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Biomedical subjects

Ralf Paus

Publications and source records attributed to Ralf Paus.

At least 73 records · Page 4Linked to original sources
PubMed2004

Estrogens and the hair follicle.

While it is undisputed that estrogens (1 beta-estradiol, E2) are mainly involved in skin physiology and operate as potent hair growth modulators, our knowledge about the estrogen target cells in skin and exact signaling pathways is still very limited. The current review provides an overview of estrogen effects on hair follicle cycling, cutaneous expression of estrogen receptors, and potential functions of estrogens in hair biology. We discuss potential target genes of estrogen receptor-mediated signaling in the skin, explore the interplay of estrogens with other hormones, growth factors and enzymes, and define major open questions in this intriguing and far too long neglected area of hair research.

Animals↗
PubMed2004

Burden of hair loss: stress and the underestimated psychosocial impact of telogen effluvium and androgenetic alopecia.

Hair loss, as it occurs with telogen effluvium and androgenetic alopecia, provokes anxieties and distress more profound than its objective severity would appear to justify. This reflects the profound symbolic and psychosocial importance of hair. Stress has long been implicated as one of the causal factors involved in hair loss. Recently, in vivo studies in mice have substantiated the long-held popular belief that stress can exert profound hair growth-inhibitory catagen-inducing and hair-damaging pro-inflammatory effects. Insights into the negative impact of stress on hair growth and the integration of stress-coping strategies into the management of hair loss disorders as well as the development of new pharmacotherapeutic strategies might lead to enhanced therapeutic modalities with the alleviation of clinical symptoms as well as the concomitant psychological implications.

Adaptation, Psychological↗
PubMed2004

FOXN1 is critical for onycholemmal terminal differentiation in nude (Foxn1) mice.

Nude mice have a mutation in the transcription factor Foxn1(nu), resulting in downregulation of hair keratins. Although hair follicles develop normally, the hair fibers become structurally weak, curl, and break off at the surface. Nails in nude mice are deformed, based on alterations of the onychocyte differentiation process. Elemental microanalysis of the nail plate reveals marked decreases in sulfur concentrations in the nude mouse nail plates. Immunohistochemistry shows a lack of keratin 1 expression in terminally differentiating keratinocytes of the nail matrix. Instead, the typical differentiation process of the matrix is altered toward an epidermis-like differentiation pattern, comprising the production of filaggrin-containing keratohyalin granules in cells resembling those of the stratum granulosum, which are never observed in normally haired mice. The nail plate has diffuse basophilic stippling. It is thinner than normal, weak, and in most Foxn1(nu)/Foxn1(nu) mice breaks where it separates from the hyponychium. These studies indicate that the Foxn1(nu) mutated gene has effects beyond downregulating keratin expression, including changes in filaggrin expression, and is critical for normal onycholemmal differentiation. The nails of nude mice provide new insights into the molecular controls of onychocyte differentiation, and they offer a useful model to investigate the pathogenesis of nail hypergranulosis, a common feature in human nail diseases.

Animals↗
PubMed2004

Neurotrophin-3 regulates mast cell functions in neonatal mouse skin.

