[Biology of the hair follicle].
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Alopecia↗
Biomedical subjects
R Paus
Publications and source records attributed to R Paus.
Towards defining receptors for L-tyrosine and L-dopa.
We postulate that in mammalian systems neurotransmitter and hormone-like functions of L-tyrosine (LT) and L-DOPA (LD) are mediated via specific membrane-bound and/or nuclear receptors. The structure and function of these receptors may represent an evolutionary continuum of regulatory proteins binding LT or LD in unicellular and lower multicellular organisms.
Animals↗
Correlation of proteolytic activities of organ cultured intact mouse skin with defined hair cycle stages.
The cyclic growth activity of the hair follicle is characterized by substantial remodelling of the extracellular matrix, yet, little is known about the proteolytic activities regulating this process. In murine skin, hair cycling is highly synchronized and is associated with dramatic remodeling of all skin compartments. We therefore have assessed, in this pilot study, proteolytic activities of murine skin from various stages of the depilation-induced hair cycle. We show that the defined proteolytic activities displayed by organ cultured intact mouse skin differ between hair cycle stages. Skin with all follicles in telogen or mid anagen displayed only minimal lysis of collagen type I gels, while early anagen skin had significant collagenase activity. Skin cultured on gelatin gels at the air-liquid interphase ('histoculture') completely lysed the gel within 5 days when all follicles were in early anagen, while this was not observed with mid and very late-anagen skin. Zymography of conditioned medium from these cultures revealed the secretion of activated interstitial collagenase and of gelatinases of 72 and 92 kDa, with the maximum of interstitial collagenase activity secreted by anagen IV skin. Addition of TPA or TNF-alpha to the culture medium stimulated secreted collagenase type I activity. The C 57 BL-6 mouse offers an attractive model for dissecting and manipulating hair cycle-associated proteolysis in a physiologically relevant system.
Animals↗
Bulge-activation hypothesis (continued)
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Apoptosis↗
Melanogenesis during the anagen-catagen-telogen transformation of the murine hair cycle.
Melanin synthesis of follicular melanocytes is strictly coupled to the growth stage of the hair cycle (anagen), ceases during follicle regression (catagen), and is absent throughout the resting stage (telogen). Having previously characterized the expression and activity of melanogenesis-related proteins during the telogen-anagen transition of the murine hair cycle (JID 96:172, 1991), we here report a biophysical and biochemical analysis of follicular melanogenesis during the anagen-catagen-telogen transformation of the C57 BL-6 mouse hair cycle. Tyrosinase activity and concentration as well as dopachrome tautomerase activity were compared with melanin synthesis, as measured by electron paramagnetic resonance spectroscopy (EPR). The visible changes in skin color and the histologically appreciable switch-off of melanin formation during the anagen-catagen transformation were accompanied by a steep decline in 1) the melanin-associated EPR signal of full-thickness mouse skin, 2) tyrosinase and dopachrome tautomerase activities, and 3) the skin concentration of 80-85-kD melanogenesis related protein and 66-68-kD tyrosinase protein. Telogen skin displayed a minimum of the EPR amplitude as well as of tyrosinase and dopachrome tautomerase activity detected. By EPR, only eumelanin was identified during all hair cycle stages. The gradual switch-off of melanogenesis during anagen VI started with an unexpectedly early decline of the EPR melanin signal, followed by dopachrome tautomerase activity and the concentration of 80-85-kD melanogenesis related protein. The initiation of catagen was characterized by a significant and rapid decrease in activity and concentration of tyrosinase, and was accompanied by a second drop in dopachrome tautomerase activity. Together, these biochemical and biophysical parameters of follicular melanogenesis serve as novel and differential markers for the imminent termination of anagen and the development of catagen. They also show that the switch-off of melanogenesis during the anagen-catagen-telogen transition is a stochastic process commencing already in mid anagen VI.
Animals↗
Distribution of constitutive nitric oxide synthase immunoreactivity and NADPH-diaphorase activity in murine telogen and anagen skin.
