Ralf Paus

Ralf Paus
Univerity of Manchester · The Centre for Dermatology Research, Institut of Inflammation and Repair

MD

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893
Publications
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Publications

Publications (893)
Article
The physiology and pathology of the skin are influenced by daily oscillations driven by a master clock located in the brain, and peripheral clocks in individual cells. The pathogenesis of psoriasis is circadian‐rhythmic, with flares of disease and symptoms such as itch typically being worse in the evening / night‐time. Patients with psoriasis have...
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Transplanting aged human skin onto young SCID/beige mice morphologically rejuvenates the xenotransplants. This is accompanied by angiogenesis, epidermal repigmentation, and substantial improvements in key aging-associated biomarkers, including ß-galactosidase, p16 ink4a , SIRT1, PGC1α, collagen 17A, and MMP1. Angiogenesis- and hypoxia-related pathw...
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While popular belief harbors little doubt that perceived stress can cause hair loss and premature graying, the scientific evidence for this is arguably much thinner. Here, we investigate whether these phenomena are real, and show that the cyclic growth and pigmentation of the hair follicle (HF) provides a tractable model system for dissecting how p...
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Introduction: The analysis of the role of the mitochondria in oxidative damage and skin aging is a significant aspect of dermatological research. Mitochondria generate most reactive oxygen species (ROS); however, excessive ROS are cytotoxic and DNA-damaging and promote (photo-)aging. ROS also possesses key physiological and regulatory functions an...
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Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are primary, lymphocytic cicatricial hair loss disorders. These model epithelial stem cell diseases are thought to result from a CD8+ T cell-dominated immune attack on the hair follicle’s stem cell niche (bulge) after the latter has lost its immune privilege for as yet unknown reasons....
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The microbiome of human hair follicles (HFs) has emerged as an important player in different HF and skin pathologies, yet awaits in‐depth exploration. This raises questions regarding the tightly linked interactions between host environment, nutrient dependency of host‐associated microbes, microbial metabolism, microbe‐microbe interactions and host...
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The evolutionarily ancient methoxyindoleamine, melatonin, has long perplexed investigators by its versatility of functions and mechanisms of action, which include the regulation of vertebrate pigmentation. Although first discovered through its potent skin‐lightening effects in amphibians, melatonin's role in human skin and hair follicle pigmentatio...
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Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of the hypothalamic-pituitary-thyroid axis, and even generate melatonin and prolactin, human hair research has proven to be a treasure chest for the exploration of neurohormone function...
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Adiponectin reportedly stimulates proliferation and elongation of human scalp hair follicles (HFs) ex vivo. In the current study, we investigated how adiponectin oligomers produced by perifollicular dermal white adipose tissue (dWAT), a potent source of adiponectin isoforms, influence human HF proliferation and pigmentation. To do so, we treated mi...
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Murine γδT-cells have stress-surveillance functions and are implicated in autoimmunity. Yet, whether human γδT-cells are also stress sentinels and directly promote autoimmune responses in the skin is unknown. Using a novel (mini-)organ assay, we tested if human dermis resident γδT-cells can recognize stressed human scalp hair follicles (HFs) to pro...
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Hair follicles (HFs) are unique, multi-compartment, mini-organs that cycle through phases of active hair growth and pigmentation (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Anagen HFs have high demands for energy and biosynthesis precursors mainly fulfilled by aerobic glycolysis. Histochemistry reports the out...
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Background Permanent chemotherapy-induced alopecia (pCIA), for which preventive interventions remain limited, can manifest with scarring. While the underlying pathomechanisms of pCIA are unclear, depletion of epithelial hair follicle (HF) stem cells (eHFSCs) is likely to play a role. Objectives To explore the hypothesis that eHFSCs undergo patholo...
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MPZL3 is a nuclear‐encoded, mitochondrially localized, immunoglobulin‐like V‐type protein that functions as a key regulator of epithelial cell differentiation, lipid metabolism, ROS production, glycemic control, and energy expenditure. Recently, MPZL3 has surfaced as an important modulator of sebaceous gland function and of hair follicle cycling, a...
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Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under‐investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immun...
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It has long been known that there is a special affinity of psoriasis for the scalp: Here, it occurs most frequently, lesions terminate sharply in frontal skin beyond the hair line and are difficult to treat. Yet, surprisingly, scalp psoriasis only rarely causes alopecia, even though the pilosebaceous unit clearly is affected. Here, we systematicall...
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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...
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UDP-GlcNAc-1-phosphotransferase, a product of two separate genes (GNPTAB, GNPTG), is essential for sorting and transport of lysosomal enzymes to lysosomes. GNPTAB gene defects cause extracellular missorting of lysosomal enzymes resulting in lysosomal storage diseases, namely mucolipidosis (ML) type II, which is associated with hair discoloration. Y...
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In organ regeneration, the regulatory logic at a systems level remains largely unclear. For example, what defines the quantitative threshold to initiate regeneration, and when does the regeneration process come to an end? What leads to the qualitatively different responses of regeneration, which restore the original structure, or to repair which on...
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Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-m...
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Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since or...
