymidine also reduced IGF-1-induced expression of transcriptional factors and enzymes involved in sebocyte differentiation and lipid synthesis, respectively. Moreover, we found that IGF-1 upregulated the levels of peroxisome proliferator-activated receptorgamma coactivator-1α, LC-3B, p62, and Parkin, major regulators of mitochondrial biogenesis and mitophagy in immortalized human sebocytes. In contrast, azidothymidine inhibited IGF-1 induced mitochondrial biogenesis and mitophagy in the sebocytes.
UNASSIGNED: These results suggest that azidothymidine downregulates IGF-1-induced lipogenesis by dysregulating the quality of mitochondria through suppression of mitochondrial biogenesis and mitophagy in immortalized human sebocytes. Our study provides early evidence that azidothymidine may be an effective candidate for a new pharmacological agent for controlling lipogenesis in sebocytes.

Sebaceous glands are sebum-secreting components of pilosebaceous units. The embryological development of the sebaceous gland follows that of the hair follicle and epidermal tissue, beginning between weeks 13 and 16 of fetal development. New sebaceous glands do not normally develop following birth, but their size increases with age. Sebocytes express a multitude of hormone receptors and are heavily regulated to secrete sebum by androgens. There is a large increase of sebum excretion at birth and again at puberty, until approximately age 17. In adulthood, sebum production remains stable and declines to zero in postmenopausal women and in men aged 60-70. Besides the production and release of sebum, sebaceous glands function to lubricate the skin and hair, provide thermoregulation, and exhibit antimicrobial activity. Research has shown sebaceous glands to possess the cellular capability to transcribe genes necessary for androgen metabolism. Dysfunction of the sebaceous gland can be seen primarily in steatocystoma simplex and multiplex, sebaceous gland hyperplasia, sebaceoma, sebaceous adenoma, sebaceous carcinoma, nevus sebaceus, and folliculosebaceous cystic hamartoma. Sebaceous glands are secondarily involved in acne vulgaris, seborrheic dermatitis, and androgenic alopecia.

Acantholytic dyskeratotic acanthoma is a rare variant of epidermal acanthoma. It has a flat, plaque-like structure and is characterized microscopically by acantholysis and dyskeratosis. Eccrine syringofibroadenomatous hyperplasia is benign and likely reactive. It has recently been considered as a hyperplastic process affecting the eccrine ducts rather than the neoplasm because of its pathological heterogeneity and wide clinical associations. In this article, we present the case of 97-year-old Japanese women with a 10-mm wide, painful acantholytic dyskeratotic acanthoma accompanied by syringofibroadenomatous hyperplasia in the right femoral region. Although syringofibroadenomatous hyperplasia is known to occur as a reactive process with various dermatoses and cutaneous tumors, to date, there have been no reports of cases of acantholytic dyskeratotic acanthoma accompanying syringofibroadenomatous hyperplasia. Moreover, this case also includes the unusual finding of an increase in the mature sebocytes in the area of the syringofibroadenomatous hyperplasia.

Uncoupling protein 1 (UCP-1) was believed to be an exclusive protein found in the brown adipose tissue of small rodents and humans; however, recent studies show that the expression of UCP-1 protein has been found in the sebaceous glands of the mouse tail and human skin. There are a few reports about the presence of UCP-1 in the sebaceous glands of other rodents, such as the Sunda porcupine (Hystrix javanica), a wild spiny rodent commonly found in Indonesia with a large sebaceous gland. The aim of this study was to identify the presence of UCP-1 in the sebaceous glands on the skin of the Sunda porcupine. The skin from three regions (thoracodorsal, lumbosacral and apex caudal) of eight adult Sunda porcupines was used to detect UCP-1-immunopositive cells through immunohistochemistry. All three regions were found immunopositive to anti-UCP-1 antibody in the sebaceous gland of quill and hair follicles, and the epidermal layer in quill and hair follicles with various intensities. The result of immunohistochemistry revealed that the thoracodorsal and apex caudal region was the most intense immunoreaction followed by the lumbosacral region. These findings proved that the presence of UCP-1 was also identified in the sebaceous glands of other rodent (Hystrix javanica) and regions of the body, which has not been reported previously.

