Mammalian Skin Research Articles

Differentiation of pluripotent stem cells for modeling human skin development and potential applications.

The skin of mammals is a multilayered and multicellular tissue that forms an environmental barrier with key functions in protection, regulation, and sensation. While animal models have long served to study the basic functions of the skin in vivo, new insights are expected from in vitro models of human skin development. Human pluripotent stem cells (PSCs) have proven to be invaluable tools for studying human development in vitro. To understand the mechanisms regulating human skin homeostasis and injury repair at the molecular level, recent efforts aim to differentiate PSCs towards skin epidermal keratinocytes, dermal fibroblasts, and skin appendages such as hair follicles and sebaceous glands. Here, we present an overview of the literature describing strategies for human PSC differentiation towards the components of skin, with a particular focus on keratinocytes. We highlight fundamental advances in the field employing patient-derived human induced PSCs (iPSCs) and skin organoid generation. Importantly, PSCs allow researchers to model inherited skin diseases in the search for potential treatments. Skin differentiation from human PSCs holds the potential to clarify human skin biology.

Collagen: An Overview from Past to Future Applications

Collagen, a structural protein, prevalent in animals, especially in skin, bones, and joints, responsible for providing fundamental structural support, is being used extensively in cosmetics. Mammalian and fish skin are the most common sources of collagen. Collagen's unique qualities, such as its role as a natural humectant and moisturizer for the skin, have piqued the curiosity of both academics and the cosmetic industry. In this review study, collagen biosynthesis, collagen sources used in the cosmetic industry, and collagen's function in cosmetics are discussed along with future aspects of collagen-based materials in cosmetics.

Large Rab GTPase Rab44 regulates microtubule-dependent retrograde melanosome transport in melanocytes

Melanosomes are melanin-containing organelles in melanocytes, and they are responsible for skin and hair pigmentation in mammals. The intracellular distribution of melanosomes is mainly determined by the balance between their anterograde transport on actin filaments and retrograde transport on microtubules. Although we have shown previously that melanoregulin and Rab36 serve as cargo receptors on melanosomes for retrograde transport, their knockdown does not completely inhibit retrograde melanosome transport, suggesting the existence of an additional cargo receptor(s) in melanocytes. In this study, we investigated the possible involvement of an atypical large Rab, Rab44, which also contains EF-hand domains and a coiled-coil domain, in retrograde melanosome transport in mouse melanocytes (Rab27A-deficient melan-ash cells). Our results showed that Rab44 localizes on mature melanosomes through lipidation of its C-terminal Rab-like GTPase domain, and that its knockdown results in suppression of retrograde melanosome transport. In addition, our biochemical analysis indicated that Rab44 interacts with the dynein–dynactin motor complex via its coiled-coil domain–containing middle region. Since simultaneous depletion of Rab44, melanoregulin, and Rab36 resulted in almost complete inhibition of retrograde melanosome transport, we propose that Rab44 is the third cargo receptor. We also showed that the N-terminal region of Rab44, which contains EF-hand domains, is required for both retrograde melanosome transport and its Ca2+-modulated activities. Our findings indicated that Rab44 is a third melanosomal cargo receptor, and that, unlike other cargo receptors previously described, its transport function is regulated by Ca2+.

Identification and characterization of the pathogenic potential of phenol-soluble modulin toxins in the mouse commensal Staphylococcus xylosus.

In contrast to the virulent human skin commensal Staphylococcus aureus, which secretes a plethora of toxins, other staphylococci have much reduced virulence. In these species, commonly the only toxins are those of the phenol-soluble modulin (PSM) family. PSMs are species-specific and have only been characterized in a limited number of species. S. xylosus is a usually innocuous commensal on the skin of mice and other mammals. Prompted by reports on the involvement of PSMs in atopic dermatitis (AD) and the isolation of S. xylosus from mice with AD-like symptoms, we here identified and characterized PSMs of S. xylosus with a focus on a potential involvement in AD phenotypes. We found that most clinical S. xylosus strains produce two PSMs, one of the shorter α- and one of the longer β-type, which were responsible for almost the entire lytic and pro-inflammatory capacities of S. xylosus. Importantly, PSMα of S. xylosus caused lysis and degranulation of mast cells at degrees higher than that of S. aureus δ-toxin, the main PSM previously associated with AD. However, S. xylosus did not produce significant AD symptoms in wild-type mice as opposed to S. aureus, indicating that promotion of AD by S. xylosus likely requires a predisposed host. Our study indicates that non-specific cytolytic potency rather than specific interaction underlies PSM-mediated mast cell degranulation and suggest that the previously reported exceptional potency of δ-toxin of S. aureus is due to its high-level production. Furthermore, they suggest that species that produce cytolytic PSMs, such as S. xylosus, all have the capacity to promote AD, but a high combined level of PSM cytolytic potency is required to cause AD in a non-predisposed host.

