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Unlike other mammals that must pant or seek shade or water when overheated, humans are able to self-cool to tolerate extreme heat. Sweat glands, which enable humans to run in marathons, are instrumental for this remarkable feat. Lu et al. investigated skin appendage diversity during development of the furry backs and sweaty paws of mice (see the Perspective by Lai and Chuong). They also examined human skin, which is capable of making both hairs and sweat glands in the same area of the body. Epithelialmesenchymal interactions, with varied signaling pathways that act at specific times in development, are key to producing different skin appendages for adaptation to the environment. Science , this issue p. 10.1126/science.aah6102 ; see also p. 1533 Mice and humans exploit the epithelial-mesenchymal circuitry in different ways to direct sweat gland or hair follicle generation. The gain of eccrine sweat glands in hairy body skin has empowered humans to run marathons and tolerate temperature extremes. Epithelial-mesenchymal cross-talk is integral to the diverse patterning of skin appendages, but the molecular events underlying their specification remain largely unknown. Using genome-wide analyses and functional studies, we show that sweat glands are specified by mesenchymal-derived bone morphogenetic proteins (BMPs) and fibroblast growth factors that signal to epithelial buds and suppress epithelial-derived sonic hedgehog (SHH) production. Conversely, hair follicles are specified when mesenchymal BMP signaling is blocked, permitting SHH production. Fate determination is confined to a critical developmental window and is regionally specified in mice. In contrast, a shift from hair to gland fates is achieved in humans when a spike in BMP silences SHH during the final embryonic wave(s) of bud morphogenesis.

Bromhidrosis has a great negative impact on personal occupation and social psychology. It is not yet clear whether bromhidrosis is caused by apocrine sweat glands or the co-action of apocrine sweat glands and eccrine sweat glands. To distinguish between apocrine sweat glands and eccrine sweat glands, specific antigen markers for apocrine sweat glands and eccrine sweat glands must be found first. In the study, we detected the expression of K7, K18, K19, Na+-K+-2Cl- cotransporter 1 (NKCC1), carbonic anhydrase II (CAII), Forkhead transcription factor a1 (Foxa1), homeobox transcription factor engrailed homeobox1 (En1), gross cystic disease fluid protein-15 (GCDFP-15), mucin-1 (MUC-1), cluster of differentiation 15 (CD15) and apolipoprotein (APOD) in eccrine sweat glands and apocrine sweat glands by immunofluorescence staining. The results showed that K7, K18, K19, Foxa1, GCDFP-15 and MUC-1 were expressed in both apocrine and eccrine sweat glands, CD15 and APOD were only expressed in apocrine sweat glands, and CAII, NKCC1 and En1 were only expressed in eccrine sweat glands. We conclude that CD15 and APOD can serve as specific markers for apocrine sweat glands, while CAII, NKCC1 and En1 can serve as specific markers for eccrine sweat glands to differentiate the two sweat glands.

Humans sweat to cool their bodies and have by far the highest eccrine sweat gland density among primates. Humans’ high eccrine gland density has long been recognized as a hallmark human evolutionary adaptation, but its genetic basis has been unknown. In humans, expression of the Engrailed 1 (EN1) transcription factor correlates with the onset of eccrine gland formation. In mice, regulation of ectodermal En1 expression is a major determinant of natural variation in eccrine gland density between strains, and increased En1 expression promotes the specification ofmore eccrine glands. Here, we show that regulation of EN1 has evolved specifically on the human lineage to promote eccrine gland formation. Using comparative genomics and validation of ectodermal enhancer activity in mice, we identified a human EN1 skin enhancer, hECE18. We showed that multiple epistatically interacting derived substitutions in the human ECE18 enhancer increased its activity compared with nonhuman ape orthologs in cultured keratinocytes. Repression of hECE18 in human cultured keratinocytes specifically attenuated EN1 expression, indicating this element positively regulates EN1 in this context. In a humanized enhancer knock-in mouse, hECE18 increased developmental En1 expression in the skin to induce the formation of more eccrine glands. Our study uncovers a genetic basis contributing to the evolution of one of the most singular human adaptations and implicates multiple interacting mutations in a single enhancer as a mechanism for human evolutionary change.

