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

Abstract

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.

Ginsenoside F2 Reduces Hair Loss by Controlling Apoptosis through the Sterol Regulatory Element-Binding Protein Cleavage Activating Protein and Transforming Growth Factor-β Pathways in a Dihydrotestosterone-Induced Mouse Model

“…Treatment with DHT causes hair cell apoptosis and entry into catagen and telogen. 24) In Fig. 3, in vivo experiments are described in which the hair coverage, density and thickness after oral administration of ginsenoside F2 were measured.…”

Dissecting the Impact of Chemotherapy on the Human Hair Follicle

“…HF morphology and HF cycle staging were done on hematoxylin and eosin (H&E)-stained sections (Sigma), 49 whereas for histochemical visualization of melanin, routine Masson-Fontana stain was performed. 55 As a sensitive indicator of HF dystrophy, which becomes evident as defective melanosome formation and transfer, 11,14 -16 the presence of abnormally large melanin clumps (ie, Masson-Fontana ϩ conglomerates that were larger than keratinocyte nuclei) was counted as a useful parameter for quantitatively assessing the degree of HF dystrophy (modified after Hendrix et al 23 ).…”

“…11,23 Therefore, it is important to note that 4-HC indeed induced premature catagen-like In contrast, 80% of HFs treated with 100 mol/L 4-HC were arrested in a highly dystrophic, both necrotic and apoptotic pseudo-anagen VI stage, suggesting that these maximally damaged HFs had become incapable of regular catagen-associated organ remodeling and involution because of massive, 4-HC-induced tissue death (Figures 2 and 5, see below). Interestingly, the lowest 4-HC dose tested (1 mol/L) slightly (although nonsignificantly) increased the percentage of anagen VI HFs and reduced that of late catagen HFs compared with the vehicle control ( Figure 2).…”

“…The DP fibroblasts are much less affected, whereas massively and primarily affected cells are the keratinocytes of the hair matrix and the melanocytes of the HF pigmentary unit. 6,23 The melanocytes of the HF pigmentary unit are in intimate contact with hair matrix keratinocytes and differ in several respects from epidermal melanocytes. [32][33][34] Only during the growth stage of the hair cycle (anagen III to VI) are melanosomes transported to the keratinocytes, whereas HF involution (catagen) is proceeded and characterized by a complete arrest of melanin production.…”

“…[32][33][34] The melanin-producing and -transporting pigmentary unit is one of the primary targets of CIA, leading to disruption of normal melanin production and transfer (eg, 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). 6,18,23,35,36 Such pigmentation abnormalities are not restricted to the HF, because chemotherapy can be associated with epidermal hyperpigmentation. 18 In mice, this enhanced pigmentation may result from CYP-induced proliferation and migration of the follicular melanocytes into the interfollicular epidermis.…”