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Xenografts of scalp skin from patients with androgenetic alopecia (AGA) on immunocompromised mice provide an excellent preclinical research system for testing candidate AGA therapeutics under clinically relevant conditions in vivo.¹ Therefore, we asked in a further refined version of this humanized AGA mouse model whether autologous platelet‐rich p...
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The immunophilin ligand, cyclosporine A (CsA), which inhibits nuclear factor of activated T cells (NFAT) activity, is a cornerstone of immunosuppressive therapy. Yet, the molecular basis of its prominent, nonimmunosuppression-related adverse skin effects, namely drug-induced excessive hair growth (hypertrichosis), is insufficiently understood. Here...
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Psychological stress exacerbates mast cell (MC)-dependent inflammation, including nasal allergy, but the underlying mechanisms are not thoroughly understood. Because the key stress-mediating neurohormone, corticotropin-releasing hormone (CRH), induces human skin MC degranulation, we hypothesized that CRH may be a key player in stress-aggravated nas...
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Human scalp hair follicles (HF) preferentially engage in glycolysis followed by lactate production in the presence of oxygen (i.e. the Warburg effect). Through the spatiotemporally controlled expression of key metabolic proteins, we hypothesise that the Warburg effect and other HF metabolic programmes are compartmentalised by region in order to reg...
Article
The endocannabinoid system (ECS) regulates multiple aspects of human epithelial physiology, including inhibition/stimulation of keratinocyte proliferation/apoptosis, respectively. Yet, how the ECS impacts on human adult epithelial stem cell (eSC) functions remains unknown. Scalp hair follicles (HFs) offer a clinically relevant, prototypic model sys...
Article
Hair follicles (HFs) are immersed within dermal white adipose tissue (dWAT), yet human adipocyte-HF communication remains unexplored. Therefore, we investigated how perifollicular adipocytes affect the physiology of organ-cultured human anagen scalp HFs. Quantitative (immuno-)histomorphometry, microCT and transmission electron microscopy showed tha...
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Organ culture of microdissected scalp hair follicles (HFs) has become the gold standard for human ex vivo hair research; however, availability is becoming very limited. Although various simplistic "HF-equivalent" in vitro models have been developed to overcome this limitation, they often fail to sufficiently mimic the complex cell-cell and cell-mat...
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Mouse models for atopic dermatitis (AD) are an indispensable preclinical research tool for testing new candidate AD therapeutics and for interrogating AD pathobiology in vivo. In this Viewpoint, we delineate why, unfortunately, none of the currently available so‐called “AD” mouse models satisfactorily reflect the clinical complexity of human AD, bu...
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The C3H/HeJ model has long dominated basic alopecia areata (AA) in vivo research and has been used as proof-of-principle that Jak inhibitors are suitable agents for AA management in vivo. However, its histologic features are not typical of human AA, and it is questionable whether it is sufficiently clinically predictive for evaluating the therapeut...
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The molecular nature of the hair cycle clock (HCC), i.e. the intrinsic oscillator system that drives hair follicle (HF) cycling, remains incompletely understood; therefore, all relevant key players need to be identified. Here, we present evidence that implicates myelin protein zero‐ like 3 (MPZL3), a multifunctional nuclear‐encoded mitochondrial pr...
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Skin is a comparatively accessible organ possessing many conserved regulatory and signaling pathways, drawing researchers from varied fields toward its study. Hair follicle (HF) biology in particular has expanded rapidly over the preceding decade, helping to shape and develop scientific knowledge across diverse areas of biomedical research, beyond...
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Human skin responds to numerous neurohormones, neuropeptides, and neurotransmitters that reach it via the vasculature or skin nerves, and/or are generated intracutaneously, thus acting in a para- and autocrine manner. This review focuses on how neurohormones impact on human skin physiology and pathology. We highlight basic concepts, major open ques...
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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 ag...
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Background: It is widely accepted that NKG2D+cells are critically involved in alopecia areata (AA) pathogenesis. However, besides being expressed in CD8+T-cells and NK cells, NKG2D is also found in human γδT-cells. AA lesional hair follicles (HFs) overexpress NKG2D and γδTCR activating ligands, e.g. MICA and CD1d, and chemoattractants for γδT-cell...
Article
Human hair follicles (HF) carry complex microbial communities that differ from skin surface microbiota. This likely reflects that the HF epithelium differs from the epidermal barrier in that it provides a moist, less acidic, and relatively UV‐protected environment, part of which is immune‐privileged, thus facilitating microbial survival. Here we re...
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Anagen stage hair follicles (HFs) exhibit “immune privilege (IP)” from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra‐follicular ant...
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Objective Human hair follicles (HFs) express the olfactory receptor OR2AT4, which is selectively stimulated by the synthetic sandalwood‐like odorant, Sandalore®. In organ‐cultured, human scalp HFs, Sandalore® prolongs anagen, and suppresses apoptosis by up‐regulating intra‐follicular IGF‐1 mediated signalling. The objective of this study is to demo...
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Vascular endothelial growth factor‐A (VEGF‐A), the main angiogenic mediator, plays a critical role in the pathogenesis of several inflammatory immune‐mediated diseases, including psoriasis. Even though anti‐angiogenic therapies, such as VEGF inhibitors, are licensed for the treatment of various cancers and eye disease, VEGF‐targeting interventions...
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Chemotherapy-induced hair loss (alopecia, CIA) remains a major unsolved problem in clinical oncology. CIA is often considered to be a consequence of the anti-mitotic and apoptosis-promoting properties of chemotherapy drugs acting on rapidly proliferating hair matrix keratinocytes. Here we show that in a mouse model of CIA, down-regulation of Shh si...