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Ralf Paus

Publications and source records attributed to Ralf Paus.

86 records · Page 5Linked to original sources
PubMed2003

Plasticity and cytokinetic dynamics of the hair follicle mesenchyme during the hair growth cycle: implications for growth control and hair follicle transformations.

Hair fiber production is the macroscopic end-point of a highly complex set of interactions between the hair follicle's epithelial and mesenchymal components. The nature of this relationship is largely set during hair follicle morphogenesis, but is dramatically revisited in the adult during the unique tissue remodeling events required for hair follicle cycling. Whereas significant attention has focused on the fate of the hair follicle epithelium during these events, associated changes in hair follicle fibroblast subpopulations remain unclear. Here, we present a speculative review that represents a critical and innovative synthesis of the current literature and summarizes a recently submitted original study by the authors, on the nature of hair cycle-dependent fibroblast dynamics and on how perturbations thereof may lead to several clinical manifestations of altered human hair growth.

Animals↗
PubMed2003

Plasticity and cytokinetic dynamics of the hair follicle mesenchyme: implications for hair growth control.

The continuously remodeled hair follicle is a uniquely exploitable epithelial-mesenchymal interaction system. In contrast to the cyclical fate of the hair follicle epithelium, the dynamics of the supposedly stable hair follicle mesenchyme remains enigmatic. Here we address this issue using the C57BL/6 hair research model. During hair growth, increase in total follicular papilla size was associated with doubling of papilla cell numbers, much of which occurred before intra-follicular papilla cell proliferation, and subsequent to mitosis in the proximal connective tissue sheath. This indicates that some papilla cells originate in, and migrate from, the proliferating pool of connective tissue sheath fibroblasts. Follicular papilla cell number and total papilla size were maximal by anagen VI, but intriguingly, decreased by 25% during this period of sustained hair production. This cell loss, which continued during catagen, was not associated with intra-follicular papilla apoptosis, strongly indicating that fibroblasts migrate out of the late anagen/early catagen papilla and re-enter the proximal connective tissue sheath. Low-level apoptosis occurred only here, along with the "detachment" of cells from the regressing connective tissue sheath. Thus, the hair follicle mesenchyme exhibits significant hair cycle-associated plasticity. Modulation of these cell interchanges is likely to be important during clinically important hair follicle transformations, e.g. vellus-to-terminal and terminal-to-vellus during androgenetic alopecia.

Animals↗
PubMed2003

Expression patterns of the transcription factor AP-2alpha during hair follicle morphogenesis and cycling.

AP-2alpha is a member of a family of transcription factors expressed in cells of the epithelial and neural crest lineage. AP-2alpha plays an essential role in embryonic development and in regulation of epithelial gene transcription. To further characterize the role of AP-2alpha in skin biology, we assessed its expression in the skin of C57BL/6J mice during defined stages of hair follicle morphogenesis and cycling. During early hair follicle morphogenesis, AP-2alpha was upregulated in the epidermal placode, in the basal keratinocytes of the hair follicle bud, and then in the inner root sheath. The follicular papilla cells underwent a brief upregulation of AP-2alpha expression during the initiation of hair shaft formation and active hair follicle downward growth. Completion of hair follicle morphogenesis was associated with a marked reduction of AP-2alpha immunoreactivity in the lower portion of the hair follicle including both epithelial and mesenchymal compartments. In adolescent mouse skin, consistently strong AP-2alpha expression was found in the basal keratinocytes of the epidermis, in the hair follicle infundibulum, and in the sebocytes. In the follicular papilla, AP-2alpha was weakly expressed in telogen, significantly upregulated in early anagen, then gradually declined, and reappeared again in middle catagen. In the inner root sheaths, AP-2alpha expression was detected during early and middle anagen and during middle catagen stages. Prominent AP-2alpha expression was also seen in the zone of club hair formation. Therefore, AP-2alpha upregulation in both epithelial and mesenchymal hair follicle compartments was coordinated with initiation of major remodeling processes. Our findings support the use of the hair follicle as a model to explore the role of AP-2alpha in physiologic remodeling of developing organs and in reciprocal ectodermal-mesenchymal interactions.