Reconstruction of hair follicles (HFs) and eccrine sweat glands (ESGs) is essential for functional skin regeneration. In skin reconstruction research, we found that foreskin-derived epidermal cells reconstructed HF organoids unidirectionally, but not ESG organoids. To investigate key genes and pathways influencing the fate of ESG and HF, a transcriptome profiling of ESG placode-containing skin and HF placode-containing skin was employed, and key DEGs were identified and validated by RT-qPCR and immunofluorescence staining in mice and rats. Subsequently, adult human epidermal cell-derived organoids were reconstructed to probe functional roles and mechanisms of FGF7 and FGF10 by series of approaches integrating RT-qPCR, immunofluorescence-staining, WB, apoptosis assay, and pathway interference assay. All members of FGF7 subfamily were among the key DEGs screened, the differential expression of FGF7 and FGF10 and their receptors FGFR1/FGFR2 was verified between ESG placode-containing skin and HF placode-containing skin. and Matrigel plug models showed that both FGF7 and FGF10 promoted fate transition of human epidermal cell-derived organoids to ESG phenotype organoids, FGF7 and FGF10 had a synergistic effect, and mainly function through the FGFR1/2-MEK1/2-ERK1/2 pathway. Adult epidermal cells can be manipulated to reconstruct personalized HF and ESG to meet different needs.

Interactions between the extracellular matrix (ECM) and epithelial cells are necessary for the proper organization and function of the epithelium. In the present study, we show that human eccrine sweat gland epithelial cells cultured in matrigel, a representation of ECM components, constitute a good model for studying three-dimensional reconstruction, wound repair and regeneration and differentiation of the human eccrine sweat gland. In matrigel, epithelial cells from the human eccrine sweat gland form tubular-like structures and then the tubular-like structures coil into sphere-like shapes that structurally resemble human eccrine sweat glands in vivo. One sphere-like shape can be linked to another sphere-like shape or to a cell monolayer via tubular-like structures. Hematoxylin and eosin staining has revealed that the tubular-like structures have a single layer or stratified epithelial cells located peripherally and a lumen at the center, similar to the secretory part or duct part, respectively, of the eccrine sweat gland in sections of skin tissue. Immunohistochemical analysis of the cultures has demonstrated that the cells express CK7, CK19, epithelial membrane antigen and actin. Thus, matrigel promotes the organization and differentiation of epithelial cells from the human eccrine sweat gland into eccrine sweat gland tissues.

Eccrine sweat glands play a vital role in human thermoregulation; however, their self-repair function is minimal. Therefore, developing methods to regenerate and improve sweat gland function that use cultured sweat gland cells presents an urgent issue. The tissue microenvironment, especially hypoxic niches, essentially maintain cell stemness, highlighting the importance of oxygen concentration in the culture environment. Therefore, we evaluated the effects of different oxygen environments on human sweat glands and their regulatory mechanisms. Human eccrine sweat glands express HIF-1α and HIF-2α, suggesting that they respond to hypoxia in vivo. Primary human-derived eccrine sweat gland cells were cultured for two weeks using the spheroid culture method at 0.5%, 2%, 10%, and 21% O2 concentration. HIF-1, Wnt/β-Catenin, and TGFβ1 signaling increased in sweat gland cells cultured in 0.5% O2 conditions, along with increased undifferentiated cell marker expression. The results of this study will contribute to in vitro research models of sweat glands and treatment development for damage to sweat glands, including burns.

Purpose The purpose of the present study was to develop and describe a simple method to evaluate the rate of ion reabsorption of eccrine sweat glands in human using the measurement of galvanic skin conductance (GSC) and local sweating rate (SR). This purpose was investigated by comparing the SR threshold for increasing GSC with following two criteria of sweat ion reabsorption in earlier studies such as (1) the SR threshold for increasing sweat ion was at approximately 0.2–0.5 mg/cm 2 /min and (2) exercise heat acclimation improved the sweat ion reabsorption ability and would increase the criteria 1. Methods Seven healthy non-heat-acclimated male subjects received passive heat treatment both before and after 7 days of cycling in hot conditions (50 % maximum oxygen uptake, 60 min/day, ambient temperature 32 °C, and 50 % relative humidity). Results Subjects became partially heat-acclimated, as evidenced by the decreased end-exercise heart rate ( p  < 0.01), rate of perceived exhaustion ( p  < 0.01), and oesophageal temperature ( p  = 0.07), without alterations in whole-body sweat loss, from the first to the last day of training. As hypothesized, we confirmed that the SR threshold for increasing GSC was near the predicted SR during passive heating before exercise heat acclimation, and increased significantly after training (0.19 ± 0.09–0.32 ± 0.10 mg/cm 2 /min, p  < 0.05). Conclusions The reproducibility of sweat ion reabsorption by the eccrine glands in the present study suggests that the relationship between GSC and SR can serve as a new index for assessing the maximum rate of sweat ion reabsorption of eccrine sweat glands in humans.