Nerve growth factor (NGF) has long been recognized as an important mast cell (MC) growth factor. To explore whether other neurotrophins (NTs) of the NGF family, which are widely expressed in mouse skin, affect the numbers and/or functions of MCs we examined the effects of NT-3 on neonatal skin MCs. We demonstrate that TrkC, the high affinity NT-3 receptor, is expressed by virtually all neonatal skin MCs in C57BL/6 mice, which indicates that MCs can respond to NT-3. Skin of neonatal and early postnatal NT-3-overexpressing mice (promoter: K14) displayed significantly and up to twofold increased numbers of MCs during the first 20 days after birth, as compared to wild-type mice. To check whether this increase in MC numbers in NT-3 transgenic mice reflects a higher rate of proliferation, we performed immunohistochemistry, which revealed that only 1-2% of all skin MCs both in NT-3-overexpressing and in wild-type controls showed Ki-67-positive nuclei, suggesting that the observed differences in the number of MCs do not reflect a higher rate of MC proliferation. Additionally, we show that the effect of NT-3 on the number of MCs is most likely to be stem cell factor (SCF)-independent, because NT-3 significantly downregulates secretion of SCF-protein in cultured dermal fibroblasts, as assessed by enzyme-linked immunosorbent assay. Numbers of skin MCs in neonatal TrkC-deficient mice were found to be modestly reduced, as compared to wild-type mice, indicating that NT-3 can modulate the number of MCs directly via TrkC, although TrkC does not seem to be essential for the number of basal MCs. To further analyze the effects of NT-3 on MCs, we stimulated skin organ culture of early postnatal C57BL/6 mouse skin with 5-50 ng/ml NT-3, which induced a significant increase in MC degranulation, as visualized by Giemsa staining. However, stimulation of isolated neonatal dermal skin MCs with NT-3 in vitro failed to result in MC activation, as measured by serotonin release. Our data suggest a role for NT-3 in the maturation of MCs, such as a TrkC-mediated stimulation of the differentiation of pre-existing, less mature MCs and/or by enhancing the migration of circulating MC precursors into the skin.

Animals↗
PubMed2004

Limitations of human occipital scalp hair follicle organ culture for studying the effects of minoxidil as a hair growth enhancer.

Minoxidil induces new hair growth in approximately one-third of patients with androgenetic alopecia after 1 year of treatment. With several conflicting reports in the literature based on small-scale studies, the current study aimed to clarify whether organ culture of human scalp anagen VI hair follicles is a suitable in vitro test system for reproducing, and experimentally dissecting, the recognized in vivo hair-growth-promoting capacity of minoxidil. Hair shaft elongation was studied in terminal anagen VI hair follicles microdissected from the occipital scalp of 36 healthy adults. A total of 2300 hair follicles, approximately 65 per individual, were tested using modifications of a basic organ culture protocol. It is shown here that minoxidil does not significantly increase hair shaft elongation or the duration of anagen VI in ex vivo culture despite several enhancements on the conventional methodology. This disparity to what is seen clinically in minoxidil responders may be explained by the following: (i) use of occipital (rather than frontotemporal or vertex) hair follicles; (ii) use of, already maximally growing, anagen VI hair follicles; (iii) a predominance of hair follicles from minoxidil unresponsive-donors; (iv) use of minoxidil rather than its sulfate metabolite; and/or (v) use of a suboptimal minoxidil dosage. This disparity questions the usefulness of standard human hair follicle organ culture in minoxidil research. Unexpectedly, minoxidil even inhibited hair shaft elongation in the absence of insulin, which may indicate that the actual hair-growth-modulatory effects of minoxidil depend on the concomitant local presence/absence of other growth modulators.

Adult↗
PubMed2004

In search of the "hair cycle clock": a guided tour.

The hair follicle, a unique characteristic of mammals, represents a stem cell-rich, prototypic neuroectodermal-mesodermal interaction system. This factory for pigmented epithelial fibers is unique in that it is the only organ in the mammalian body which, for its entire lifetime, undergoes cyclic transformations from stages of rapid growth (anagen) to apoptosis-driven regression (catagen) and back to anagen, via an interspersed period of relative quiescence (telogen). While it is undisputed that the biological "clock" that drives hair follicle cycling resides in the hair follicle itself, the molecular nature of the underlying oscillator system remains to be clarified. To meet this challenge is of profound general interest, since numerous key problems of modern biology can be studied exemplarily in this versatile model system. It is also clinically important, since the vast majority of patients with hair growth disorders suffers from an undesired alteration of hair follicle cycling. Here, we sketch basic background information and key concepts that one needs to keep in mind when exploring the enigmatic "hair cycle clock"(HCC), and summarize competing models of the HCC. We invite the reader on a very subjective guided tour, which focuses on our own trials, errors, and findings toward the distant goal of unravelling one of the most fascinating mysteries of biology: Why does the hair follicle cycle at all? How does it do it? What are the key players in the underlying molecular controls? Attempting to offer at least some meaningful answers, we share our prejudices and perspectives, and define crucial open questions.

