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Recent GWAS have uncovered consistent genetic linkage of SSc fibrotic phenotypes with TNFAIP3, encoding the ubiquitin-editing enzyme A20. A20 has been previously implicated in negative regulation of innate immunity, and hypomorphic A20 variants are associated with autoimmunity in SLE, RA,and others.The transcription factor DREAM binds to the A20 promoter to repress expression. Unbiased transcriptome analysis of skin and lung biopsies from SSc patients showed significantly decreased A20 levels and robust anti-correlation with fibrotic TGF-beta signaling.
Psoriasis is a pathology mainly characterized by the hyperproliferation of epidermal cells, which leads to abnormal cell differentiation. A change in cyclic adenosine monophosphate (cAMP) levels could be causing this altered proliferation, as cAMP plays a major role in epidermis cellular growth. However, whether levels of cAMP in psoriatic skin are enhanced or decreased is a matter of much controversy. The aim of this study was therefore to quantify the levels of cAMP in psoriatic skin substitutes produced with two different cAMP enhancers, cholera toxin and isoproterenol, and to evaluate what impacts these levels have on the main characteristics of the pathology.
YAP/TAZ are key molecules in the Hippo signaling pathway that regulate organ size and promote the development and progression of proliferative diseases such as tumors through the induction of cell growth and inhibition of apoptosis. Skin fibrosis is characterized by persistent proliferation of fibroblasts and excessive production of extracellular matrix. Given the key role of the Hippo signaling pathway in other cells, we speculate that YAP/TAZ may also be involved in the pathogenesis of fibrosis.
Psoriasis is a chronic inflammatory dermatosis mediated by T cells through the IL-23/IL-17 axis. The hallmark cytokine of the Th17 cells, IL-17A, activates keratinocytes leading to the secretion of various chemokines that also account for leukocytes infiltration, thus producing an activation loop leading to the chronicization of the psoriatic lesions. The lack of suitable preclinical models reflecting the complex phenotype of this skin disease is a major obstacle to the further study of psoriasis pathogenesis.
Living skin equivalents (LSEs) containing well-differentiated keratinocytes cultivated on fibroblast-populated dermal substitutes have been used to treat burn wounds, skin defects of epidermolysis bullosa. The dermal matrix and the fibroblasts in LSEs modulate epidermal growth and differentiation through dynamic interactions. Various biomaterials have been used as dermal matrix substitutes, but the search has continued for an ideal matrix that is readily available and has minimal toxicity. The non-reducing disaccharide trehalose is a singular molecule, which has been conserved throughout evolution in prokaryotes, plants, invertebrates, but is absent in vertebrates including mammals.
Wound Induced Hair follicle Neogenesis (WIHN) is a rare adult organogenesis model where stem cells form de novo hair follicles following full-thickness wounding. As wounds inevitably contact the skin microbiota, it is important to understand the role of the skin microbiome in WIHN. To do so, we modified bacterial burdens and tested WIHN. We used 3 levels of microbial burden to measure WIHN: For minimal bacteria loads, we used germ-free (GF) mice, applied antibiotic ointment (Neosporin) or frequent cage changes of standard specific pathogen free (SPF) mice housing.
When compared to animals across other phyla, mammals have restricted regeneration and more fibrosis. This limited regenerative capacity may reflect a loss of pro-regeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover the programs governing regeneration in mammals, we investigated Wound Induced Hair Neogenesis (WIHN), a rare example of regeneration in adult mammals. Through comprehensive screening of transcripts associated with WIHN—as well as after rejuvenation lasers in human subjects--, we found that the endoribonuclease RNase L associates with regeneration/rejuvenation, but actually functions as a powerful suppressor of regeneration.
Application of low level AC or DC current to the skin to assist drug delivery, reduce pain, affect muscle contraction, accelerate bone and chronic wound healing have been used medically since 1830 when Carlo Matteucci reported that injured tissue generated an electrical current. In some therapeutic modalities, such as the treatment of Bell’s palsy, a reduction of fine lines and wrinkles, improved skin tone and plumpness have been reported. In the early 1970s skin aestheticians incorporated microcurrent treatment into their product offerings claiming improvement in the appearance of the skin.
Type I collagen, the most abundant protein in human skin is integral to cutaneous wound healing, promoting fibroblast proliferation whilst increasing wound tensile strength. Ageing leads to decreased type I collagen synthesis and greater disorganisation within the extracellular matrix resulting in impaired wound healing, an increasing burden in an ageing population. Synthetic type I collagen peptides have been shown to enhance cell migration and proliferation leading to the current hypothesis that nutraceutical porcine type I collagen peptides may enhance dermal collagen levels in aged individuals and promote cutaneous wound healing.
In humans, heat dissipation is mainly achieved by the evaporation of sweat. Key to the effectiveness of this thermoregulatory mechanism is the human-specific evolution of a dramatic increase in eccrine sweat gland density. The genetic changes underlying the evolution of this adaptive trait are unknown. In humans, expression of the Engrailed 1 (En1) transcription factor correlates with the onset of sweat gland formation. In mice, regulation of ecotdermal En1 expression is a major determinant of natural variation in gland density between strains and increased En1 promotes the specification of more eccrine glands.
