Search

Skin in vitro models offer much promise for research, testing drugs, cosmetics, and medical devices, reducing animal testing and extensive clinical trials. There are several in vitro approaches to mimicking human skin behavior, ranging from simple cell monolayer to complex organotypic and bioengineered 3-dimensional models. Some have been approved for preclinical studies in cosmetics, pharmaceuticals, and chemicals. However, development of physiologically reliable in vitro human skin models remains in its infancy. This review reports on advances in in vitro complex skin models to study skin homeostasis, aging, and skin disease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8 + T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration-approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell-mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell-signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell-signaling pathways is also provided in this review., Competing Interests: TP has received honoraria and/or consultation fees from AbbVie, Almirall, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Sanofi Genzyme, Sun Pharma, UCB Pharma, and Vyne Therapeutics. BK has received honoraria and/or consultation fees from AbbVie, Aclaris Therapeutics, AltruBio, Almirall, Arena Pharmaceuticals, Bioniz Therapeutics, Bristol Myers Squibb, Concert Pharmaceuticals, Dermavant Sciences, Eli Lilly, Incyte, LEO Pharma, Otsuka/Visterra, Pfizer, Regeneron, Sanofi Genzyme, TWi Biotechnology, and Viela Bio and speakers bureau fees from Pfizer. JS has been an advisor, speaker, or investigator for AbbVie, Calypso Biotech, Eli Lilly, Novartis, Pierre Fabre, and Sanofi Genzyme. MS has received honoraria, consultation fees, or investigator fees from AbbVie, Almirall, Arena, Algorithm, Avon, Baiersdorf, Bayer Health, BMS, Celgene, Chugai, Ducray, Eli Lilly, Galderma, Genentech, GSK, Incyte, Kiniksa, LEO Pharma, L’Oreal, Maruho, Mitsubishi, Janssen, Novartis, Pfizer, Pierre Fabre, Qatar Pharma, Regeneron, Sanofi, Toray, Trevi, Vertex, and ZymoGenetics. AJ has received institutional grants from Arena Pharmaceuticals, InSilico Medicine, and Pfizer and honoraria and/or consultation fees from Pfizer. MO has received lecture fees from Eli Lilly Japan; advisory fees from Eli Lilly Japan, Pfizer Japan Inc., Maruho Co., Bristol Myers Squibb Japan., Taisho Pharmaceutical Co., AbbVie GK, and ROHTO Pharmaceutical Co.; and research grants not related to the submitted work from Maruho Co., Shiseido Co, Advantest Corp., and Sun Pharma Japan Ltd. DT has been an advisor, speaker, or investigator for Pfizer, Frequency Therapeutics, Nacuity Pharmaceuticals, Menarini Group, Galderma, Sanofi Genzyme, and Janssen. SR, AW, J-BT, DM, and AL are employees of Pfizer and hold stock or stock options in Pfizer. The authors declare that this study received funding from Pfizer. The funder had the following involvement in the study: the study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication., (Copyright © 2023 Passeron, King, Seneschal, Steinhoff, Jabbari, Ohyama, Tobin, Randhawa, Winkler, Telliez, Martin and Lejeune.)

The visual appearance of humans is derived significantly from our skin and hair color. While melanin from epidermal melanocytes protects our skin from the damaging effects of ultraviolet radiation, the biological value of pigmentation in the hair follicle, particularly on the scalp, is less clear. In this study, we explore the heterogeneity of pigment cells in the human scalp anagen hair follicle bulb, a site conventionally viewed to be focused solely on pigment production for transfer to the hair shaft. Using c-KIT/CD117 microbeads, we isolated bulbar c-KIT-positive and c-KIT-negative melanocytes. While both subpopulations expressed MITF, only the c-KIT-positive fraction expressed SOX10. We further localized bulbar melanocyte subpopulations (expressing c-KIT, SOX10, MITF, and DCT) that exhibited distinct/variable expression of downstream differentiation-associated melanosome markers (e.g., gp100 and Melan-A). The localization of a second 'immature' SOX10 negative melanocyte population, which was c-KIT/MITF double-positive, was identified outside of the melanogenic zone in the most peripheral/proximal matrix. This study describes an approach to purifying human scalp anagen hair bulb melanocytes, allowing us to identify unexpected levels of melanocyte heterogeneity. The function of the more immature melanocytes in this part of the hair follicle remains to be elucidated. Could they be in-transit migratory cells ultimately destined to synthesize melanin, or could they contribute to the hair follicle in non-melanogenic ways?

The efficacy of blue light therapy in dermatology relies on numerous clinical studies. The safety remains a topic of controversy, where potentially deleterious effects were derived from in vitro rather than in vivo experiments. The objectives of this work were (1) to highlight the nuances behind "colors" of blue light, light propagation in tissue and the plurality of modes of action; and (2) to rigorously analyze studies on humans reporting both clinical and histological data from skin biopsies with focus on DNA damage, proliferation, apoptosis, oxidative stress, impact on collagen, elastin, immune cells, and pigmentation. We conclude that blue light therapy is safe for human skin. It induces intriguing skin pigmentation, in part mediated by photoreceptor Opsin-3, which might have a photoprotective effect against ultraviolet irradiation. Future research needs to unravel photochemical reactions and the most effective and safe parameters of blue light in dermatology., (© 2022 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