Age Factors↗
PubMed2003

Kit is expressed by epithelial cells in vivo.

In mammalian skin, stem cell factor (SCF) regulates the proliferation and maturation of mast cells and melanocytes, which are thought to be the only cutaneous cells that express the Kit-tyrosine kinase receptor (Kit) and respond to epithelial and mesenchymal-derived SCF. We previously had noted, however, the presence of Kit+ cells in murine hair follicles, in an introepithelial tissue compartment devoid of melanocytes and mast cells. Here we have identified the nature of this Kit+ population of cells in hair follicles of C57BL/6 mice. Anagen hair follicles showed strong Kit immunoreactivity not only in the pigmentary unit above the follicular dermal papilla but also in a much more proximally located, homogenous group of nondendritic, nonmelanized cells. By immunohistochemistry (desmoplakin+/Trp-1-) and electron microscopy (presence of tonofilaments, desmosomes, lack of melanosomes), these Kit+ cells were shown to be hair matrix keratinocytes and were also found in melanocyte-deficient hair follicles (Kit(Sl)/Kit(Sl-d) mice, Kit-neutralizing antibody-treated C57BL/6 mice). Expression of Kit and SCF was strongly hair-cycle-dependent, suggesting a functional role of epithelial Kit expression in hair growth control. This was supported by the observation that mice unable to respond to SCF stimulation (Kit(W)/Kit(W-v)) showed a significant retardation of anagen development compared to their wild-type littermates. The expression of Kit in the most rapidly proliferating compartment of the hair follicle epithelium suggests intriguing, as yet unexplored new functions of Kit signaling in epithelial cell biology.

Animals↗
PubMed2003

Interleukin-21 inhibits dendritic cell-mediated T cell activation and induction of contact hypersensitivity in vivo.

Interleukin (IL)-21 is a newly described cytokine that is produced by activated T cells and displays structural homology to IL-4 and IL-15. We here analyzed the role of IL-21 in dendritic cell (DC)-induced, T cell-mediated contact hypersensitivity (CHS) in vivo and on T cell activation and unspecific mixed lymphocyte reaction in vitro. By PCR, we demonstrate here constitutive expression of the specific IL-21 receptor and the common gamma-chain in DC, which together are able to mediate IL-21 signaling. Short-time incubation of in vitro generated DC with IL-21 significantly reduced their potential to induce an antigen-specific CD8+ T cell proliferation. Interestingly, 2h incubation of these DC with IL-21 before injection completely inhibited the potential of these DC to induce a CHS reaction to the hapten fluorescein 5-isothiocyanate in vivo. Mice injected with IL-21-treated DC even failed to mount a CHS response after repetitive injection of non-IL-21-treated DC 2 weeks later, suggesting that an antigen-specific unresponsiveness can be induced by IL-21-treated DC. Our data demonstrate that IL-21 is a new modulator of DC-T cell interaction with the potential to induce DC-mediated antigen-specific tolerance.

Animals↗
PubMed2002

Signaling through P2X7 receptor in human T cells involves p56lck, MAP kinases, and transcription factors AP-1 and NF-kappa B.

ATP-gated ion channel P2X receptors are expressed on the surface of most immune cells and can trigger multiple cellular responses, such as membrane permeabilization, cytokine production, and cell proliferation or apoptosis. Despite broad distribution and pleiotropic activities, signaling pathways downstream of these ionotropic receptors are still poorly understood. Here, we describe intracellular signaling events in Jurkat cells treated with millimolar concentrations of extracellular ATP. Within minutes, ATP treatment resulted in the phosphorylation and activation of p56(lck) kinase, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase but not p38 kinase. These effects were wholly dependent upon the presence of extracellular Ca(2+) ions in the culture medium. Nevertheless, calmodulin antagonist calmidazolium and CaM kinase inhibitor KN-93 both had no effect on the activation of p56(lck) and ERK, whereas a pretreatment of Jurkat cells with MAP kinase kinase inhibitor P098059 was able to abrogate phosphorylation of ERK. Further, expression of c-Jun and c-Fos proteins and activator protein (AP-1) DNA binding activity were enhanced in a time-dependent manner. In contrast, DNA binding activity of NF-kappa B was reduced. ATP failed to stimulate the phosphorylation of ERK and c-Jun N-terminal kinase and activation of AP-1 in the p56(lck)-deficient isogenic T cell line JCaM1, suggesting a critical role for p56(lck) kinase in downstream signaling. Regarding the biological significance of the ATP-induced signaling events we show that although extracellular ATP was able to stimulate proliferation of both Jurkat and JCaM1 cells, an increase in interleukin-2 transcription was observed only in Jurkat cells. The nucleotide selectivity and pharmacological profile data supported the evidence that the ATP-induced effects in Jurkat cells were mediated through the P2X7 receptor. Taken together, these results demonstrate the ability of extracellular ATP to activate multiple downstream signaling events in a human T-lymphoblastoid cell line.