Animals↗
PubMed2003

Molecular biology of hair morphogenesis: development and cycling.

In mammals, hair follicles produce hairs that fulfill a number of functions including thermoregulation, collecting sensory information, protection against environmental trauma, social communication, and mimicry. Hair follicles develop as a result of epithelial-mesenchymal interactions between epidermal keratinocytes committed to hair-specific differentiation and cluster of dermal fibroblasts that form follicular papilla. During postnatal life, hair follicles show patterns of cyclic activity with periods of active growth and hair production (anagen), apoptosis-driven involution (catagen), and relative resting (telogen). During last decade, substantial progress has been achieved in delineating molecular mechanisms that control hair follicle development and cyclic activity. In this review, we summarize the data demonstrating that regulation of hair follicle development in the embryo and control of hair follicle growth during postnatal life are highly conserved and both require involvement of similar molecular mechanisms. Since many of the molecules that control hair follicle development and cycling are also involved in regulating morphogenesis and postnatal biology of other ectodermal derivatives, such as teeth, feathers, and mammary glands, basic principles and molecular mechanisms that govern hair follicle development and growth may also be applicable for other developmental systems.

Animals↗
PubMed2003

Mast cells express novel functional IL-15 receptor alpha isoforms.

Mast cells previously have been reported to be regulated by IL-15 and to express a distinct IL-15R, termed IL-15RX. To further examine IL-15 binding and signaling in mast cells, we have studied the nature of the IL-15R and some of its biological activities in these cells. In this study, we report the existence of three novel isoforms of the IL-15R alpha chain in murine bone marrow-derived mast cells as a result of an alternative exon-splicing mechanism within the IL-15R alpha gene. These correspond to new mRNA transcripts lacking exon 4; exons 3 and 4; or exons 3, 4, and 5 (IL-15R alpha Delta 4, IL-15R alpha Delta 3,4, IL-15R alpha Delta 3,4,5). After transient transfection in COS-7 cells, all IL-15R alpha isoforms associate with the Golgi apparatus, the endoplasmic reticulum, the perinuclear space, and the cell membrane. Analysis of glycosylation pattern demonstrates the usage of a single N-glycosylation site, while no O-glycosylation is observed. Importantly, IL-15 binds with high affinity to, and promotes the survival of, murine BA/F3 cells stably transfected with the IL-15R alpha isoforms. Furthermore, we report that signaling mediated by IL-15 binding to the newly identified IL-15R alpha isoforms involves the phosphorylation of STAT3, STAT5, STAT6, Janus kinase 2, and Syk kinase. Taken together, our data indicate that murine mast cells express novel, fully functional IL-15R alpha isoforms, which can explain the selective regulatory effects of IL-15 on these cells.

Alternative Splicing↗
PubMed2003

Control of pelage hair follicle development and cycling by complex interactions between follistatin and activin.

Members of the transforming growth factor beta/bone morphogenetic protein (TGF-beta/BMP) family are involved in the control of hair follicle (HF) morphogenesis and cycling. The activities of several members of this family activins and BMP-2, -4, -7, and -11) are controlled by antagonists such as follistatin. Because follistatin-deficient mice show abnormalities in vibrissae development, we explored the role of follistatin and activin in pelage HF development and cycling. We show here that during HF development follistatin mRNA was prominently expressed by hair matrix and outer root sheath keratinocytes as well as by interfollicular epidermal cells, whereas activin betaA mRNA was mainly expressed in dermal papilla cells. Compared with age-matched wild-type controls, both follistatin knockout mice and activin betaA transgenic mice showed a significant retardation of HF morphogenesis. Treatment of wild-type embryonic skin explants with follistatin protein stimulated HF development. This effect was inhibited by addition of recombinant activin A protein. Activin betaA transgenic mice demonstrated retardation of catagen entry, down-regulation of BMP-2, and up-regulation of expression of its antagonist matrix GLA protein. These observations suggest that follistatin and activin interaction plays an important role in both HF development and cycling, possibly in part by regulating expression of BMP-2 and its antagonist.