Alopecia areata (AA) is a chronic, multifactorial, polygenic, and heterogeneous disorder affecting growing hair follicles in susceptible individuals, which results in a non-scarring and reversible hair loss with a highly unpredictable course. Despite very considerable research effort, the nature of the precipitating factor(s) responsible for initiating AA in any given hair follicle remains unclear, due largely to significant gaps in our knowledge of the precise sequence of the etiopathogenic events in this dermatosis. However, disease-related changes in the immune-competence of the lower growing hair follicle, together with an active immune response (humoral and cellular) to hair follicle-associated antigens, are key associated phenomena. Confirmation of the hair follicle antigen(s) implicated in AA disease onset has remained stubbornly elusive. While it may be considered somewhat philosophical by some, it is also unclear whether immune-mediated hair loss in AA results from a) an ectopic (i.e., in an abnormal location) immune response to native (unmodified) self-antigens expressed by the healthy hair follicle, b) a normal immune response against modified self-antigens (or neoantigens), or c) a normal immune response against self-antigens (modified/non-modified) that were not previously visible to the immune system (because they were conformationally-hidden or sequestered) but become exposed and presentable in an MHC-I/-II molecule-restricted manner. While some candidate hair follicle antigen target(s) in AA are beginning to emerge, with a potential role for trichohyalin, it is not yet clear whether this represents the initial and immunodominant antigenic focus in AA or is simply one of an expanding repertoire of exposed hair follicle tissue damage-associated antigens that are secondary to the disease. Confirmation of autoantigen identity is essential for our understanding of AA etiopathogenesis, and consequently for developing a more informed therapeutic strategy. Major strides have been made in autoantigen discovery in other autoimmune conditions. In particular, some of these conditions may provide insights into how post-translational modifications (e.g., citrullination, deamidation, etc.) of hair follicle-restricted proteins may increase their antigenicity and so help drive the anti-hair follicle immune attack in AA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jadeja and Tobin.)

Cutaneous melanoma can be a most challenging neoplasm of high lethality, in part due to its extreme heterogeneity and characteristic aggressive and invasive nature. Indeed, its moniker 'the great masquerader' reflects that not all melanomas are created equal in terms of their originating cellular contexts, but also that melanoma cells in the malignant tumor can adopt a wide range of different cell states and variable organotropism. In this review, we focus on the early phases of melanomagenesis by discussing how the originating pigment cell of the melanocyte lineage can be influenced to embark on a wide range of tumor fates with distinctive microanatomical pathways. In particular, we assess how cells of the melanocyte lineage can differ by maturation status (stem cell; melanoblast; transiently amplifying cell; differentiated; post-mitotic; terminally-differentiated) as well as by micro-environmental niche (in the stratum basale of the epidermis; within skin appendages like hair follicle, eccrine gland, etc). We discuss how the above variable contexts may influence the susceptibility of the epidermal-melanin unit (EMU) to become unstable, which may presage cutaneous melanoma development. We also assess how unique features of follicular-melanin unit(s) (FMUs) can, by contrast, protect melanocytes from melanomagenesis. Lastly, we postulate how variable melanocyte fates in vitiligo, albinism, psoriasis, and alopecia areata may provide new insights into immune-/non immune-mediated outcomes for melanocytes in cutaneous melanin units., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Casalou, Moreiras, Mayatra, Fabre and Tobin.)

Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase inhibitor (HDACi), to attenuate growth of primary ocular UM cell lines and, in particular, a liver MUM cell line in vitro and in vivo, and elucidate the underlying molecular mechanisms. A significant ( p = 0.0001) dose-dependent reduction in surviving clones of the primary ocular UM cells, Mel270, was observed upon treatment with increasing doses of ACY-1215. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant ( p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo attenuation of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase ( p = 0.0001) following 24 h of treatment, and significant apoptosis was triggered in a time- and dose-dependent manner ( p < 0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome profiling, the attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329 significantly reduced OMM2.5 cell survival and viability in vitro ( p = 0.0001) and reduced OMM2.5 cells in vivo ( p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of OMM2.5 MUM cells.

In order to develop optimum microneedle designs, researchers must first develop robust, repeatable and adaptable test methods which are representative of in vivo conditions. However, there is a lack of experimental tools which can accurately comparatively interrogate functional microneedle penetration of tissue. In this study, we seek to develop a state of the art finite element model of microneedle insertion into and penetration of human skin. The developed model employs a 3D hyperelastic, anisotropic pre-stressed multi-layered material which more accurately reflects in vivo skin conditions, while the microneedle is modeled as an array, which can capture the influence of adjacent microneedles on the overall response. Using the developed finite element model, we highlight the importance of accurate computational modeling which can decipher the mechanics of microneedle insertion, including the influence of its position within an array and how it correlates well with experimental observations. In particular, we have concluded that, for our model microneedle array, increasing skin pretension from 0 to 10% strain reduces the penetration force by 13%, ultimate local deformation about the microneedle by 22% and the ultimate penetration efficiency by 15%. We have also concluded that the presence of a base plate limits the penetration efficiency by up to 24%, while the penetration efficiency across a 5 × 1 microneedle array may vary by 27%. This model elucidates, for the first time, the combined effects of skin tension and needle geometry on accurately predicting microneedle penetration efficiency. STATEMENT OF SIGNIFICANCE: Microneedles arrays (MNAs) are medical devices with microscale protrusions, typically designed to penetrate the outermost layer of the skin, that upon optimisation, could lead to disruptive minimally-invasive disease management. However, the mechanics of MNA insertion are complex, due in part to a 'bed of nails' effect, and difficult to elucidate experimentally. Therefore, comparisons between designs, functional assessment of production batches and ultimately the likelihood of clinical translation are challenging to predict. Here, we have develop the most sophisticated in silico model of MNA insertion into pre-tensioned human skin to predict the extent of MNA penetration and therefore the likelihood of successful therapeutic delivery. Researchers can customise this model to predict the penetration efficiency of any MNA design., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors Nicky Bertollo and Eoin D. O'Cearbhaill are co-inventors on several patent applications and granted patents related to microneedle technology and are shareholders in Latch Medical Limited, a microneedle technology-based company. Nicky Bertollo is a paid employee of Latch Medical Limited., (Copyright © 2021. Published by Elsevier Ltd.)