Limonene protects human skin keratinocytes against UVB-induced photodamage and photoaging by activating the Nrf2-dependent antioxidant defense system.

Long term exposure to solar ultraviolet B (UVB) radiation is one of the primary factors of premature skin aging and is referred to as photoaging. Also, mammalian skin exposed to UVB triggers an increase in production of α-melanocyte-stimulating hormone (α-MSH), which is critically involved in the pathogenesis of hyperpigmentary skin diseases. This study investigated the protective effect of limonene on UVB-induced photodamage and photoaging in immortalized human skin keratinocytes (HaCaT) in vitro. Initially, we determined cell viability and levels of reactive oxygen species (ROS) in UVB-irradiated HaCaT cells. Pretreatment with limonene increased cell viability followed by inhibition of intracellular ROS generation in UVB-irradiated HaCaT cells. Interestingly, the antioxidative activity of limonene was directly correlated with an increase in expression of endogenous antioxidants, including heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1), and γ-glutamylcysteine synthetase (γ-GCLC), which was associated with enhanced nuclear translocation and activation of NF-E2-related factor-2 (Nrf2). Indeed, Nrf2 knockdown reduced limonene's protective effects. Additionally, we observed that limonene treatment inhibited UVB-induced α-MSH secretion followed by inhibition of proopiomelanocortin (POMC) via suppression of p53 transcriptional activation. Moreover, limonene prevented UVB-mediated depletion of tight junction regulatory proteins, including occludin and zonula occludens-1. On the other hand, limonene treatment significantly decreased matrix metalloproteinase-2 levels in UVB-irradiated HaCaT cells. Based on these results, limonene may have a dermato-protective effect in skin cells by activating the Nrf2-dependent cellular antioxidant defense system.

Pharmaceutical development of metronidazole loaded transferosome gel for skin delivery

Objective: The focus of this research was out whether a transfersomal gel formulation for transdermal delivery of Metronidazole. Methods: Azole Antifungals include metronidazole, which is used to treat fungal and yeast infections. Transferosomes are supra-molecular aggregates that are ultra-flexible and have a high ability to penetrate mammalian skin intact. Drug encapsulation in various transfersomal formulations containing various ratios of different drug concentrations (0.05, 0.1, 0.2, 0.3, 0.4, 0.5 g) and Carbopol-934 (0.5, 1, 2 g) is being researched for use as a transferosomal gel.Results: Entrapment efficiency (EE %), drug content, in-vitro skin permeation tests, and stability investigations were performed on the produced formulations. The vesicles were spherical in shape, as confirmed by Transmission Electron Microscopy. Metronidazole was successfully pinned with a standardised drug content in all formulations, according to the resultsThe 0.1 g Metronidazole optimised transferosome formulation MG2 showed promising results, with maximum drug release (94.32%) and maximum drug release (94.32%). Conclusion: According to this report, transferosomes are a promising long-term delivery mechanism for metronidazole and have reasonably good stability.This study suggests that transferosomes containing Metronidazole may be used as a transdermal drug delivery tool for fungal skin infections.

Two novel CreERT2 transgenic mouse lines to study melanocytic cells in vivo.

The skin of adult mammals protects from radiation, physical and chemical insults. While melanocytes and melanocyte-producing stem cells contribute to proper skin function in healthy organisms, dysfunction of these cells can lead to the generation of malignant melanoma-the deadliest type of skin cancer. Addressing cells of the melanocyte lineage in vivo represents a prerequisite for the understanding of melanoma on cellular level and the development of preventive and treatment strategies. Here, the inducible Cre-loxP-system has emerged as a promising tool to specifically target, monitor, and modulate cells in adult mice. Re-analysis of existing sequencing data sets of melanocytic cells revealed that genes with a known function in neural cells, including neural stem cells (Aldh1L1 and Nestin), are also expressed in melanocytic cells. Therefore, in this study, we explored whether the promoter activity of Nestin and Aldh1L1 can serve to target cells of the melanocyte lineage using the inducible CreERT2 -loxP-system. Using an immunohistochemical approach and different time points of analysis, we were able to map the melanocytic fate of recombined stem cells in the adult hair follicle of Nestin-CreERT2 and Aldh1L1-CreERT2 transgenic mice. Thus, we here present two new mouse models and propose their use to study and putatively modulate adult melanocytic cells in vivo.