Activin Receptors↗
PubMed2003

Dendritic cell-derived IL-15 controls the induction of CD8 T cell immune responses.

The development and the differentiation of CD8(+) T cells are dependent on IL-15. Here, we have studied the source and mechanism of how IL-15 modulates CD8(+) T cell-mediated Th1 immune responses by employing two delayed-type hypersensitivity (DTH) models. IL-15-deficient (IL-15(-/-)) mice or mice treated with soluble IL-15Ralpha as an IL-15 antagonist showed significantly reduced CD8(+) T cell-dependent DTH responses, while activation of CD4(+) T cell and B cell functions remained unaffected. Injection of antigen-labeled dendritic cells (DC) from IL-15(+/+), IL-15(-/-) or IL-15Ralpha(-/-) mice revealed that DC-derived IL-15 is an absolute requirement for the initiation of DTH response. The re-establishment of the interaction of IL-15 with the IL-15Ralpha by incubating IL-15(-/-) DC with IL-15 completely restored the capacity to prime T cells for DTH induction in vivo. Moreover, IL-15 also enhanced secretion of pro-inflammatory cytokines by DC and triggered in vitro CD8(+) T cell proliferation and IL-2 release. Taken together, the data suggest that an autocrine IL-15/IL-15Ralpha signaling loop in DC is essential for inducing CD8(+)-dependent Th1 immune responses in mice. Therefore, targeted manipulation of this loop promises to be an effective, novel strategy for therapeutic modulation of clinically relevant DTH reactions.

Animals↗
PubMed2003

Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.

It has been much disputed whether or not stress can cause hair loss (telogen effluvium) in a clinically relevant manner. Despite the paramount psychosocial importance of hair in human society, this central, yet enigmatic and controversial problem of clinically applied stress research has not been systematically studied in appropriate animal models. We now show that psychoemotional stress indeed alters actual hair follicle (HF) cycling in vivo, ie, prematurely terminates the normal duration of active hair growth (anagen) in mice. Further, inflammatory events deleterious to the HF are present in the HF environment of stressed mice (perifollicular macrophage cluster, excessive mast cell activation). This provides the first solid pathophysiological mechanism for how stress may actually cause telogen effluvium, ie, by hair cycle manipulation and neuroimmunological events that combine to terminate anagen. Furthermore, we show that most of these hair growth-inhibitory effects of stress can be reproduced by the proteotypic stress-related neuropeptide substance P in nonstressed mice, and can be counteracted effectively by co-administration of a specific substance P receptor antagonist in stressed mice. This offers the first convincing rationale how stress-induced hair loss in men may be pharmacologically managed effectively.

Acoustic Stimulation↗
PubMed2003

Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen.