The freely diffusible radical nitric oxide is generated by nitric oxide synthase, and is a pleiotropic, bioregulatory molecule that regulates, e.g., the vascular tone, functions as a major neurotransmitter, and is involved in macrophage-mediated cytotoxicity and platelet aggregation. Constitutive nitric oxide synthase exhibits NADPH-diaphorase activity that can be demonstrated histochemically. To study whether this enzyme is present in mammalian skin during distinct phases of the murine hair cycle, we have examined cryosections of C 57 BL-6 mouse skin in telogen and depilation-induced anagen VI. Histochemical analysis of NADPH-diaphorase activity was complemented by immunohistology, using two specific rabbit antisera against constitutive neuronal nitric oxide synthase. Epidermis and the outer root sheath showed both immunoreactivity for the enzyme and NADPH-diaphorase activity, whereas dermal papilla and sebaceous glands displayed only strong NADPH-diaphorase activity, suggesting that this enzyme histochemical test measures additional enzymes besides nitric oxide synthase. Intrinsic nitric oxide synthase immunoreactivity was also detected by immunoblot in mouse skin homogenates, staining proteins of an apparent 160-kDa molecular weight. Compared to telogen skin, these immunoreactive proteins were quantitatively increased in anagen VI skin. Thus, our study suggests that defined epithelial compartments of normal murine skin are capable of synthesizing nitric oxide and that the molecule may be involved in skin physiology, growth, and remodeling.
Amino Acid Oxidoreductases↗
A murine model for inducing and manipulating hair follicle regression (catagen): effects of dexamethasone and cyclosporin A.
Most cases of hair loss are based on premature induction of follicle regression (catagen). Deciphering the unknown regulation of catagen is therefore clinically important, but catagen is also an excellent model for organ involution by rapid terminal differentiation and for epithelial cell death (apoptosis). We here report an assay for the controlled pharmacologic induction and manipulation of catagen follicles. Dexamethasone-21-acetate (0.1%) was applied once daily to depilation-induced, growing follicles (anagen VI) on the backs of C57 B1-6 mice. Characteristic catagen-associated changes in skin color were photodocumented and assessed by morphometric histology. Topical dexamethasone induced catagen-like follicles significantly earlier, more homogeneously, and also more extensively than vehicle. This process was inhibited by high intraperitoneal doses of cyclosporin A. In addition to its clinical relevance as a screening assay for catagen-blocking drugs, this simple murine model is an attractive tool for dissecting the molecular, cellular, and developmental biology of catagen.
Alopecia Areata↗
Inhibition of melanogenesis for melanoma therapy?
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Humans↗
Nerve growth factor modulates keratinocyte proliferation in murine skin organ culture.
Despite the fact that several cell types residing in or travelling through the skin are targets and/or sources of nerve growth factor (NGF), little is known about the role of NGF in skin development, physiology and disease. Employing a previously defined skin organ culture assay for studying the proliferation of murine keratinocytes in their natural tissue environment, we have assessed the effect of murine NGF (7S) on keratinocyte proliferation in intact skin derived from two defined stages of the murine hair cycle. We found that 10-200 ng/ml NGF stimulated epidermal keratinocyte proliferation in organ-cultured C57 BL-6 mouse skin in the telogen phase of the hair cycle. Follicle keratinocyte proliferation was stimulated by 100 ng/ml NGF in telogen skin organ culture, but this concentration of NGF inhibited both epidermal and follicle keratinocyte proliferation in organ culture of anagen skin. The latter inhibitory effect of NGF was abrogated by co-incubation with neutralizing anti-NGF antibodies or with the protein kinase C inhibitor staurosporine. The proliferation-modulatory effects of NGF were associated with the induction of significant mast cell degranulation, and were inhibited by cromoglycate co-administration. This is the first report of a modulatory, hair cycle-dependent effect of NGF on keratinocyte proliferation in situ, which may require the presence of mast cells. Our study supports the notion of auto- and paracrine functions of NGF in murine skin physiology, which can be further assessed in the physiologically relevant mouse model delineated here.
Alkaloids↗
Distribution and changing density of gamma-delta T cells in murine skin during the induced hair cycle.