The innate immune system of human skin consists of a multi-layered barrier consisting of cells and soluble effector molecules charged with maintaining homeostasis and responding to insults and infections. It has become increasingly clear that these barrier layers become compromised in skin diseases, especially in disorders of an (auto)inflammatory nature. In the case of hidradenitis suppurativa, great strides have been made in recent years in characterizing the underlying breakdown in homeostatic innate immunity, including an increasing understanding of the central role of the hair follicle in this process. This breakdown appears to occur at multiple levels: the pilosebaceous unit, associated epithelium, the cutaneous microbiome, alteration of immune cell function and local molecular events such as complement activation. This review seeks to summarize, contextualize and analyse critically our current understanding of how these innate immune barriers become dysregulated in the early stage(s) of hidradenitis suppurativa, and to speculate on where potential hidradenitis suppurativa research could be most fruitful., (© 2021 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Melanin is synthesised within melanocytes and transferred to keratinocytes in human skin, thereby regulating skin colour and protecting skin cells against UVR-induced damage. We commonly divide human skin into six phototypes (SPT)-I to -VI (Fitzpatrick scale) according to the skin's tanning response to UVR. In this pilot study, we investigated the impact of UVR (maximum 311nm), blue (peak 450nm) and green visible light (peak 530nm) on melanin production and type in healthy human skin histocultures (SPT-I, -II and -III). UVR, blue and green light stimulated a surface tanning response in SPT-II and -III, but not SPT-I. Using the Warthin-Starry stain for sensitive melanin detection, all three light treatments induced melanogenesis in SPT-II and -III skin. Surprisingly, blue and green light (but not UVR) stimulated melanin synthesis in SPT-I skin. Moreover, melanin synthesis induced by blue and green visible light in SPT-I, SPT-II, and SPT-III skin was not associated with a detectable increase in DNA damage or cell apoptosis. By contrast, both responses were detected after UVR. These data suggest that blue and green visible light can stimulate melanin production in fair-skinned individuals without, at least some of, the harmful consequences of UVR-induced pigmentation. We are currently examining the molecular basis of UVR-independent melanogenesis in fair skin., (© 2021 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: Hair greying is a hallmark of aging generally believed to be irreversible and linked to psychological stress., Methods: Here, we develop an approach to profile hair pigmentation patterns (HPPs) along individual human hair shafts, producing quantifiable physical timescales of rapid greying transitions., Results: Using this method, we show white/grey hairs that naturally regain pigmentation across sex, ethnicities, ages, and body regions, thereby quantitatively defining the reversibility of greying in humans. Molecularly, grey hairs upregulate proteins related to energy metabolism, mitochondria, and antioxidant defenses. Combining HPP profiling and proteomics on single hairs, we also report hair greying and reversal that can occur in parallel with psychological stressors. To generalize these observations, we develop a computational simulation, which suggests a threshold-based mechanism for the temporary reversibility of greying., Conclusions: Overall, this new method to quantitatively map recent life history in HPPs provides an opportunity to longitudinally examine the influence of recent life exposures on human biology., Funding: This work was supported by the Wharton Fund and NIH grants GM119793, MH119336, and AG066828 (MP)., Competing Interests: AR, SR, JR, EM, GS, RO, PP, RK, CL, DT, RP, MP No competing interests declared, (© 2021, Rosenberg et al.)

High-quality dermatology patient registries often require considerable time to develop and produce meaningful data. Development time is influenced by registry complexity and regulatory hurdles that vary significantly nationally and institutionally. The rapid emergence of the coronavirus disease 2019 (COVID-19) global pandemic has challenged health services in an unprecedented manner. Mobilization of the dermatology community in response has included rapid development and deployment of multiple, partially harmonized, international patient registries, reinventing established patient registry timelines. Partnership with patient organizations has demonstrated the critical nature of inclusive patient involvement. This global effort has demonstrated the value, capacity, and necessity for the dermatology community to adopt a more cohesive approach to patient registry development and data sharing that can lead to myriad benefits. These include improved utilization of limited resources, increased data interoperability, improved ability to rapidly collect meaningful data, and shortened response times to generate real-world evidence. We call on the global dermatology community to support the development of an international federation of patient registries to consolidate and operationalize the lessons learned during this pandemic. This will provide an enduring means of applying this knowledge to the maintenance and development of sustainable, coherent, and impactful patient registries of benefit now and in the future., Competing Interests: Conflict of interest C.F. is Chief Investigator of the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR). C.F., A.I., and P.S. co-lead the SECURE-AD register, which studies the impact of COVID-19 infection episodes on atopic dermatitis. D.W. and R.S. co-lead and are members of the Steering Committee, along with L.B., N.M., D.J.T., and K.Y., of the SECURE-Alopecia registry, which studies the impact of COVID-19 infection on patients with all forms of hair loss. R.S., D.W., N.M., K.Y., and L.B. are leading the development of Global Registry of Alopecia areata disease Severity and treatment Safety (GRASS). C.F., P.S., and C.A. are members of the international TREatment of Atopic eczema Taskforce (TREAT) Executive Committee. C.E.M.G. is Chief Investigator of the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) and an Executive Member of the PsoProtect and Psoprotectme Registries. C.H.S. is Research Chair of BADBIR, and joint Principle Investigator (PI) of PsoProtect and PsoProtectMe Registries. S.K.M. is joint Principle Investigator of PsoProtect and PsoProtectMe Registries. I.L.C. is part of the Pediatric Dermatology Research Alliance COVID-19 Response Task Force, a collaboration between the Society for Pediatric Dermatology (SPD) and the Pediatric Dermatology Research Alliance (PeDRA). B.W.M.A. is a patient representative for the SECURE-AD patient register, and the Dutch TREAT NL and BioDAY registers. P.S. is member of the PsoProtect International Scientific Advisory Board. H.B.N is a board member of the Hidradenitis Suppurativa Foundation. R.A., J.R.I., and H.B.N. are members of the Steering Committee of the Global Hidradenitis Suppurativa COVID-19 Registry., (Copyright © 2021. Published by Elsevier Inc.)