Adenosine Triphosphate↗
PubMed2002

Developmental timing of hair follicle and dorsal skin innervation in mice.

The innervation of hair follicles offers an intriguing, yet hardly studied model for the dissection of the stepwise innervation during cutaneous morphogenesis. We have used immunofluorescence and a panel of neuronal markers to characterize the developmental choreography of C57BL/6 mouse backskin innervation. The development of murine skin innervation occurs in successive waves. The first cutaneous nerve fibers appeared before any morphological evidence of hair follicle development at embryonic day 15 (E15). Stage 1 and 2 developing hair follicles were already associated with nerve fibers at E16. These fibers approached a location where later in development the follicular (neural) network A (FNA) is located on fully developed pelage hair follicles. Prior to birth (E18), some nerve fibers had penetrated the epidermis, and an additional set of perifollicular nerve fibers arranged itself around the isthmus and bulge region of stage 5 hair follicles, to develop into the follicular (neural) network B (FNB). By the day of birth (P1), the neuropeptides substance P and calcitonin gene-related peptide became detectable in subcutaneous and dermal nerve fibers first. Newly formed hair follicles on E18 and P1 displayed the same innervation pattern seen in the first wave of hair follicle development. Just prior to epidermal penetration of hair shafts (P5), peptide histidine methionine-IR nerve fibers became detectable and epidermal innervation peaked; such innervation decreased after penetration (P7- P17). Last, tyrosine hydroxylase-IR and neuropeptide Y-IR became readily detectable. This sequence of developing innervation consistently correlates with hair follicle development, indicating a close interdependence of neuronal and epithelial morphogenesis.

Aging↗
PubMed2002

The lysosomal protease cathepsin L is an important regulator of keratinocyte and melanocyte differentiation during hair follicle morphogenesis and cycling.

We have previously shown that the ubiquitously expressed lysosomal cysteine protease, cathepsin L (CTSL), is essential for skin and hair follicle homeostasis. Here we examine the effect of CTSL deficiency on hair follicle development and cycling in ctsl(-/-) mice by light and electron microscopy, Ki67/terminal dUTP nick-end labeling, and trichohyalin immunofluorescence. Hair follicle morphogenesis in ctsl(-/-) mice was associated with several abnormalities. Defective terminal differentiation of keratinocytes occurred during the formation of the hair canal, resulting in disruption of hair shaft outgrowth. Both proliferation and apoptosis levels in keratinocytes and melanocytes were higher in ctsl(-/-) than in ctsl(+/+) hair follicles. The development of the hair follicle pigmentary unit was disrupted by vacuolation of differentiating melanocytes. Hair cycling was also abnormal in ctsl(-/-) mice. Final stages of hair follicle morphogenesis and the induction of hair follicle cycling were retarded. Thereafter, these follicles exhibited a truncated resting phase (telogen) and a premature entry into the first growth phase. Further abnormalities of telogen development included the defective anchoring of club hairs in the skin, which resulted in their abnormal shedding. Melanocyte vacuolation was again apparent during the hair cycle-associated reconstruction of the hair pigmentary unit. A hallmark of these ctsl(-/-) mice was the severe disruption in the exiting of hair shafts to the skin surface. This was mostly because of a failure of the inner root sheath (keratinocyte layer next to the hair shaft) to fully desquamate. These changes resulted in a massive dilation of the hair canal and the abnormal routing of sebaceous gland products to the skin surface. In summary, this study suggests novel roles for cathepsin proteases in skin, hair, and pigment biology. Principal target tissues that may contain protein substrate(s) for this cysteine protease include the developing hair cone, inner root sheath, anchoring apparatus of the telogen club, and organelles of lysosomal origin (eg, melanosomes).