Gamma-delta T cells (gdTC) are recognized as the predominant intraepidermal T-cell population in murine skin, although their physiological functions are still unclear. Little is known of the exact distribution of gdTC in the other epithelial skin compartments of normal mice. Using selective gdTC-receptor antibodies in immunohistology (alkaline phosphatase technique), the distribution and density of gdTC was analysed morphometrically in cryostat sections of full-thickness back skin of normal, adolescent C57 BL-6 mice in all the different stages of the depilation-induced hair cycle. We found that, during the entire hair cycle, V gamma 3-TCR-bearing lymphocytes are restricted to the epidermis, and to the epithelial hair bulb in, and distal to, the bulge area. No gdTC were seen in the sebaceous glands. During early anagen development, the number of pan-gdTC receptor-positive cells increased significantly (P < 0.005) in the interfollicular epidermis and the suprainfundibular portion of the hair bulb, whereas the number decreased in the infrainfundibular region (P < 0.005). As gdTC are thought to migrate into the skin only during embryogenesis, this finding suggests hair cycle-dependent, differential intraepithelial proliferation of gdTC in murine skin. We advocate employing only skin of defined hair cycle stages in immunological studies on murine skin, and discuss the value of the C57 BL-6 model for assessing the functions of gdTC in skin and hair biology.
Animals↗
Expression of classical and non-classical MHC class I antigens in murine hair follicles.
Not all keratinocytes in human and rat hair follicles express MHC class I antigens (MHC I). In the present study, we report the first immunohistological profile of classical and non-classical MHC I expression in the skin of adolescent C57 BL-6 mice during the induced hair cycle. MHC I immunoreactivity (H-2b, H-2Db) is absent in the matrix and inner root sheath of growing (= anagen) hair follicles, and the dermal papillae are H-2b negative during catagen and telogen. This lack of normal MHC I expression may serve to sequester potentially damaging autoantigens from immune recognition. In addition, we present the first evidence of non-classical MHC class I antigen expression in normal mammalian skin: during the entire hair cycle, the distal hair follicle shows strong Qa-2 immunoreactivity, which appears to be restricted to an epithelial follicle compartment densely populated by gamma-delta T cells with which Qa-2 molecules may interact as part of a primitive antibacterial defense system of the follicle. The murine hair cycle is an attractive model for dissecting the functional roles of H-2b and Qa-2 molecules in hair biology and in related tissue-interaction systems.
Animals↗
Alkaline phosphatase activity and localization during the murine hair cycle.
For unknown reasons, the pilosebaceous unit displays prominent alkaline phosphatase (AP) activity, and alterations in AP activity are seen in alopecia areata. The role of AP in hair biology and pathology has been obscured by contradictory reports on the localization and activity of AP during the hair cycle, and by a paucity of instructive models for studying AP functions. Using the C57 BL-6 mouse model for hair research, we have characterized endogenous AP with a simple histochemical developing solution routinely employed for AP immunohistology. This method was selective for AP, and revealed distinctive hair cycle-dependent changes in AP activity and localization. Although the dermal papilla displays unusually strong AP activity during the entire hair cycle, the outer root sheath is AP-positive only during late anagen and early catagen. Strong, rather homogeneous AP activity is seen in the sebaceous gland (SG) only during catagen and telogen. This AP staining pattern indicates hair cycle-dependent changes in SG functions, and differs to some extent from the previously reported AP activity during the hair cycle of various species. We propose a simple and effective technique for follicle classification based on the AP histochemistry of dermal papilla and sebaceous gland, and discuss uses of the C57 BL-6 mouse model for functional AP studies.
Alkaline Phosphatase↗
Hair follicle expression of 1,25-dihydroxyvitamin D3 receptors during the murine hair cycle.
Because the hair follicle is a highly hormone-sensitive miniorgan, the role of hormones produced locally in the skin in the control of hair growth deserves systematic analysis. It has been shown previously that the potent steroid hormone 1,25-dihydroxyvitamin D3 (1,25-D3) modulates growth and differentiation of keratinocytes via binding to a high-affinity nuclear vitamin D receptor (VDR). In this study, we have examined the in situ expression of VDR during the murine hair cycle. VDR expression was detected immunohistochemically. To obtain defined stages of the murine hair cycle, hair growth was induced by depilation in C57 BL-6 mice. In addition to the recognized VDR expression of outer root sheath keratinocytes, we detected VDR immunoreactive cells in the dermal papilla, the mesenchymal key structure of the hair follicle. Furthermore, VDR immunoreactivity in the nuclei of outer root sheath keratinocytes and in dermal papilla cells was stronger during anagen IV-VI and catagen than during telogen and anagen I-III. This suggests hair cycle-associated changes in the expression of VDR, and points to a potential role for 1,25-D3 in hair follicle biology. Selected follicular cell populations may display hair cycle-dependent sensitivity to 1,25-D3 stimulation.