Importance: A recent expert consensus exercise emphasized the importance of developing a global network of patient registries for alopecia areata to redress the paucity of comparable, real-world data regarding the effectiveness and safety of existing and emerging therapies for alopecia areata., Objective: To generate core domains and domain items for a global network of alopecia areata patient registries., Evidence Review: Sixty-six participants, representing physicians, patient organizations, scientists, the pharmaceutical industry, and pharmacoeconomic experts, participated in a 3-round eDelphi process, culminating in a face-to-face meeting at the World Congress of Dermatology, Milan, Italy, June 14, 2019., Findings: Ninety-two core data items, across 25 domains, achieved consensus agreement. Twenty further noncore items were retained to facilitate data harmonization in centers that wish to record them. Broad representation across multiple stakeholder groups was sought; however, the opinion of physicians was overrepresented., Conclusions and Relevance: This study identifies the domains and domain items required to develop a global network of alopecia areata registries. These domains will facilitate a standardized approach that will enable the recording of a comprehensive, comparable data set required to oversee the introduction of new therapies and harness real-world evidence from existing therapies at a time when the alopecia areata treatment paradigm is being radically and positively disrupted. Reuse of similar, existing frameworks in atopic dermatitis, produced by the Treatment of Atopic Eczema (TREAT) Registry Taskforce, increases the potential to reuse existing resources, creates opportunities for comparison of data across dermatology subspecialty disease areas, and supports the concept of data harmonization.

Melanin granules cluster within supra-nuclear caps in basal keratinocytes (KCs) of the human epidermis, where they protect KC genomic DNA against ultraviolet radiation (UVR) damage. While much is known about melanogenesis in melanocytes (MCs) and a moderate amount about melanin transfer from MC to KC, we know little about the fate of melanin once inside KCs. We recently reported that melanin fate in progenitor KCs is regulated by rare asymmetric organelle movement during mitosis. Here, we explore the role of actin, microtubules, and centrosome-associated machinery in distributing melanin within KCs. Short-term cultures of human skin explants were treated with cytochalasin-B and nocodazole to target actin filaments and microtubules, respectively. Treatment effects on melanin distribution were assessed by the Warthin-Starry stain, on centrosome-associated proteins by immunofluorescence microscopy, and on co-localisation with melanin granules by brightfield microscopy. Cytochalasin-B treatment disassembled supra-nuclear melanin caps, while nocodazole treatment moved melanin from the apical to basal KC domain. Centrosome and centriolar satellite-associated proteins showed a high degree of co-localisation with melanin. Thus, once melanin granules are transferred to KCs, their preferred apical distribution appears to be facilitated by coordinated movement of centrosomes and centriolar satellites. This mechanism may control melanin's strategic position within UVR-exposed KCs.

Hair greying (canities) is one of the earliest, most visible ageing-associated phenomena, whose modulation by genetic, psychoemotional, oxidative, senescence-associated, metabolic and nutritional factors has long attracted skin biologists, dermatologists, and industry. Greying is of profound psychological and commercial relevance in increasingly ageing populations. In addition, the onset and perpetuation of defective melanin production in the human anagen hair follicle pigmentary unit (HFPU) provides a superb model for interrogating the molecular mechanisms of ageing in a complex human mini-organ, and greying-associated defects in bulge melanocyte stem cells (MSCs) represent an intriguing system of neural crest-derived stem cell senescence. Here, we emphasize that human greying invariably begins with the gradual decline in melanogenesis, including reduced tyrosinase activity, defective melanosome transfer and apoptosis of HFPU melanocytes, and is thus a primary event of the anagen hair bulb, not the bulge. Eventually, the bulge MSC pool becomes depleted as well, at which stage greying becomes largely irreversible. There is still no universally accepted model of human hair greying, and the extent of genetic contributions to greying remains unclear. However, oxidative damage likely is a crucial driver of greying via its disruption of HFPU melanocyte survival, MSC maintenance, and of the enzymatic apparatus of melanogenesis itself. While neuroendocrine factors [e.g. alpha melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH), ß-endorphin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH)], and micropthalmia-associated transcription factor (MITF) are well-known regulators of human hair follicle melanocytes and melanogenesis, how exactly these and other factors [e.g. thyroid hormones, hepatocyte growth factor (HGF), P-cadherin, peripheral clock activity] modulate greying requires more detailed study. Other important open questions include how HFPU melanocytes age intrinsically, how psychoemotional stress impacts this process, and how current insights into the gerontobiology of the human HFPU can best be translated into retardation or reversal of greying., (© 2020 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)

The prevalence of Type 2 diabetes mellitus (T2DM) is escalating globally. Patients suffer from multiple complications including the development of chronic wounds that can lead to amputation. These wounds are characterised by an inflammatory environment including elevated tumour necrosis factor alpha (TNF-α). Dermal fibroblasts (DF) are critical for effective wound healing, so we sought to establish whether there were any differences in DF cultured from T2DM donors or those without diabetes (ND-DF). ND- and T2DM-DF when cultured similarly in vitro secreted comparable concentrations of TNF-α. Functionally, pre-treatment with TNF-α reduced the proliferation of ND-DF and transiently altered ND-DF morphology; however, T2DM-DF were resistant to these TNF-α induced changes. In contrast, TNF-α inhibited ND- and T2DM-DF migration and matrix metalloprotease expression to the same degree, although T2DM-DF expressed significantly higher levels of tissue inhibitor of metalloproteases (TIMP)-2. Finally, TNF-α significantly increased the secretion of pro-inflammatory cytokines (including CCL2, CXCL1 and SERPINE1) in ND-DF, whilst this effect in T2DM-DF was blunted, presumably due to the tendency to higher baseline pro-inflammatory cytokine expression observed in this cell type. Collectively, these data demonstrate that T2DM-DF exhibit a selective loss of responsiveness to TNF-α, particularly regarding proliferative and secretory functions. This highlights important phenotypic changes in T2DM-DF that may explain the susceptibility to chronic wounds in these patients.

