Stéphane Commo

Human hair greying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath

Background  Although hair greying is a very common phenomenon characterized by loss of pigment in the hair shaft, the events that cause and control natural hair whitening with age in humans are still unclear.

Melanins and melanogenesis: from pigment cells to human health and technological applications

During the past decade, melanins and melanogenesis have attracted growing interest for a broad range of biomedical and technological applications. The burst of polydopamine‐based multifunctional coatings in materials science is just one example, and the list may be expanded to include melanin thin films for organic electronics and bioelectronics, drug delivery systems, functional nanoparticles and biointerfaces, sunscreens, environmental remediation devices. Despite considerable advances, applied research on melanins and melanogenesis is still far from being mature. A closer intersectoral interaction between research centers is essential to raise the interests and increase the awareness of the biomedical, biomaterials science and hi‐tech sectors of the manifold opportunities offered by pigment cells and related metabolic pathways. Starting from a survey of biological roles and functions, the present review aims at providing an interdisciplinary perspective of melanin pigments and related pathway with a view to showing how it is possible to translate current knowledge about physical and chemical properties and control mechanisms into new bioinspired solutions for biomedical, dermocosmetic, and technological applications.

Androgenetic alopecia and microinflammation

Today, androgenetic alopecia (AGA) is considered to be an alteration of hair growth and/or a premature aging of the pilosebaceous unit with a multifactorial and even polygenic etiology.1 The fact that the success rate of treatment with either antihypertensive agents, or modulators of androgen metabolism, barely exceeds 30% means that other pathways may be envisioned. The implication of various activators of inflammation in the etiology of AGA has progressively and recently emerged from several independent studies.2–11 A fibroplasia of the dermal sheath, which surrounds the hair follicle, is now suspected to be a common terminal process resulting in theminiaturization and involution of the pilosebaceous unit in AGA.2–8 We review here several observations underlining the possible implication of a slow, silent, and painless process in AGA. Because we think that it should not be confused with a classical inflammatory process, we have called it microinflammation. An early study referred to an inflammatory infiltrate of mononuclear cells and lymphocytes in about 50% of the scalp samples studied.2 Another more recent study by Jaworsky et al.3 confirmed an inflammatory infiltrate of activated T cells and macrophages in the upper third of the hair follicles from transitional regions of alopecia (i.e. which are characterized by actively progressing alopecia). This study also reported the occurrence of a developing fibrosis of the perifollicular sheath, together with the degranulation of follicular adventitial mast cells. The miniaturization of the hair follicles was found to be associated with a deposit of so-called ‘‘collagen or connective tissue streamers’’ beneath the follicle,2,7 as well as a 2–2.5 times enlargement of the follicular dermal sheath composed of densely packed collagen bundles.3 This thickening of the dermal sheath in progression zones of AGA has also recently been observed in our laboratory using immunohistochemical staining (Fig. 1). Horizontal section studies of scalp biopsies indicate that the so-called perifollicular fibrosis is generally mild, consisting of loose, concentric layers of fibrotic collagen that must be distinguished from cicatricial alopecia.4 It is unclear whether or not the fibrosis seen in follicular streamers (stelae or fibrous tracts) is permanent and/or alters the downgrowth of anagen hair follicles. Only 55% of male pattern AGA patients with microinflammation had hair regrowth in response to minoxidil treatment, which was less than the 77% of patients with no signs of inflammation,4 suggesting that, to some extent, perifollicular microinflammation may account for some cases of male pattern AGA which do not respond to minoxidil.4 Another study on 412 patients (193 men and 219 women) confirmed the presence of a significant degree of inflammation and fibrosis in at least 37% of AGA cases.5 The upper location of the infiltrate near the infrainfundibulum2–7 clearly distinguishes AGA from alopecia areata (AA), the latter disease being characterized by infiltrates in the bulb and dermal papilla zone.12 The aim of this review is to determine the location and chronology of the microinflammation process within the complex pathophysiology of the human pilosebaceous unit in order to improve the possible approaches for the reduction or prevention of the development of AGA.

TRP-2 specifically decreases WM35 cell sensitivity to oxidative stress.

TRP-2 (dopachrome tautomerase) is a melanogenic enzyme whose expression was recently reported to modulate melanocyte response to different cytotoxic events. Here we studied a possible role of TRP-2 in the oxidative stress response in the amelanotic WM35 melanoma cell line. Cell viability assays showed that TRP-2 overexpression in WM35 cells reduced their sensitivity to oxidative stress. Comet assays linked TRP-2 expression to DNA damage protection, and high-performance liquid chromotography-tandem mass spectrometry experiments showed an increase in intracellular glutathione in TRP-2-overexpressing cells. These effects were specifically reversed when TRP-2 was silenced by RNA interference. Nevertheless, these properties appeared to depend on a particular cell environment because expression of TRP-2 failed to rescue HEK epithelial cells exposed to similar treatments.