A Self‐Powered, Single‐Mode Tactile Sensor Based on Sensory Adaptation Using Piezoelectric‐Driven Ion Migration

AbstractA piezoelectric tactile sensor is beneficial for creating a self‐powered system with a compact design, which is essential in electronic‐skin technology. However, piezoelectricity is only capable of dynamic pressure detection because it responds to sudden environmental changes. Since it is common to add another sensing unit to detect static pressure that accompanies bulkiness, including a measuring apparatus, we demonstrate a self‐powered, single‐mode piezoelectric tactile sensor by fabricating a piezoelectric gel through the electrospinning technique. As piezoelectricity senses the dynamic pressure without an external power supply, ions detect the static pressure by maintaining the potential difference upon sustained pressure. Since each component outputs a voltage signal of the same type but different profiles upon pressure, it is possible to distinguish dynamic and static pressure in a single mode. Moreover, inspired by the sensory adaptation of mammalian skin, an ion‐assisted piezoelectric tactile sensor efficiently detects concurrently stacked stimuli by decreasing the output signal for sustained stimuli. The sensitivity for superimposed pressure upon initial 14.7 kPa increases by more than four times compared to that without sensory adaptation for both dynamic and static pressure.

736 Defining the epigenetic regulation of fibroblast lineages during embryonic development

The mammalian skin can support hair follicle formation during embryonic development, but this ability is lost as the skin matures. We have previously shown that, in murine skin starting at embryonic day 16.5 (E16.5), the dermal fibroblasts contained two distinct lineages with different functions. The upper papillary fibroblasts population supports the formation of new hair follicles. However, the mechanism by which embryonic fibroblasts lineages are established remained undefined. By performing ChIP-seq for different histone modifications markers comparing early embryonic fibroblasts (E14.5) and late differentiated embryonic fibroblasts (E17.5), we found a significant difference in H3K27me3 peaks at genes associated with fibroblast differentiation.

LB1016 Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer

In the mammalian skin epidermis, it has long been unclear how molecularly heterogenous stem/progenitor cell populations fit into the complete trajectory of epidermal differentiation. Here, we combine in vivo imaging with single-cell RNA sequencing to define the early stages of epidermal stem cell differentiation at the molecular and behavioral level. We show that differentiation, from commitment to exit from the stem cell layer, is a multi-day process wherein cells transit through a gradual continuum of transcriptional changes. By tracking epidermal regions over many days, we find that differentiation-committed cells remain capable of dividing to produce daughter cells fated to further differentiate, demonstrating that differentiation is uncoupled from cell cycle exit. These cell divisions occur as a response to local density changes, and are not required as part of an obligate transit amplifying program but instead help to buffer the differentiating cell pool upon disruption of the epidermal barrier. Thus, instead of distinct contributions from multiple progenitor types, a single continuous differentiation process shaped by feedback from the local environment fuels lifelong turnover of the epidermis.

745 Regional expression of secreted WNT inhibitors dictates formation of hairless and poorly haired skin

Different regions of mammalian skin vary in characteristics such as thickness, and hair follicle and sweat gland presence, size and density, that are reflected in differential responses to injury and disease. Positional information resides in the upper dermis but the responsible molecular mechanisms are poorly understood. To uncover these, we carried out comparative scRNA-seq of mouse embryonic dorsal, ear and plantar skin. This revealed differential regional expression of several secreted Wnt inhibitors, including Dkk2 and Sostdc1, suggesting regional modulation of Wnt signaling as an important mechanism controlling skin heterogeneity. In line with this, we showed previously that Dkk2-null mice develop regenerative hair follicles in normally hairless plantar skin. However, hair follicles in other regions had normal density and size. Loss of Sostdc1 is known to cause ectopic hair formation in nipple skin, extra vibrissae, and larger hair follicle placodes in trunk skin. We hypothesized that Dkk2 and Sostdc1 function partially redundantly to control additional regional skin features. To test this, we generated mice lacking both inhibitors. Double mutants displayed elevated Wnt signaling in embryonic plantar and ear skin, increased formation of plantar hair compared with Dkk2 single mutants, and growth of abnormally dense, long, thick hair on the external ears. Thus, regional modulation of Wnt signaling controls both the formation of hairless versus hairy skin, and the size and density of hair follicles in haired skin. These data support a new paradigm in which, rather than being dictated by an activating dermal signal as postulated in classical models, hair follicle formation is a default pathway that is actively suppressed by secreted inhibitors in skin regions that lack hair follicles or are poorly haired.