As of July 9, 2020, there were more than 12 million confirmed cases of coronavirus disease 2019 (COVID-19) across the globe, with more than 550,000 deaths. Many European countries, including Belgium, the United Kingdom, Italy, and Spain, have had the highest numbers of fatalities per capita. This indicates the potential for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to overwhelm even the most advanced health care systems despite extreme societal interventions. Since its emergence, SARS-CoV-2 has disseminated across the globe, affecting the structure of global societies, infrastructure, and economies. Patients with alopecia are a diverse group who, for various indications, are prescribed a number of antimicrobials and antiandrogen treatments in addition to immunomodulatory therapies such as hydroxychloroquine, oral corticosteroids, and a range of broad immunosuppressants. These drugs are being scrutinized for their capacity to potentially affect SARS-CoV-2 outcomes. We examine these treatments and highlight the critical role that patient registries will play in generating real-world evidence to assess their impact on COVID-19 outcomes., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Malignant melanoma, one of the most aggressive human malignancies, is responsible for 80% of skin cancer deaths. Whilst early detection of disease progression or metastasis can improve patient survival, this remains a challenge due to the lack of reliable biomarkers. Importantly, these clinical challenges are not unique to humans, as melanoma affects many other species, including companion animals, such as the dog and horse. Extracellular vesicles (EVs) are tiny nanoparticles involved in cell-to-cell communication. Several protein and genomic EV markers have been described in the literature, as well as a wide variety of methods for isolating EVs from body fluids. As such, they may be valuable biomarkers in cancer and may address some clinical challenges in the management melanoma. This review aimed to explore the translational applications of EVs as biomarkers in melanoma, as well as their role in the clinical setting in humans and animals. A summary of melanoma-specific protein and genomic EV markers is presented, followed by a discussion of the role EVs in monitoring disease progression and treatment response. Finally, herein, we reviewed the advantages and disadvantages of methods utilised to isolate EVs from bodily fluids in melanoma patients (human and animals) and describe some of the challenges that will need to be addressed before EVs can be introduced in the clinical setting.

Canities (or hair greying) is an age-linked loss of the natural pigment called melanin from hair. While the specific cause(s) underlying the loss of melanogenically-active melanocytes from the anagen hair bulbs of affected human scalp remains unclear, oxidative stress sensing appears to be a key factor involved. In this study, we examined the follicular melanin unit in variably pigmented follicles from the aging human scalp of healthy individuals (22-70 years). Over 20 markers were selected within the following categories: melanocyte-specific, apoptosis, cell cycle, DNA repair/damage, senescence and oxidative stress. As expected, a reduction in melanocyte-specific markers in proportion to the extent of canities was observed. A major finding of our study was the intense and highly specific nuclear expression of Ataxia Telangiectasia Mutated (ATM) protein within melanocytes in anagen hair follicle bulbs. ATM is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks and functions as an important sensor of reactive oxygen species (ROS) in human cells. The incidence and expression level of ATM correlated with pigmentary status in canities-affected hair follicles. Moreover, increased staining of the redox-associated markers 8-OHdG, GADD45 and GP-1 were also detected within isolated bulbar melanocytes, although this change was not clearly associated with donor age or canities extent. Surprisingly, we were unable to detect any specific change in the expression of other markers of oxidative stress, senescence or DNA damage/repair in the canities-affected melanocytes compared to surrounding bulbar keratinocytes. By contrast, several markers showed distinct expression of markers for oxidative stress and apoptosis/differentiation in the inner root sheath (IRS) as well as other parts of the hair follicle. Using our in vitro model of primary human scalp hair follicle melanocytes, we showed that ATM expression increased after incubation with the pro-oxidant hydrogen peroxide (H 2 O 2 ). In addition, this ATM increase was prevented by pre-incubation of cells with antioxidants. The relationship between ATM and redox stress sensing was further evidenced as we observed that the inhibition of ATM expression by chemical inhibition promoted the loss of melanocyte viability induced by oxidative stress. Taken together these new findings illustrate the key role of ATM in the protection of human hair follicle melanocytes from oxidative stress/damage within the human scalp hair bulb. In conclusion, these results highlight the remarkable complexity and role of redox sensing in the status of human hair follicle growth, differentiation and pigmentation.

Background: Infinium Human Methylation BeadChip is an array platform for complex evaluation of DNA methylation at an individual CpG locus in the human genome based on Illumina's bead technology and is one of the most common techniques used in epigenome-wide association studies. Finding associations between epigenetic variation and phenotype is a significant challenge in biomedical research. The newest version, HumanMethylationEPIC, quantifies the DNA methylation level of 850,000 CpG sites, while the previous versions, HumanMethylation450 and HumanMethylation27, measured >450,000 and 27,000 loci, respectively. Although a number of bioinformatics tools have been developed to analyse this assay, they require some programming skills and experience in order to be usable., Results: We have developed a pipeline for the Galaxy platform for those without experience aimed at DNA methylation analysis using the Infinium Human Methylation BeadChip. Our tool is integrated into Galaxy (http://galaxyproject.org), a web-based platform. This allows users to analyse data from the Infinium Human Methylation BeadChip in the easiest possible way., Conclusions: The pipeline provides a group of integrated analytical methods wrapped into an easy-to-use interface. Our tool is available from the Galaxy ToolShed, GitHub repository, and also as a Docker image. The aim of this project is to make Infinium Human Methylation BeadChip analysis more flexible and accessible to everyone., (© The Author(s) 2020. Published by Oxford University Press.)

Tryptophan hydroxylase (TPH) activity was detected in cultured epidermal melanocytes and dermal fibroblasts with respective Km of 5.08 and 2.83 mM and Vmax of 80.5 and 108.0 µmol/min. Low but detectable TPH activity was also seen in cultured epidermal keratinocytes. Serotonin and/or its metabolite and precursor to melatonin, N-acetylserotonin (NAS), were identified by LC/MS in human epidermis and serum. Endogenous epidermal levels were 113.18 ± 13.34 and 43.41 ± 12.45 ng/mg protein for serotonin (n = 8/8) and NAS (n = 10/13), respectively. Their production was independent of race, gender, and age. NAS was also detected in human serum (n = 13/13) at a concentration 2.44 ± 0.45 ng/mL, while corresponding serotonin levels were 295.33 ± 17.17 ng/mL (n = 13/13). While there were no differences in serum serotonin levels, serum NAS levels were slightly higher in females. Immunocytochemistry studies showed localization of serotonin to epidermal and follicular keratinocytes, eccrine glands, mast cells, and dermal fibrocytes. Endogenous production of serotonin in cultured melanocytes, keratinocytes, and dermal fibroblasts was modulated by UVB. In conclusion, serotonin and NAS are produced endogenously in the epidermal, dermal, and adnexal compartments of human skin and in cultured skin cells. NAS is also detectable in human serum. Both serotonin and NAS inhibited melanogenesis in human melanotic melanoma at concentrations of 10 -4 -10 -3  M. They also inhibited growth of melanocytes. Melanoma cells were resistant to NAS inhibition, while serotonin inhibited cell growth only at 10 -3  M. In summary, we characterized a serotonin-NAS system in human skin that is a part of local neuroendocrine system regulating skin homeostasis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We report a genome-wide association scan in >6,000 Latin Americans for pigmentation of skin and eyes. We found eighteen signals of association at twelve genomic regions. These include one novel locus for skin pigmentation (in 10q26) and three novel loci for eye pigmentation (in 1q32, 20q13 and 22q12). We demonstrate the presence of multiple independent signals of association in the 11q14 and 15q13 regions (comprising the GRM5/TYR and HERC2/OCA2 genes, respectively) and several epistatic interactions among independently associated alleles. Strongest association with skin pigmentation at 19p13 was observed for an Y182H missense variant (common only in East Asians and Native Americans) in MFSD12, a gene recently associated with skin pigmentation in Africans. We show that the frequency of the derived allele at Y182H is significantly correlated with lower solar radiation intensity in East Asia and infer that MFSD12 was under selection in East Asians, probably after their split from Europeans.

