Topical Estrogen Accelerates Hair Regrowth in Mice After Chemotherapy-Induced Alopecia by Favoring the Dystrophic Catagen Response Pathway to Damage

Estrogen receptor ligands are important modulators of skin physiology and are involved in the control of normal hair follicle cycling. Here, we have studied the effects of topically applied 17-β-estradiol on pathologic hair follicle cycling as seen during chemotherapy-induced alopecia, one of the major unresolved problems of clinical oncology. For this study we employed a well-established murine model that mimics chemotherapy-induced alopecia in humans. For precisely quantifying the area of hair loss and hair regrowth in this model in vivo, we developed a simple planimetric assay (dotmatrix planimetry). We show that topical 17-β-estradiol significantly alters the cycling response of murine follicles to cyclophosphamide, whereas the estrogen antagonist ICI 182.780 exerted no such effects. Initially, topical 17-β-estradiol enhanced chemotherapy-induced alopecia significantly by forcing the follicles into the dystrophic catagen response pathway to hair follicle damage, whereas follicles treated by ICI 182.780 or vehicle shifted into the dystrophic anagen response pathway. Consequently, the regrowth of normally pigmented hair shafts after chemotherapy-induced alopecia was significantly accelerated in the 17-β-estradiol treated group. Our data encourage one to explore topical estrogens as a potential stimulant for hair re-growth after chemotherapy-induced alopecia

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

A Guide to Assessing Damage Response Pathways of the Hair Follicle: Lessons From Cyclophosphamide-Induced Alopecia in Mice

After chemical, biological, or physical damage, growing (i.e. anagen) hair follicles develop abnormalities that are collectively called hair follicle dystrophy. Comparatively lower follicular damage induces the “dystrophic anagen” response pathway (=prolonged, dystrophic anagen, followed by severely retarded follicular recovery). More severe follicular damage induces the dystrophic catagen pathway (=immediate anagen termination, followed by a dystrophic, abnormally shortened telogen and maximally fast follicular recovery). In order to recognize these distinct damage response strategies of the hair follicle in a clinical or histopathological context, we have used the well-established C57BL/6J mouse model of cyclophosphamide-induced alopecia to define pragmatic classification criteria for hair follicle dystrophy (e.g., structure and pigmentation of the hair shaft, location, and volume of ectopic melanin granules, distension of follicular canal, number of TdT-mediated dUTP nick end labeling positive keratinocytes in the hair bulb; neural cell-adhesion molecule immunoreactivity and alkaline phosphatase activity as markers for the level of damage to the follicular papilla). These classification criteria for hair follicle dystrophy are useful not only in chemotherapy-induced alopecia models, but also in the screening of drug-treated or mutant mice in a highly standardized, accurate, sensitive, reproducible, easily applicable, and quantifiable manner

Electron paramagnetic resonance (EPR) spectroscopy for investigating murine telogen skin after spontaneous or depilation-induced hair growth

Depilation has greatly promoted our understanding of hair follicle biology, however, only marginally of telogen (the “resting” stage of the hair cycle). Since electron paramagnetic resonance (EPR) spectroscopy provides an instructive technique for analyzing hair biology, it may be useful for telogen research. To identify differences in murine telogen skin after a spontaneous and depilation-induced hair follicle cycling, and to analyze applicability of EPR to investigate telogen. Spontaneous or depilation-induced hair cycling in C57BL/6 mice. EPR spectroscopy of unshaven skin and of shaved hair shafts, microscopical examination of plucked or shed hair shafts, standardized histomorphometry. Melanin EPR signals did not differ qualitatively between the two examined types of skin, nor did depilation change the hair length. However, unmanipulated telogen skin revealed greater thickness, stronger EPR signals, 25% more hair shafts, and lower melanin content of individual hair shafts, as creating a much more intricate mosaic of telogen hair follicles with various numbers of hair shafts (0–3) than the skin after depilation-induced hair growth. In both types of skin empty pilary canals were found. Both groups of animals lost hair shafts which were typical of exogen (the actively controlled process of hair shedding). EPR spectroscopy can be profitably employed to study telogen. Murine telogen skin reveals a kenogen-like phenomenon (the “lag” phase following telogen and exogen when hair follicles remain empty, i.e. are devoid of hair shafts). Murine skin thickness in telogen and individual hair shaft pigmentation depend on the way of hair growth induction. Telogens after a spontaneous or depilation-induced hair growth are biologically distinct