Cytokeratin positive cells are frequently found in the blood and bone marrow of patients with epithelial cancers and are attributed to metastasis. Interestingly, we observed in a number of publications that unaffected human controls expressed traces of cytokeratin mRNAs. To determine the presence of epithelial cells in normal blood and bone marrow, we used immunofluorescence microscopy (IF), Krt1-14;mTmG transgenic mice, qRT-PCR, and fluorescence activated cell sorting (FACS). We have made several interesting findings.
The hairless (Hr) gene plays an essential role in hair follicle development and skin homeostasis. Both humans and mice lacking hairless activity suffer from complete hair loss and abnormal epidermal proliferation and differentiation, although the mechanisms underlying such developmental defects remain largely unknown. We recently demonstrated that Hr encodes a histone demethylase and acts as an epigenetic regulator of the expression of its target genes. Gene expression profiling studies identified pro-inflammatory IL-1 family cytokines, including IL-36 and IL-1β, among the major targets of Hr.
Murine hair follicle stem cells containing the KrasG12D mutation and p53 loss of function are able to form tumors that represent mesenchymal-like spindle cell morphology. This spindle form of squamous cell carcinomas exhibit hallmarks of epithelial to mesenchymal transition and grow rapidly with invasive characteristics. This mouse model thus provides a method for testing molecular candidates that are critical for a mesenchymal-like phenotype in cutaneous tumors. Cox-2 has been shown to have a role in progression of cutaneous squamous cell carcinomas composed of epithelial-like cells.
Interleukin 17A (IL17A) is a key cytokine in psoriasis and IL17A antibody therapy is an effective treatment for psoriasis. We previously showed that IL17A increases asymmetric stem cell self-renewal divisions in human keratinocytes and plays a role in the hyperproliferation of the epidermis observed in psoriasis. We hypothesized that downstream IL17A-induced keratinocyte cytokines were mediators of the increased asymmetric stem cell self-renewal divisions of psoriasis. We studied cytokines produced by keratinocytes after IL17A treatment and determined their effects on asymmetric stem cell self-renewal divisions in human keratinocytes in vitro, using sister pair analysis.
Vitamin C (vitC) plays key roles in many biological processes and it is a powerful anti-oxidant which protect the skin against UV exposure. Nevertheless, vitC is unstable under oxidative conditions. A pro-vitamin C, Ascorbic acid 2-glucoside (AA2G) was developed to stabilize vitC. The purpose of the study was to assess skin delivery, metabolism and antioxidant effect of AA2G compared to two concurrent products with 5% of encapsulated vitC or with 15% of free vitC. Skin delivery and metabolism studies were performed on human skin explants by UHPLC/UV.
Empirical and anecdotal evidence have associated stress with accelerated hair greying (formation of unpigmented hairs), but the scientific evidence linking the two is scant. Here, we report that acute stress leads to hair greying through fast depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of immune attack or adrenal stress hormones.
The skin forms the interface between an organism and its environment. To venture into diverse eco-spaces, animals evolve different integumentary organs to adapt. Here we study how feathers are made from a flat epidermis. A feather is made of two modules: a central shaft (rachis) and the bilateral vane which is made of barb branches. The feather has to be light and strong. In the follicle, feather epidermis first forms an epithelial cylinder with basal cells facing the pulp dermis inside. Then supra-basal cells are partitioned to form the rachis and barbs.
Hair transplantation for the management of androgenetic alopecia is often limited by the number of donor HFs available for transplantation. Therefore, HF neogenesis technologies that enlarge the number of donor HFs are needed. Here, we assessed the potential of human primary adult hair matrix keratinocytes (HMx), i.e. the cells interacting with dermal papilla fibroblasts (DPs) in vivo, in generating HF organoids when co-cultured with DP spheroids in vitro and in human skin organ culture, compared to primary human adult epidermal keratinocytes (NHEK).
Itch sensation is initiated by the activation of a specific subset of sensory neurons that project their peripheral and central axons to the skin and spinal cord respectively. Different subtypes of sensory neurons exhibit distinct terminal arborization subserving their functions. Sensory arborization of itch-sensing neurons has never been observed due to the lack of proper molecular genetic tool. Here we have genetically labeled a small subset of DRG sensory neurons using a newly generated MrgprC11CreER mouse line.
Atopic dermatitis (AD), a chronic inflammatory disease marked by skin itching and lesions, affects >26 million people in the US. A detailed understanding of the molecular pathogenesis of AD may provide novel means for the management of this debilitating disease. To this end, here we used 2,4-dinitrofluorobenzene (DNFB)-induced NC/NgaTnd mouse model that closely mimics AD in humans. After hair removal, AD was induced in 5-week-old female mice by weekly topical application of 0.15% DNFB to dorsal skin.