Background: Melanin is synthesized by melanocytes in the basal layer of the epidermis. When transferred to surrounding keratinocytes melanin is the key ultraviolet radiation-protective biopolymer responsible for skin pigmentation. Most melanin is observable in the proliferative basal layer of the epidermis and only sparsely distributed in the stratifying/differentiating epidermis. The latter has been explained as 'melanin degradation' in suprabasal layers., Objectives: To re-evaluate the currently accepted basis for melanin distribution in human epidermis and to discover whether this pattern is altered after a regenerative stimulus., Methods: Normal epidermis of adult human skin, at rest and after tape-stripping, was analysed by a range of (immuno)histochemical and high-resolution microscopy techniques. In vitro models of melanin granule uptake by human keratinocytes were attempted., Results: We propose a different fate for melanin in the human epidermis. Our evidence indicates that the bulk of melanin is inherited only by the nondifferentiating daughter cell postmitosis in progenitor keratinocytes via asymmetric organelle inheritance. Moreover, this preferred pattern of melanin distribution can switch to a symmetric or equal daughter cell inheritance mode under conditions of stress, including regeneration., Conclusions: In this preliminary report, we provide a plausible and histologically supported explanation for how human skin pigmentation is efficiently organized in the epidermis. Steady-state epidermis pigmentation may involve much less redox-sensitive melanogenesis than previously thought, and at least some premade melanin may be available for reuse. The epidermal melanin unit may be an excellent example with which to study organelle distribution via asymmetric or symmetric inheritance in response to microenvironment and tissue demands., (© 2018 British Association of Dermatologists.)

Background Objectives: The past decade has witnessed a rapid expansion of photobiomodulation (PBM), demonstrating encouraging results for the treatment of cutaneous disorders. Confidence in this approach, however, is impaired not only by a lack of understanding of the light-triggered molecular cascades but also by the significant inconsistency in published experimental outcomes, design of the studies and applied optical parameters. This study aimed at characterizing the response of human dermal fibroblast subpopulations to visible and near-infrared (NIR) light in an attempt to identify the optical treatment parameters with high potential to address deficits in aging skin and non-healing chronic wounds., Materials and Methods: Primary human reticular and papillary dermal fibroblasts (DF) were isolated from the surplus of post-surgery human facial skin. An in-house developed LED-based device was used to irradiate cell cultures using six discrete wavelengths (450, 490, 550, 590, 650, and 850 nm). Light dose-response at a standard oxygen concentration (20%) at all six wavelengths was evaluated in terms of cell metabolic activity. This was followed by an analysis of the transcriptome and procollagen I production at a protein level, where cells were cultured in conditions closer to in vivo at 2% environmental oxygen and 2% serum. Furthermore, the production of reactive oxygen species (ROS) was accessed using real-time fluorescence confocal microscopy imaging. Here, production of ROS in the presence or absence of antioxidants, as well as the cellular localization of ROS, was evaluated., Results: In terms of metabolic activity, consecutive irradiation with short-wavelength light (⇐530 nm) exerted an inhibitory effect on DF, while longer wavelengths (>=590 nm) had essentially a neutral effect. Cell behavior following treatment with 450 nm was biphasic with two distinct states: inhibitory at low- to mid- dose levels (<=30 J/cm 2 ), and cytotoxic at higher dose levels (>30 J/cm 2 ). Cell response to blue light was accompanied by a dose-dependent release of ROS that was localized in the perinuclear area close to mitochondria, which was attenuated by an antioxidant. Overall, reticular DFs exhibited a greater sensitivity to light treatment at the level of gene expression than did papillary DFs, with more genes significantly up- or down- regulated. At the intra-cellular signaling pathway level, the up- or down- regulation of vital pathways was observed only for reticular DF, after treatment with 30 J/cm 2 of blue light. At the cellular level, short visible wavelengths exerted a greater inhibitory effect on reticular DF. Several genes involved in the TGF-β signaling pathway were also affected. In addition, procollagen I production was inhibited. By contrast, 850 nm near-infrared (NIR) light (20 J/cm 2 ) exerted a stimulatory metabolic effect in these cells, with no detectable intracellular ROS formation. Here too, reticular DF were more responsive than papillary DF. This stimulatory effect was only observed under in vivo-like low oxygen conditions, corresponding to normal dermal tissue oxygen levels (approximately 2%)., Conclusion: This study highlights a differential impact of light on human skin cells with upregulation of metabolic activity with NIR light, and inhibition of pro-collagen production and proliferation in response to blue light. These findings open-up new avenues for developing therapies for different cutaneous conditions (e.g., treatment of keloids and fibrosis) or differential therapy at distinct stages of wound healing. Lasers Surg. Med. 50:859-882, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Epidermal DNA damage, especially to the basal layer, is an established cause of keratinocyte cancers (KCs). Large differences in KC incidence (20- to 60-fold) between white and black populations are largely attributable to epidermal melanin photoprotection in the latter. The cyclobutane pyrimidine dimer (CPD) is the most mutagenic DNA photolesion; however, most studies suggest that melanin photoprotection against CPD is modest and cannot explain the considerable skin color-based differences in KC incidence. Along with melanin quantity, solar-simulated radiation-induced CPD assessed immediately postexposure in the overall epidermis and within 3 epidermal zones was compared in black West Africans and fair Europeans. Melanin in black skin protected against CPD by 8.0-fold in the overall epidermis and by 59.0-, 16.5-, and 5.0-fold in the basal, middle, and upper epidermis, respectively. Protection was related to the distribution of melanin, which was most concentrated in the basal layer of black skin. These results may explain, at least in part, the considerable skin color differences in KC incidence. These data suggest that a DNA protection factor of at least 60 is necessary in sunscreens to reduce white skin KC incidence to a level that is comparable with that of black skin.-Fajuyigbe, D., Lwin, S. M., Diffey, B. L., Baker, R., Tobin, D. J., Sarkany, R. P. E., Young, A. R. Melanin distribution in human epidermis affords localized protection against DNA photodamage and concurs with skin cancer incidence difference in extreme phototypes.