Indications for a brain‐hair follicle axis: inhibition of keratinocyte proliferation and up‐regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P

ABSTRACT It has long been suspected that stress can cause hair loss, although convincing evidence of this has been unavailable. Here, we show that in mice sonic stress significantly increased the number of hair follicles containing apoptotic cells and inhibited intrafollicular keratinocyte proliferation in situ. Sonic stress also significantly increased the number of activated perifollicular macrophage clusters and the number of degranulated mast cells, whereas it down‐regulated the number of intraepithelial γδ T lymphocytes. These stress‐induced immune changes could be mimicked by injection of the neuropeptide substance P in nonstressed mice and were abrogated by a selective substance P receptor antagonist in stressed mice. We conclude that stress can indeed inhibit hair growth in vivo, probably via a substance P‐dependent activation of macrophages and/or mast cells in the context of a brain‐hair follicle axis

Is there a 'gut-brain-skin axis'?

Emerging evidence arising from interdisciplinary research supports the occurrence of communication axes between organs, such as the brain-gut or brain-skin axis. The latter is employed in response to stress challenge, along which neurogenic skin inflammation and hair growth inhibition is mediated. We now show that ingestion of a Lactobacillus strain in mice dampens stress-induced neurogenic skin inflammation and the hair growth inhibition. In conclusion, we are introducing a hypothesis, encouraged by our pilot observations and resting upon published prior evidence from the literature, which amalgamates previously proposed partial concepts into a new, unifying model, i.e. the gut-brain-skin axis. This concept suggests that modulation of the microbiome by deployment of probiotics can not only greatly reduce stress-induced neurogenic skin inflammation but even affect a very complex cutaneous phenomenon of (mini-) organ transformation, i.e. hair follicle cycling. These observations raise the intriguing prospect that feeding of just the right kind of bacteria can exert profound beneficial effects on skin homoeostasis, skin inflammation, hair growth and peripheral tissue responses to perceived stress

Pharmacological Disruption of Hair Follicle Pigmentation by Cyclophosphamide as a Model for Studying the Melanocyte Response to and Recovery from Cytotoxic Drug Damage In Situ

Here we show that cyclophosphamide induces disruption of follicular melanogenesis, which is characterized by abnormal transfer of pigment granules to ectopic hair bulb locations, extrafollicular melanin incontinence, disordered formation of melanosomes, and inhibition of melanosome transfer into precortical keratinocytes. This is in contrast to dexamethasone-induced termination of follicle melanogenesis, which activates premature but predominantly normal catagen development. Cyclophosphamide-induced pigmentation disruption was accompanied by significant alterations of biochemical and biophysical markers of melanogenesis, compared to control mice treated either with vehicle or with topical dexamethasone. Electron paramagnetic resonance spectroscopy shows a decline in the melanin signal and predominant eumelanin production. Tyrosine hydroxylase activity of tyrosinase and dihydroxyphenylalanine oxidation drop rapidly, while DOPAchrome tautomerase activity increases and dihydroxyindole carboxylic acid conversion factor activity remains unchanged in cyclophosphamide-treated mice compared to controls. These observations emphasize the key role of tyrosinase as opposed to post-dihydroxyphenylalanine oxidase steps in normal and pathological termination of melanogenesis and shows that tyrosinase is the most sensitive target of the melanogenic apparatus for pharmacological regulation. Follicle pigmentation recovers only during the subsequent hair cycle, i.e., after a new anagen hair bulb has been constructed, which points to the existence of a relatively chemoresistant melanoblast-like cell population residing in the noncycling part of the hair follicle