Sweating is a basic skin function in body temperature control. In sweat glands, salt excretion and reabsorption are regulated to avoid electrolyte imbalance. To date, the mechanism underlying such regulation is not fully understood. Corin is a transmembrane protease that activates atrial natriuretic peptide (ANP), a cardiac hormone essential for normal blood volume and pressure. Here, we report an unexpected role of corin in sweat glands to promote sweat and salt excretion in regulating electrolyte homeostasis. In human and mouse eccrine sweat glands, corin and ANP are expressed in the luminal epithelial cells. In corin-deficient mice on normal- and high-salt diets, sweat and salt excretion is reduced. This phenotype is associated with enhanced epithelial sodium channel (ENaC) activity that mediates Na + and water reabsorption. Treatment of amiloride, an ENaC inhibitor, normalizes sweat and salt excretion in corin-deficient mice. Moreover, treatment of aldosterone decreases sweat and salt excretion in wild-type (WT), but not corin-deficient, mice. These results reveal an important regulatory function of corin in eccrine sweat glands to promote sweat and salt excretion.

Most mammals rely upon scent for intraspecific communication. As most bear species have large home ranges and are non-territorial, scent deposit while walking could be an effective way to communicate with conspecifics. Here, we investigate the existence of pedal glands in brown bears and their role in chemical communication from a histological, biochemical and behavioural perspective. We found eccrine glands in footpads, and prominent apocrine and sebaceous glands in the interdigital, metacarpal and metatarsal skin sections. Pedal scent contained 26 compounds including carboxylic acids, important constituents of mammalian secretions. Six of these compounds were exclusive for males. Finally, we describe a specific marking gait recorded in the field, mostly performed by males. Our study supports the existence of chemical communication through pedal marking in brown bears and suggests sex-coding potential of pedal scent.

Background: Fractional microneedle radiofrequency (FMR) devices deliver energy to the deep dermis through insulated microneedles without destroying the epidermis. These FMR devices have been shown to be effective for the treatment of wrinkles, acne scars and large pores. In this study it was postulated that FMR energy could specifically affect the sweat glands, preserving the skin surface even if sweat glands were seated in the deep dermis. Objective: To evaluate the efficacy and safety of FMR for primary axillary hyperhidrosis (PAH) treatment and to conduct a histological analysis before and after treatment. Methods: Twenty patients with PAH had 2 sessions of bipolar FMR treatment at 4-week intervals. Clinical improvement was evaluated using a Hyperhidrosis Disease Severity Scale (HDSS) and photographs were taken using the starch-iodine test at every visit and 2 months after the last treatment. The amount of sweat reduction was indirectly assessed using a Tewameter™. Skin biopsies were obtained from 3 of the enrolled patients before and after treatment. The satisfaction and adverse reactions of the research participants were recorded at every follow-up visit. Results: HDSS scores decreased significantly from a baseline of 3.3 to 1.5 and 1.8 after the first and second months of posttreatment follow-up sessions, respectively (p < 0.001). In response to a subjective assessment at 1 month after the second treatment, 75% of patients (n = 15) had an HDSS score of 1 or 2, and 70% of patients (n = 14) expressed more than 50% improvement in their sweating. The starch-iodine reaction was also remarkably reduced in 95% of patients (n = 19) after FMR treatment. Histological findings showed a decrease in the number and size of both apocrine and eccrine glands 1 month after the final treatment. Side effects were minimal and included mild discomfort, transient swelling and postinflammatory hyperpigmentation. Conclusion: FMR treatment was effective for the treatment of PAH without significant adverse reactions due to direct volumetric heating of the lower dermis.