Here, we provide the first study of prolactin (PRL) and prolactin receptor (PRLR) expression during the nonseasonal murine hair cycle, which is, in contrast to sheep, comparable with the human scalp and report that both PRL and PRLR are stringently restricted to the hair follicle epithelium and are strongly hair cycle-dependent. In addition we show that PRL exerts functional effects on anagen hair follicles in murine skin organ culture by down-regulation of proliferation in follicular keratinocytes. In telogen follicles, PRL-like immunoreactivity was detected in outer root sheath (ORS) keratinocytes. During early anagen (III to IV), the developing inner root sheath (IRS) and the surrounding ORS were positive for PRL. In later anagen stages, PRL could be detected in the proximal IRS and the inner layer of the ORS. The regressing (catagen) follicle showed a strong expression of PRL in the proximal ORS. In early anagen, PRLR immunoreactivity occurred in the distal part of the ORS around the developing IRS, and subsequently to a restricted area of the more distal ORS during later anagen stages and during early catagen. The dermal papilla (DP) stayed negative for both PRL and PRLR throughout the cycle. Telogen follicles showed only a very weak PRLR staining of ORS keratinocytes. The long-form PRLR transcript was shown by real-time polymerase chain reaction to be transiently down-regulated during early anagen, whereas PRL transcripts were up-regulated during mid anagen. Addition of PRL (400 ng/ml) to anagen hair follicles in murine skin organ culture for 72 hours induced premature catagen development in vitro along with a decline in the number of proliferating hair bulb keratinocytes. These data support the intriguing concept that PRL is generated locally in the hair follicle epithelium and acts directly in an autocrine or paracrine manner to modulate the hair cycle.

Animals↗
PubMed2003

Topical minoxidil counteracts stress-induced hair growth inhibition in mice.

Stress has long been suspected as a possible cause of hair loss in various species, even though convincing experimental evidence has not been available. Recently, we have shown in a murine model that sonic stress alters hair growth and cycling in vivo, and have postulated the existence of a 'brain-hair follicle axis' (BHA). In order to study whether a clinically available and widely used topically active hair growth stimulator mitigates stress-triggered hair growth inhibition in this stress model, we have applied a 5% minoxidil solution. Female CBA/J mice were depilated and randomized in to two groups: control (n = 20) and sonic stress (n = 20). These groups were further divided and either treated daily with 5% minoxidil solution or vehicle alone. The stress group was exposed to sonic stress for 24 h starting 14 days after anagen induction by depilation. All mice were sacrificed 16 days after the depilation and assessed by quantitative histomorphometry. Sonic stress significantly increased the number of hair follicles with apoptotic cells and inhibited intrafollicular keratinocyte proliferation. In addition, the number of clusters of perifollicular MHC class II+ cells and degranulated perifollicular mast cells was significantly enhanced in the stressed mice. In accordance with previous findings, all stressed mice showed an advanced hair cycle progression towards catagen. All of these stress-induced hair growth inhibitory changes along the BHA were down-regulated by topical minoxidil application. This encourages one to explore clinically whether topical minoxidil is a safe and effective pharmacologic tool for the management of stress-associated telogen effluvium in humans.

Alopecia↗
PubMed2003

The hair follicle and immune privilege.

This essay reviews the available evidence that the proximal hair follicle epithelium generates and maintains an area of relative immune privilege during a defined segment of the hair cycle (i.e., during anagen). This immune privilege is chiefly characterized by a very low level of expression of MHC class Ia antigens and by the local production of potent immunosuppressive agents, such as alpha-MSH and TGF-beta1. We discuss the putative functions of immune privilige of the anagen hair bulb, favoring the view that immune privilege serves mainly to sequester anagen- and/or melanogenesis-associated autoantigens from immune recognition by autoreactive CD8+ T cells. On this basis, we develop how the "immune privilege collapse model" of alopecia areata pathogenesis was conceived. In our discussion of the clinical implications of immune privilege, we outline the currently available evidence in support of this still hypothetical scenario to explain the initiation, progression, and termination of alopecia areata lesions. We review the most recent evidence from our laboratory that alpha-MSH, IGF-1, and TGF-beta1 can downregulate IFN-gamma-induced ectopic MHC class I expression in human anagen hair bulbs in vitro. Finally, we suggest that hair follicle-derived alpha-MSH, IGF-gamma, and TGF-beta1 form part of a constitutively active "IP restoration machinery" of the anagen hair bulb, which we propose to be recruited whenever the hair follicle suffers immune injury. Finally, we sketch some particularly promising avenues for future investigation into the far too long ignored hair follicle immune privilege.

Animals↗