Animals↗
PubMed2002

Mutant laboratory mice with abnormalities in pigmentation: annotated tables.

Mammalian pigment cell research has recently entered a phase of significantly increased activity due largely to the exploitation of the many mutant mouse stocks that are coming on stream. Numerous transgenic, targeted mutagenesis (so-called 'knockouts'), conditional (so-called 'gene switch') and spontaneous mutant mice develop abnormal coat color phenotypes. The number of mice that exhibit such abnormalities is increasing exponentially as genetic engineering methods become routine. Since defined abnormalities in such mutant mice provide important clues to the as yet often poorly understood functional roles of many gene products, this overview includes a corresponding, annotated table of mutant mice with pigmentation alterations. These range from early developmental defects via a large array of coat color abnormalities to a melanoma metastasis model. This overview should provide helpful pointers to investigators who are looking for mouse models to explore or to compare functional activities of genes of interest and for comparing coat color phenotypes of spontaneous or genetically engineered mouse mutants with novel ones. Secondly, this review includes a table of mouse models of specific human diseases with genetically defined pigmentation abnormalities. In summary, this annotated table should serve as a useful reference for anyone interested in the molecular controls of pigmentation.

Animals↗
PubMed2002

Simple and rapid method to isolate and culture follicular papillae from human scalp hair follicles.

Study of the involvement of the hair follicle papilla in hair growth regulation was greatly facilitated by the isolation and cultivation of this tiny cluster of fibroblast-like cells in the rat vibrissae and in the human hair follicle. While isolation of the hair follicle papilla from the former is relatively straightforward, the current method to isolate the much smaller human hair follicle requires significant skill. Thus, the routine initiation of primary cultures of human scalp hair follicle papilla cells requires significant training, time, and commitment. In an attempt to simplify hair follicle papilla cell culture methodology for new laboratory personnel, we have made significant refinements to the current method. Our method requires only two simple manipulations to isolate hair follicle papilla from intact isolated hair follicles. This very rapid and easy method isolates clean and intact hair follicle papillae. Together with their attachment via scratching to the growth surface, the isolation and cultivation of this important hair follicle component can now be achieved easily by the laboratory newcomer. The method relies for its simplicity on the removal of the hair follicle papilla from the outside of the intact hair follicle rather than via internal manipulations from within the hair follicle.

Animals↗
PubMed2002

Contrasting expression patterns of CCAAT/enhancer-binding protein transcription factors in the hair follicle and at different stages of the hair growth cycle.

Hair follicles undergo repeated cycles of growth and regression, throughout the entire life of the organism. These dynamic changes require closely co-ordinated regulation of gene expression. The CCAAT/enhancer-binding proteins are a family of basic region/leucine zipper transcription factors that regulate gene transcription in various tissues. They have been implicated in epidermal differentiation and may therefore play an important role in the hair follicle. We have investigated the localization of four members of this family--CCAAT/enhancer-binding protein-alpha, -beta, and -delta, and Gadd153--in both human and murine hair follicles by immunohistochemistry. Furthermore, we examined CCAAT/enhancer-binding protein-alpha, -beta, and -delta immunoreactivity at different stages of the depilation-induced murine hair growth cycle. Distinct immunoreactivity patterns for CCAAT/enhancer-binding protein-alpha, -beta, and -delta, and Gadd153 were observed in the outer root sheath, sebaceous gland, dermal papilla, and connective tissue sheath of human anagen hair follicles. In murine follicles, CCAAT/enhancer-binding protein-alpha was expressed in the outer root sheath, sebaceous gland, and dermal papilla, whereas CCAAT/enhancer-binding protein-beta expression was confined to the matrix, sebaceous gland, and inner and outer root sheaths. Both CCAAT/enhancer-binding protein-alpha and -beta were upregulated during anagen, then downregulated in catagen follicles. In contrast, CCAAT/enhancer-binding protein-delta showed no hair cycle-dependent variation in immunoreactivity. These data suggests that the expression of CCAAT/enhancer-binding protein-alpha and -beta may, in turn, play a part in regulating hair cycle-dependent gene expression. Moreover, as CCAAT/enhancer-binding protein-alpha, -beta, and -delta are crucial in the regulation of adipocyte differentiation and lipid metabolism, their expression in sebocytes suggests they may also play a similar role in differentiation and lipid metabolism of the sebaceous gland.