558 An aging-susceptible circadian rhythm controls cutaneous antiviral immunity

Aged skin is prone to viral infections, but the mechanisms responsible for this are unclear. We hypothesize that an aging circadian rhythm compromises cutaneous innate antiviral immunity. In support of this hypothesis, we observed that aged mammalian skin exhibits significant reduction in transcriptional levels of antiviral proteins (AVPs) and circadian transcriptional regulators including BMAL1 and CLOCK, in vivo and in vitro. Using BMAL1 and CLOCK knockout mouse models, we found that loss of circadian factors significantly reduces AVP expression in the skin.

Analysis of the main biological properties of <em>Kocuria</em>

Representatives of the genus Kocuria are found in soil, marine sediments, water, on the skin and oropharynx of mammals. This paper presents the results of a study to determine the biological properties of Kocuria sp. isolated from goat milk. There is evidence of association of opportunistic Kocuria spp. with the development of severe septic conditions, meningitis, endocarditis, cholecystitis, and osteomyelitis.

Infestation, histology, and molecular confirmation of Sarcoptes scabiei in an Andean porcupine (Coendou quichua) from the Central Andes of Colombia.

Sarcoptic mange is a highly contagious, worldwide disease that affects the skin of mammals, including humans. It is caused by the mite Sarcoptes scabiei, however, the information available in wild mammal populations in the world, and particularly in Colombia is limited. Here, we document a new case of sarcoptic mange in an Andean porcupine (Coendou quichua) from the Andean region of Colombia. We morphologically and molecularly confirmed the mite as S. scabiei and documented the histopathology associated with scabies, and show the different stages of the life cycle of S. scabiei from the Andean porcupine skin samples. Our review of reports of additional cases of scabies in wild mammal species in South America showed 15 species, mostly carnivores, artiodactyls, and rodents. Considering the limited information in Colombia, it is urgent to evaluate the risk of this condition on mammals which would contribute to the epidemiological knowledge and the potential implications of sarcoptic mange in the ecology and conservation of wild mammals in the country.

The effect of differences extraction solutions on the gelatin characteristic fishbone of bader bang (Barbonymus balleroides)

Gelatin is a polypeptide derived from collagen in the skin and bones of mammals or fish. The utilization of bader bang especially bader bang fish bones as raw material for gelatin is still not widely found. The purpose of this study was to determine the effect of different extraction solutions on the characteristics of bader bang fish bone gelatin and to compare the characteristics of the bader bang fish bone gelatin produced with the standard. The study was carried out using a completely randomized design (CRD). The best results from the three treatments were found in the extraction of gelatin in the treatment NaOH 0,2% + H2SO4 0,2% The characteristics of water content, ash content, viscosity and gel strength complied with SNI 06-3735 and British Standard 757.

Robotic Hair with Rich Sensation and Piloerection Functionalities Biomimicked by Stimuli‐Responsive Materials

AbstractLiving organisms are imparted with compact intelligence in which a myriad of functionalities are delivered by highly integrated and demodularized subunits, as in the case of the mammalian skin in which different embedding stimuli‐receptors and follicles work together to provide rich sensation for temperature and tactility, as well as the visible and regulatory response of hair erection via the arrector pili muscle. A breakthrough in robotics is to create similar intelligence using emerging stimuli‐responsive materials. Here, a thin film composite comprising a transition metal oxide/hydroxide layer for sensation and high‐performing actuation under environmental stimuli including visible light, humidity, and temperature, and a graphene‐based layer for feedback strain sensing, is developed to demonstrate such an approach of robotics. The system is used to construct robotic hair that mimics well mammalian hair in functionality, and devices for sensing objects for their effective manipulation. This research opens a “material intelligence” approach for robotics.