Nicotinic acid (NA) activates hydroxycarboxylic acid receptor 2 (HCA2 ), and it is widely used in treating dyslipidaemias. Since its side effects include skin dryness, whereas its deficiency can be accompanied by dyssebacia, characterized by sebaceous gland enlargement, we asked if HCA2 is expressed on human sebocytes, and if NA influences sebocyte functions. By using human immortalized SZ95 sebocytes, we found that non-cytotoxic (≤100 μmol/L; MTT-assay) concentrations of NA had no effect on the homeostatic sebaceous lipogenesis (SLG; Nile Red), but normalized excessive, acne-mimicking SLG induced by several lipogenic agents (arachidonic acid, anandamide, linoleic acid + testosterone; Nile Red; 48-hr treatments). Moreover, it exerted significant anti-proliferative actions (CyQUANT-assay), and increased [Ca2+ ]IC (Fluo-4 AM-based Ca2+ -measurement). Although NA did not prevent the lipopolysaccharide-induced pro-inflammatory response (up-regulation [Q-PCR] and release [ELISA] of several pro-inflammatory cytokines) of the sebocytes, collectively, these data support the concept that NA may be effective in suppressing sebum production in vivo. While exploring the mechanism of the sebostatic actions, we found that sebocytes express HCA2 (Q-PCR, immunofluorescent labelling), siRNA-mediated silencing of which prevented the NA-induced Ca2+ -signal and the lipostatic action. Collectively, our data introduce NA, and HCA2 activators in general, as novel, potent and most likely safe sebostatic agents, with possible anti-acne potential.

The aryl hydrocarbon receptor (AHR) mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity that can lead to chloracne in humans. A characteristic of chloracne, in contrast to acne vulgaris, is shrinkage or loss of sebaceous glands. Acne vulgaris, on the other hand, is often accompanied by excessive sebum production. Here, we examined the role of AHR in lipid synthesis in human sebocytes using distinct classes of AHR ligands. Modulation of AHR activity attenuated the expression of lipogenic genes and key proinflammatory markers in the absence of canonical DRE-driven transcription of the AHR target gene CYP1A1. Furthermore, topical treatment with TCDD, which mediates DRE-dependent activity, and SGA360, which fails to induce DRE-mediated responses, both exhibited a decrease in the size of sebaceous glands and the number of sebocytes within each gland in the skin. To elucidate the mechanism of AHR-mediated repression of lipid synthesis, we demonstrated that selective AHR modulators, SGA360 and SGA315 increased the protein turnover of the mature sterol regulatory element-binding protein (mSREBP-1), the principal transcriptional regulator of the fatty acid synthesis pathway. Interestingly, selective AHR ligand treatment significantly activated the AMPK-dependent kinase (AMPK) in sebocytes. Moreover, we demonstrated an inverse correlation between the active AMPK and the mSREBP-1 protein, which is consistent with the previously reported role of AMPK in inhibiting cleavage of SREBP-1. Overall, our findings indicate a DRE-independent function of selective AHR ligands in modulating lipid synthesis in human sebocytes, which might raise the possibility of using AHR as a therapeutic target for treatment of acne.

Acne vulgaris is a prevalent cutaneous disease characterized by a multifactorial pathogenic process including hyperseborrhea, inflammation, over-keratinization of follicular keratinocytes and Propionibacterium acnes (P acnes) overgrowth. Salicylic acid (SA), a beta-hydroxy acid, is frequently used in the treatment of acne. SA has been found to decrease skin lipids and to possess anti-inflammatory properties. However, few studies have elucidated the mechanisms and pathways involved in such treatment of acne. In this study, we initially investigated the anti-acne properties of SA in human SEB-1 sebocytes. Treatment with SA decreased sebocyte lipogenesis by downregulating the adenosine monophosphate-activated protein kinase (AMPK)/sterol response element-binding protein-1 (SREBP-1) pathway and reduced inflammation by suppressing the NF-κB pathway in these cells. Salicylic acid also decreased the cell viability of SEB-1 by increasing apoptosis via the death signal receptor pathway. Subsequently, histopathological analysis of a rabbit ear acne model after application of SA for three weeks confirmed that SA suppressed the levels of cytokines and major pathogenic proteins around acne lesions, which supports the mechanisms suggested by our in vitro experiments. These results initially clarified that therapeutic activities of SA in acne vulgaris treatment could be associated with the regulation of SREBP-1 pathway and NF-κB pathway in human SEB-1 sebocytes.