Jean-François Michelet

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.

Prostaglandin metabolism in human hair follicle

Abstract:  Prostaglandins regulate a wide number of physiological functions. Recently PGF2α analogue such as latanoprost was shown to have a real impact on hair regrowth. The aim of this study was to investigate and describe the expression profile in human hair follicle of prostaglandin metabolism key enzymes, i.e. carbonyl reductase‐1 (CBR1), microsomal prostaglandin E synthase‐1 (mPGES‐1) and microsomal prostaglandin E synthase‐2 (mPGES‐2), cytosolic prostaglandin E synthase (cPGES), the aldoketoreductase AKR1C1 and the prostaglandin F synthase AKR1C3. Quantitative RT‐PCR on plucked hair follicles revealed some sex‐related differences, mPGES‐2 and AKR1C3 expression levels being higher in women. Cell and hair follicle compartment specificity was investigated using Western blot, PGE2 and PGF2α ELISA assays and immunohistochemistry. Most of the hair cell types were endowed with prostaglandin metabolism machinery and were thus able to produce PGE2 and/or PGF2α. The epithelial part of the hair bulb was identified by immunohistology and EIA assays as the main source of prostaglandin synthesis and interconversion. All these observations support the concept that prostaglandins might be involved in hair growth and differentiation control.

Prostanoid receptors in anagen human hair follicles

Abstract:  Prostanoid pathway in hair follicle gained closer attention since trichogenic side‐effects on hair growth has been observed concomitantly with prostaglandin F2α receptor (FP) agonist treatment of intraocular pressure. We thus investigated prostanoid receptor distribution in anagen hair follicle and different cell types from hair and skin. Using RT‐PCR, Western blot and immunohistochemistry (IHC), we found that all receptors were present in hair follicle. This data shed new light on an underestimated complex network involved in hair growth control. Indeed most of these receptors showed a wide spectrum of expression in cultured cells and the whole hair follicle. Using IHC, we observed that expression of prostaglandin E2 receptors (EP2, EP3, EP4), prostaglandin D2 receptor (DP2), prostanoid thromboxane A2 receptor (TP) and to a lesser extent EP1 involved several hair follicle compartments. On the opposite, Prostaglandin I2 receptor (IP) and DP1 were more specifically expressed in hair cuticle layer and outer root sheath (ORS) basal layer, respectively. FP expression was essentially restricted to ORS companion layer and dermal papilla (DP). Although extracting a clear functional significance from this intricate network remains open challenge, FP labelling, i.e. could explain the biological effect of PGF2α on hair regrowth, by directly modulating DP function.

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.

Pro-Inflammatory Cytokine Cascade in Human Plucked Hair

Using reverse transcriptase polymerase chain reaction we showed that freshly plucked human anagen hair expressed both type 1 (80 kD) and type 2 (60 kD) interleukin (IL)-1 receptor mRNAs. The IL-1 rece

In vitro and in vivo studies with tetra-hydro-jasmonic acid (LR2412) reveal its potential to correct signs of skin ageing.

LR2412, a synthetic derivative of jasmonic acid, improved the reconstruction and homeostasis of our organotypic skin models.

Human hair follicle pigmentary unit as a direct target for modulators of melanogenesis, as studied by [14C]‐2‐Thiouracil incorporation

Abstract:  The purpose of this study was to evaluate human hair follicle melanogenic activity using the [14C]‐2‐thiouracil, which was known to incorporate into nascent melanins. Results obtained on pigmented, grey and non‐pigmented hair follicles demonstrated that [14C]‐2‐TU incorporation was restricted to the melanogenic compartment with a strong accumulation located around dermal papilla and within the fibre of pigmented hair follicles. Quantitative analysis of [14C]‐2‐TU incorporation showed a significant increase in pigmented hair follicles upon stimulation with 1 μm forskolin concomitant to an increase in tyrosinase levels. A strong significant decrease in [14C]‐2‐TU incorporation was noted, when hair follicles were incubated with the tyrosinase competitive inhibitor kojic acid (200 μm). Incubation with the MC1‐R agonist α‐MSH (0.2 μm) did not induce a significant stimulation of hair melanogenesis. The present model could thus represent a useful new tool to identify modulators of human hair pigmentation.

A jasmonic acid derivative improves skin healing and induces changes in proteoglycan expression and glycosaminoglycan structure

BACKGROUND Jasmonates are plant hormones that exhibit anti-cancer and anti-inflammatory properties and have therefore raised interest for human health applications. The molecular basis of these activities remains poorly understood, although increasing evidence suggests that a variety of mechanisms may be involved. Recently, we have reported that a jasmonate derivative (JAD) displayed anti-aging effects on human skin by inducing extracellular matrix (ECM) remodeling. Based on this observation, we have investigated here the effects of JAD on proteoglycans and glycosaminoglycan (GAG) polysaccharides, which are major cell-surface/ECM components and are involved in a multitude of biological processes. In parallel, we have examined the ability of JAD to promote growth factor activities and improve skin wound healing. METHODS Proteoglycan expression was analyzed on epidermal primary keratinocytes and reconstituted skin epidermis, using electron/immunofluorescence microscopy, western blotting and flow cytometry. GAG composition was determined by disaccharide analysis. Finally, biological activities of JAD were assessed in cellulo, in FGF-7 induced migration/proliferation assays, as well as in vivo, using a suction blister model performed on 24 healthy volunteers. RESULTS JAD was found to induce expression of major skin proteoglycans and to induce subtle changes in GAG structure. In parallel, we showed that JAD promoted FGF-7 and improved skin healing by accelerating epithelial repair in vivo. CONCLUSION This study highlights JAD as a promising compound for investigating GAG structure-function relationships and for applications in skin cosmetic /corrective strategies. GENERAL SIGNIFICANCE We propose here a novel mechanism, by which jasmonate derivatives may elicit biological activities in mammals.

6-O glucose linoleate supports in vitro human hair growth and lipid synthesis

The hair follicle is a very active organ with a complex structure, which produces a hair fibre at a rate of 0.3 mm a day. Accordingly, the hair follicle is highly demanding in energy source, as the hair bulb matrix cells are endowed with one of the highest rates of proliferation in the human body. Moreover, recent data have shown the involvement of lipids in hair follicle function. As in vitro‐grown hair follicle keeps producing a hair fibre that closely resembles the natural hair fibre, we decided to use this model to investigate the role of a new of glucose linoleate derivative (6‐O‐linoleyl‐d‐glucose: 6‐O‐GL) as a lipid precursor and energy provider. Our results demonstrated that 6‐O‐GL was (i) quite stable and surprisingly resistant to oxidative degradation, and (ii) readily taken up and metabolized by the hair follicle into various lipids, namely neutral lipids, ceramides and polar lipids. Moreover, it supported hair follicle growth and survival in a glucose‐ and linoleic‐acid free medium. 6‐O‐GL thus appeared to be a bi‐functional nutrient, ensuring both proper fibre quality and production by the hair follicle.

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.