Remarkable floral colour variation in the functionally specialized fly-pollinated iris,Moraea lurida

AbstractSapromyophilous flowers are visited by flies seeking carrion or faeces, and flowers of this guild are typically large, purple or red-brown, often speckled and produce a pungent scent. Flowers of the South African iris Moraea lurida conform to this syndrome, but show considerable variation in colour and pattern. We were intrigued by the floral variation within a single population and investigated floral visitors and the effect of body size on pollen loads and whether different colour forms attracted different pollinator assemblages. We found a diverse array of insect visitors, but Diptera comprised the overwhelming majority, with Calliphoridae considered to be the most important for pollination on the basis of their visitation frequency and pollen loads. Effective pollination appeared to be dependent on large-bodied flies that, unlike smaller flies, fit the entire crawl space between the anthers and petals and thus acted like a key in a lock. Choice experiments revealed that the most important fly pollinators showed no colour preferences, and fly vision modelling showed that flies may not be able to discriminate among the different colour forms. This may lead to relaxed selection on colour. Floral scent was dominated by an unusual mix of aliphatic acids and alcohols, characteristic of mammalian skin products and gut microbiome, probably exploiting the perceptual bias of flies to compounds that typify the mammalian microbiome and fermenting carbohydrates.

D-Serine controls epidermal vesicle release via NMDA receptor, allowing tissue migration during the metamorphosis of the chordate Ciona.

d-Serine, a free amino acid synthesized by serine racemase, is a coagonist of N-methyl-d-aspartate–type glutamate receptor (NMDAR). d-Serine in the mammalian central nervous system modulates glutamatergic transmission. Functions of d-serine in mammalian peripheral tissues such as skin have also been described. However, d-serine’s functions in nonmammals are unclear. Here, we characterized d-serine–dependent vesicle release from the epidermis during metamorphosis of the tunicate Ciona. d-Serine leads to the formation of a pocket that facilitates the arrival of migrating tissue during tail regression. NMDAR is the receptor of d-serine in the formation of the epidermal pocket. The epidermal pocket is formed by the release of epidermal vesicles’ content mediated by d-serine/NMDAR. This mechanism is similar to observations of keratinocyte vesicle exocytosis in mammalian skin. Our findings provide a better understanding of the maintenance of epidermal homeostasis in animals and contribute to further evolutionary perspectives of d-amino acid function among metazoans.

Malassezia in Inflammatory Bowel Disease: Accomplice of Evoking Tumorigenesis.

Accumulating evidence indicates that patients with inflammatory bowel disease (IBD) have a significantly higher risk of developing different cancers, while the exact mechanism involved is not yet fully understood. Malassezia is a lipid-dependent opportunistic yeast, which colonizes on mammalian skin and internal organs. Also, dysbiosis in fungal communities accompanied by high level of Malassezia are fairly common in inflammatory diseases such as IBD and various cancers. In cancer patients, higher levels of Malassezia are associated with worse prognosis. Once it is ablated in tumor-bearing mice, their prognostic conditions will be improved. Moreover, Malassezia manifests multiple proinflammatory biological properties, such as destruction of epithelial barrier, enrichment of inflammatory factors, and degradation of extracellular matrix (ECM), all of which have been reported to contribute to tumor initiation and malignant progression. Based on these facts, we hypothesize that high levels of Malassezia together with mycobiome dysbiosis in patients with IBD, would aggravate the microecological imbalance, worsen the inflammatory response, and further promote tumorigenesis and deterioration. Herein, we will discuss the detrimental properties of Malassezia and explore the key role of this fungus in the correlation between IBD and cancer, in order to take early surveillance and intervention to minimize the cancer risk in individuals with IBD.

States and Fates of Skin Fibroblasts Revealed through Chromatin Accessibility

Adult mammalian skin harbors a myriad of stromal populations, but it is only recently that we have been able to untangle their developmental origins, lineage-specific functions, and fluctuations in influence during skin development, aging, and injury/repair. Thompson et al. (2022) now unveil the epigenetic status underlying the heterogeneity of skin stromal cells. They also show that neonatal skin stromal cells exhibit chromatin landscapes that shape two epigenetically distinct lineages: dermal papilla and adipocyte fates.