Animals↗
PubMed2002

IL-2-IgG2b fusion protein suppresses murine contact hypersensitivity in vivo.

Interleukin-15 shares several functional properties with interleukin-2, and signals through the beta and gamma chain of the interleukin-2 receptor as well as through its own high affinity alpha chain. In agreement with the concept that interleukin-2 plays a key role in type IV immune responses, we have recently shown that an IL-2-IgG2b fusion protein potently suppresses Th1-type delayed type hypersensitivity reaction and Th2-type allergic sensitization in mice. We have now compared the in vivo effects of IL-2-IgG2b fusion protein with those of IL-15-IgG2b fusion protein in a murine model of Th1-type contact hypersensitivity reaction. Daily systemic injections of IL-2-IgG2b fusion protein during the sensitization phase or application of IL-2-IgG2b fusion protein just 2 h before and 10 h after antigen challenge significantly inhibited the contact hypersensitivity ear swelling response, and this without any overt signs of associated toxicity. Even local injection of IL-2-IgG2b fusion protein into the earlobe around the time of antigen challenge inhibited the ear swelling reaction significantly. In contrast, neither systemic nor local injection of the IL-15-IgG2b fusion protein modulated the contact hypersensitivity reaction significantly. IL-2-IgG2b but not IL-15-IgG2b fusion protein reduced migration of antigen-presenting cells from the skin to local lymph nodes, inhibited the expression of CD80 and CD86, and induced a significant higher number of CD4+CD25+ T cells. Therefore, the IL-2-IgGb fusion protein offers a powerful tool for suppressing and/or preventing T-cell-mediated hypersensitivity reaction in vivo.

Animals↗
PubMed2002

Migration of melanoblasts into the developing murine hair follicle is accompanied by transient c-Kit expression.

Disruption of the c-Kit/stem cell factor (SCF) signaling pathway interferes with the survival, migration, and differentiation of melanocytes during generation of the hair follicle pigmentary unit. We examined c-Kit, SCF, and S100 (a marker for precursor melanocytic cells) expression, as well as melanoblast/melanocyte ultrastructure, in perinatal C57BL/6 mouse skin. Before the onset of hair bulb melanogenesis (i.e., stages 0-4 of hair follicle morphogenesis), strong c-Kit immunoreactivity (IR) was seen in selected non-melanogenic cells in the developing hair placode and hair plug. Many of these cells were S100-IR and were ultrastructurally identified as melanoblasts with migratory appearance. During the subsequent stages (5 and 6), increasingly dendritic c-Kit-IR cells successively invaded the hair bulb, while S100-IR gradually disappeared from these cells. Towards the completion of hair follicle morphogenesis (stages 7 and 8), several distinct follicular melanocytic cell populations could be defined and consisted broadly of (a) undifferentiated, non-pigmented c-Kit-negative melanoblasts in the outer root sheath and bulge and (b) highly differentiated melanocytes adjacent to the hair follicle dermal papilla above Auber's line. Widespread epithelial SCF-IR was seen throughout hair follicle morphogenesis. These findings suggest that melanoblasts express c-Kit as a prerequisite for migration into the SCF-supplying hair follicle epithelium. In addition, differentiated c-Kit-IR melanocytes target the bulb, while non-c-Kit-IR melanoblasts invade the outer root sheath and bulge in fully developed hair follicles.

Animals↗