Male sex hormones-androgens-regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny vellus hairs with larger, darker terminal hairs ( e.g., beard). Follicle response is epigenetically varied: some remain unaffected ( e.g., eyelashes) or are inhibited, causing balding. How sex steroid hormones alter such developmental processes is unclear, despite high incidences of hormone-driven cancer, hirsutism, and alopecia. Unfortunately, existing development models are not androgen sensitive. Here, we use hair follicles to establish an androgen-responsive human organ culture model. We show that women's intermediate facial follicles respond to men's higher androgen levels by synthesizing more hair over several days, unlike donor-matched, androgen-insensitive, terminal follicles. We demonstrate that androgen receptors-androgen-activated gene transcription regulators-are required and are present in vivo within these follicles. This is the first human organ that involves multiple cell types that responds appropriately to hormones in prolonged culture, in a way which mirrors its natural behavior. Thus, intermediate hair follicles offer a hormone-switchable human model with exceptional, unique availability of genetically identical, but epigenetically hormone-insensitive, terminal follicles. This should enable advances in understanding sex steroid hormone signaling, gene regulation, and developmental and regenerative systems and facilitate better therapies for hormone-dependent disorders.-Miranda, B. H., Charlesworth, M. R., Tobin, D. J., Sharpe, D. T., Randall, V. A. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.

Finding a path towards a more accurate prediction of light propagation in human skin remains an aspiration of biomedical scientists working on cutaneous applications both for diagnostic and therapeutic reasons. The objective of this study was to investigate variability of the optical properties of human skin compartments reported in literature, to explore the underlying rational of this variability and to propose a dataset of values, to better represent an in vivo case and recommend a solution towards a more accurate prediction of light propagation through cutaneous compartments. To achieve this, we undertook a novel, logical yet simple approach. We first reviewed scientific articles published between 1981 and 2013 that reported on skin optical properties, to reveal the spread in the reported quantitative values. We found variations of up to 100-fold. Then we extracted the most trust-worthy datasets guided by a rule that the spectral properties should reflect the specific biochemical composition of each of the skin layers. This resulted in the narrowing of the spread in the calculated photon densities to 6-fold. We conclude with a recommendation to use the identified most robust datasets when estimating light propagation in human skin using Monte Carlo simulations. Alternatively, otherwise follow our proposed strategy to screen any new datasets to determine their biological relevance., Competing Interests: The authors declare that there are no conflicts of interest related to this article.

Accumulation of large-scale mitochondrial DNA (mtDNA) deletions and chronic, subclinical inflammation are concomitant during skin aging, thus raising the question of a causal link. To approach this, we generated mice expressing a mutant mitochondrial helicase (K320E-TWINKLE) in the epidermis to accelerate the accumulation of mtDNA deletions in this skin compartment. Mice displayed low amounts of large-scale deletions and a dramatic depletion of mtDNA in the epidermis and showed macroscopic signs of severe skin inflammation. The mtDNA alterations led to an imbalanced stoichiometry of mitochondrial respiratory chain complexes, inducing a unique combination of cytokine expression, causing a severe inflammatory phenotype, with massive immune cell infiltrates already before birth. Altogether, these data unraveled a previously unknown link between an imbalanced stoichiometry of the mitochondrial respiratory chain complexes and skin inflammation and suggest that severe respiratory chain dysfunction, as observed in few cells leading to a mosaic in aged tissues, might be involved in the development of chronic subclinical inflammation., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Skin pigmentation is directed by epidermal melanin units, characterized by long-lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously, we reported that MC:KC contact is required for melanosome transfer that can be enhanced by filopodi, and by UVR/UVA irradiation, which can upregulate melanosome transfer via Myosin X-mediated control of MC filopodia. Both MC and KC express Ca 2+ -dependent E-cadherins. These homophilic adhesion contacts induce transient increases in intra-KC Ca 2+ , while ultraviolet radiation (UVR) raises intra-MC Ca 2+ via calcium-selective ORAI1 ion channels; both are associated with regulating melanogenesis. However, how Ca 2+ triggers melanin transfer remains unclear. Here we evaluated the role of E-cadherin in UVR-mediated melanin transfer in human skin cells. MC and KC in human epidermis variably express filopodia-associated E-cadherin, Cdc42, VASP and β-catenin, all of which were upregulated by UVR in human MC in vitro. Knockdown of E-cadherin revealed that this cadherin is essential for UVR-induced MC filopodia formation and melanin transfer. Moreover, Ca 2+ induced a dose-dependent increase in filopodia formation and melanin transfer, as well as increased β-catenin, Cdc42, Myosin X and E-cadherin expression in these skin cells. Together, these data suggest that filopodial proteins and E-cadherin, which are upregulated by intracellular (UVR-stimulated) and extracellular Ca 2+ availability, are required for filopodia formation and melanin transfer. This may open new avenues to explore how Ca 2+ signalling influences human pigmentation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Photobiomodulation-based (LLLT) therapies show tantalizing promise for treatment of skin diseases. Confidence in this approach is blighted however by lamentable inconsistency in published experimental designs, and so complicates interpretation. Here we interrogate the appropriateness of a range of previously-reported treatment parameters, including light wavelength, irradiance and radiant exposure, as well as cell culture conditions (e.g., serum concentration, cell confluency, medium refreshment, direct/indirect treatment, oxygen concentration, etc.), in primary cultures of normal human dermal fibroblasts exposed to visible and near infra-red (NIR) light. Apart from irradiance, all study parameters impacted significantly on fibroblast metabolic activity. Moreover, when cells were grown at atmospheric O 2 levels (i.e. 20%) short wavelength light inhibited cell metabolism, while negligible effects were seen with long visible and NIR wavelength. By contrast, NIR stimulated cells when exposed to dermal tissue oxygen levels (approx. 2%). The impact of culture conditions was further seen when inhibitory effects of short wavelength light were reduced with increasing serum concentration and cell confluency. We conclude that a significant source of problematic interpretations in photobiomodulation reports derives from poor optimization of study design. Further development of this field using in vitro/ex vivo models should embrace significant standardization of study design, ideally within a design-of-experiment setting.