Animals↗
Murine skin as a target for melatonin bioregulation.
Specific binding sites for 3H-melatonin were detected in membrane fractions prepared from C57 BL-6 mouse skin, and were localized to the epidermis and the epithelial bulb of the hair follicle by in situ autoradiography. In skin organ culture, melatonin stimulated DNA synthesis by the epidermal keratinocytes at concentration 0.1-10 nM, while at > or = 1 microM it inhibited tyrosinase activity. We concluded that murine skin is a target for melatonin bioregulation.
Animals↗
Hair growth induction by substance P.
BACKGROUND: In vitro, some neuropeptides, including the tachykinin, substance P (SP), act as growth factors. The cyclic growth of the richly innervated hair follicle offers a model for probing such functions in a complex, developmentally regulated tissue interaction system under physiologic conditions. Dissecting the role of neuropeptides in this system may also reveal as yet obscure neural mechanisms of hair growth control. EXPERIMENTAL DESIGN: The neuropeptide-releasing neurotoxin, capsaicin was injected intradermally, or SP slow-release formulations were implanted subcutaneously in the back skin of C57BL/6 mice with all follicles in the resting stage of the hair cycle (telogen) in order to see whether this induced hair growth (anagen). In addition, the endogenous SP skin concentration and the activity of the main SP-degrading enzyme, neutral endopeptidase, were determined during the induced murine hair cycle by high performance liquid chromatography-controlled radioimmuno-assay (SP) or by fluorometry (neutral endopeptidase). RESULTS: Both capsaicin and SP induced significant hair growth (anagen) in the back skin of telogen mice. This was associated with substantial mast cell degranulation. The endogenous SP skin concentration showed significant, hair cycle-dependent fluctuations during the induced murine hair cycle, which were largely independent of the activity of neutral endopeptidase. CONCLUSIONS: SP may play a role in the neural control of hair growth. Whereas this pilot study does not address the underlying mechanisms of action, it demonstrates that SP has potential as a hair growth-stimulatory agent in vivo, and serves as a basis for exploring the role of tachykinins in epithelial-mesenchymal-neuroectodermal interaction systems like the hair follicle.
Animals↗
Chemotherapy-induced alopecia in mice. Induction by cyclophosphamide, inhibition by cyclosporine A, and modulation by dexamethasone.
We introduce cyclophosphamide-induced alopecia (CYP-IA) in C57BL-6 mice as a clinically relevant model for studying the biology of chemotherapy-induced alopecia and for developing anti-alopecia drugs. One injection of CYP to mice with all back skin follicles in anagen VI induces severe alopecia that strikingly reproduces the follicle response, recovery, and histopathology seen in human CYP-IA. CYP dose-dependently induces abnormal follicular melanogenesis and dystrophic anagen or, in more severely damaged follicles, dystrophic catagen. Both dystrophy forms are followed by an extremely shortened telogen phase, but differ in the associated hair loss and in recovery patterns, which determines hair regrowth. This follicular response to CYP can be manipulated pharmacologically: systemic cyclosporine A shifts it toward a mild form of dystrophic anagen, thus retarding CYP-IA and prolonging "primary recovery". Topical dexamethasone, in contrast, forces follicles into dystrophic catagen, which augments CYP-IA, but accelerates the regrowth of normally pigmented hair ("secondary recovery").
Alopecia↗
The "bulge-activation hypothesis" does not explain hair follicle cycling but may still be valid.
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Animals↗
Melanocytes as "sensory" and regulatory cells in the epidermis.
Epidermal melanocytes (MC) are pigment-producing and secretorily active cells of neural crest origin that communicate directly with multiple targets. Here, we propose that normal epidermal MC also are "sensory" and regulatory cells operating in the context of a regulatory network for the maintenance of human epidermal homeostasis. Altered regulatory MC functions may play a role in selected skin diseases, and racial pigmentation may affect cutaneous functions.
Cell Communication↗