Age‐dependent changes in eumelanin composition in hairs of various ethnic origins

Hair pigmentation is one of the most conspicuous phenotypes of humans. From a chemical point of view, however, data remain scarce regarding human hair pigmentation characteristics. To determine melanin content and composition in human eumelanic hair from individuals of different ethnic origins and at different ages, we collected hair from 56 subjects with eumelanic hair from each group of African‐American, East Asian, and Caucasian origin. The 56 subjects consist of 14, seven each of males and females, each from four age classes of younger than 11, between 12 and 19, between 20 and 45, and older than 46. We analysed hair colour scale, total melanin value, and contents of pyrrole‐2,3,5‐tricarboxylic acid (PTCA) and pyrrole‐2,3‐dicarboxylic acid (PDCA). We measured age‐dependent increases in the relative quantity of eumelanin in pigmented human hairs in the three ethnic groups. Regarding melanin composition, we observed an increase in the PDCA/PTCA ratio with age in African‐American and Caucasian hairs until approaching the quite constant level of the ratio in East Asian hairs in the elderly individuals. Our results evidence differences in the content and composition of eumelanin in human hair among African‐American, Caucasian and East Asian individuals. Furthermore, we show evidence of age‐dependent changes in the quantity and quality of eumelanin in pigmented human hairs. In particular, the age‐dependent modification of the PDCA/PTCA ratio, a marker for 5,6‐dihydroxyindole units in eumelanin, suggests a chronological evolution of hair follicle melanocyte phenotype (e.g. decrease in dopachrome tautomerase expression).

Neutral pH and copper ions promote eumelanogenesis after the dopachrome stage.

The diversity of pigmentation in the skin, hair, and eyes of humans has been largely attributed to the diversity of pH in melanosomes with acidic pH being proposed to suppress melanin production. Tyrosinase has an optimum pH of 7.4 and its activity is suppressed greatly at lower pH values. The first step of eumelanogenesis is the oxidation of tyrosine to dopachrome (DC) via dopaquinone. However, how eumelanogenesis is controlled by pH beyond this stage is not known. In this study, we examined the effects of pH (5.3–7.3) on the conversion of DC to 5,6‐dihydroxyindole (DHI) and 5,6‐dihydroxyindole‐2‐carboxylic acid (DHICA) and the subsequent oxidation of DHI and DHICA to form eumelanin. The effects of Cu2+ ions on those reactions were also compared. The results indicate that an acidic pH greatly suppresses the late stages of eumelanogenesis and that Cu2+ ions accelerate the conversion of DC to DHICA and its subsequent oxidation.

TRP-2 expression protects HEK cells from dopamine- and hydroquinone-induced toxicity

We previously reported that melanogenic enzyme TRP-2 (or DCT for DOPAchrome tautomerase) expression in WM35 melanoma cells resulted in increased intracellular GSH levels, reduction in DNA damage induced by free radicals, and decreased cell sensitivity to oxidative stress. These effects seemed to depend on a particular cellular context, because none of them were found to occur in HEK epithelial cells. We postulated that the TRP-2 beneficial effect observed in WM35 cells in the oxidative stress situation may relate to quinone metabolization and, more precisely, to the ability of TRP-2 to clear off related toxic metabolites, resulting in a global redox status modification. Here, a comparative protein expression profiling of catecholamine biosynthesis enzymes and detoxification enzymes was conducted in WM35 melanoma cells and in HEK epithelial cells, in comparison with normal human melanocytes. Results showed that WM35 cells, but not HEK cells, expressed enzymes involved in catecholamine biosynthesis, suggesting that their quinone-related toxic metabolites were present in WM35 cells but not in HEK cells. To address the issue of a possible TRP-2 beneficial effect toward quinone toxicity, cell survival experiments were then conducted in HEK cells using dopamine and hydroquinone at toxic concentrations. We showed that TRP-2 expression significantly reduced HEK cell sensitivity to both compounds. This beneficial property of TRP-2 was likely to depend on the integrity of its DOPAchrome tautomerase catalytic site, because both TRP-2(R194Q) and TRP-2(H189G), which have lost their DOPAchrome tautomerase activity, failed to modify the HEK cell response to dopamine and hydroquinone. These results suggest that TRP-2 acts on quinone metabolites other than DOPAchrome, e.g., in the catecholamine pathway, and limits their deleterious effects.

Acid hydrolysis reveals a low but constant level of pheomelanin in human black to brown hair

We previously reported a constant ratio of the benzothiazole pheomelanin marker thiazole‐2,4,5‐tricarboxylic acid (TTCA) to the eumelanin marker pyrrole‐2,3,5‐tricarboxylic acid (PTCA) in eumelanic, black human hair. A constant level (20%–25%) of benzothiazole‐type pheomelanin was recently demonstrated in human skin with varying concentrations of melanin. Therefore, in this study, we aimed to investigate the origin of pheomelanin markers in black to brown human hair by developing a method to remove protein components from hair by heating with 6 M HCl at 110°C for 16 hr. For comparison, synthetic melanins were prepared by oxidizing mixtures of varying ratios of dopa and cysteine with tyrosinase. Hair melanins and synthetic melanins were subjected to acid hydrolysis followed by alkaline H2O2 oxidation. The results show that the hydrolysis leads to decarboxylation of the 5,6‐di‐hydroxyindole‐2‐carboxylic acid moiety in eumelanin and the benzothiazole moiety in pheomelanin and that eumelanic human hair contains 11%–17% benzothiazole‐type pheomelanin.

Polygonum multiflorum Radix extract protects human foreskin melanocytes from oxidative stress in vitro and potentiates hair follicle pigmentation ex vivo

To examine the ability of an extract from traditional Chinese medicine, Polygonum multiflorum Radix, to protect melanocyte viability from oxidative stress, a key mechanism in the initiation and progression of hair greying.