Background: The incidence of self-reported premature hair graying (PHG) seems to be on the rise. PHG has a profound impact on the patient's quality of life. It remains an incompletely understood etiology with limited and modest treatment options., Aim: The evaluation of the demographic and clinical profile of patients with premature canities, and exploration of the association of this entity with certain systemic disorders suspected to be related to its etiology., Methods: Seventy-one cases of premature canities (onset noticed by patients before 25 years of age) presenting to an urban skin clinic in Gurugram, India, between September 2012 and September 2015 with this complaint were retrospectively analyzed. The patient records were retrieved that provided details of the onset, duration and pattern of involvement, history, and examination findings (scalp, cutis, and general physical). Since all these patients had been screened for anemia, thyroid disorder, fasting blood glucose, and Vitamin B12 levels at the time of presentation, these parameters were also available for analysis., Results: The mean age at onset of graying was 10.2 ± 3.6 years (range: 5-19 years), with an almost equal gender distribution. The earliest age of onset recorded was 5 years. A positive family history of PHG (at least one of the biological parents or siblings) was obtained in 64 (90.1%) of the cases. The temporal regions of the scalp (35.2%) were most commonly involved followed by the frontal region (18.3%). Hypovitaminosis B12 and hypothyroidism showed significant association with the disorder, whereas anemia, serum ferritin, and fasting blood glucose did not., Conclusion: The age of onset of hair graying can be as low as 5 years. Temporal and frontal areas are the most commonly involved sites. A strong family history, Vitamin B12 deficiency, and hypothyroidism are strongly associated with PHG. Larger case-control studies are mandated for discerning the correlation of these and other risk factors with PHG., Competing Interests: There are no conflicts of interest. What is new? We report for the first time the statistical association of Vitamin B12 deficiency and premature graying of hairThyroid dysfunction, in particular hypothyroidism has a strong association with premature graying of hairScreening for serum Vitamin B12 levels and thyroid functions should be undertaken in all patients presenting with premature graying of hair.

Cutaneous science has seen considerable development in the last 25 years, in part due to the Omics revolution, and the appreciation that this organ is hardwired into the body's key neuro-immuno-endocrine axes. Moreover, there is greater appreciation of how stratification of skin disorders will permit more targeted and more effective treatments. Against this has been how the remarkable extension in the average human life-span, though in the West at least, this parallels worrying increases in lifestyle-associated conditions like diabetes, skin cancer etc. These demographic trends bring greater urgency to finding clinical solutions for numerous age-related deficits in skin function caused by extrinsic and intrinsic factors. Mechanisms for aging skin include the actions of reactive oxygen species (ROS), mtDNA mutations, and telomere shortening, as well as hormonal changes. We have also significantly improved our understanding of how to harness the skin's considerable regenerative capacity e.g., via its remarkable investment of stem cell subpopulations. In this way we hope to develop new strategies to selectively target the skin's capacity to undergo optimal wound repair and regeneration. Here, the unsung hero of the skin regenerative power may be the humble hair follicle, replete with its compliment of epithelial, mesenchymal, neural and other stem cells. This review introduces the topic of human skin aging, with a focus on how maintenance of function in this complex multi-cell type organ is key for retaining quality of life into old age., (Copyright © 2016 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.)

Photobiomodulation is reported to positively influence hair regrowth, wound healing, skin rejuvenation and psoriasis. Despite rapid translation of this science to commercial therapeutic solutions, significant gaps in our understanding of the underlying processes remain. The aim of this review was to seek greater clarity and rationality specifically for the selection of optical parameters for studies on hair regrowth and wound healing. Our investigation of 90 reports published between 1985 and 2015 revealed major inconsistencies in optical parameters selected for clinical applications. Moreover, poorly understood photoreceptors expressed in skin such as cytochrome c oxidase, cryptochromes, opsins etc. may trigger different molecular mechanisms. All this could explain the plethora of reported physiological effects of light. To derive parameters for optimal clinical efficacy of photobiomodulation, we recommend a more rational approach to underpin clinical studies, with research on molecular targets and pathways using well-defined biological model systems to enable translation of optical parameters from in vitro to in vivo. Furthermore, special attention needs to be paid when conducting studies for hair regrowth, aiming for double-blind, placebo-controlled randomized clinical trials as the gold standard for quantifying hair growth., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10(-8) to 3 × 10(-119)), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair.

IFNλ is important for epidermal defense against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN. Herein we report findings revealing cell type-specific differences in IFNλ signaling and function in skin resident cells. In dermal fibroblasts, IFNλ induced the expression of myxovirus protein A (MxA), a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFNλ did not phosphorylate signal transducer and activator of transcription 1 in fibroblasts, but instead activated mitogen activated protein kinases (MAPK). Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFNλ inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFNλ upregulated the expression of Tumor growth factor beta 1 (TGFβ1)-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFNλ. Our study shows cutaneous cell type-specific IFN signaling and suggests that IFNλ, although important for epidermal antiviral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.