Shigeki Inui

Androgen-inducible TGF-β1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth

We attempted establishing an in vitro coculture system by using human dermal papilla cells (DPCs) from androgenetic alopecia (AGA) and keratinocytes (KCs) to explore the role of androgens in hair growth regulation. Androgen showed no significant effect on the growth of KCs when they were cocultured with DPCs from AGA. Because the expressions of mRNA of androgen receptor (AR) decreased during subcultivation of DPCs in vitro, we transiently transfected the AR expression vector into the DPCs and cocultured them with KCs. In this modified coculture, androgen significantly suppressed the growth of KCs by ~50%, indicating that overexpression of AR can restore the responsiveness of the DPCs to androgen in vivo. We found that androgen stimulated the expression of TGF‐β1 mRNA in the cocultured DPCs. ELISA assays demonstrated that androgen treatment increased the secretion of both total and active TGF‐β1 in the conditioned medium. Moreover, the neutralizing anti‐TGF‐β1 antibody reversed the androgen‐elicited growth inhibition of KCs in a dose‐dependent manner. These findings suggest that androgen‐inducible TGF‐β1 derived from DPCs of AGA is involved in epithelial cell growth suppression in our coculture system, providing the clue to understand the paradoxical effects of androgens for human hair growth.

Clinical significance of dermoscopy in alopecia areata: analysis of 300 cases.

Objective  To determine dermoscopic findings of alopecia areata (AA) from a large‐scale study that can be used as clinical indicators of disease.

Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia1

The gene encoding a transmembrane glycoprotein LIG‐1, of which the extracellular region was organized with the leucine‐rich repeats and immunoglobulin‐like domains, was disrupted in mice by gene targeting. LIG‐1‐deficient mice developed a skin change on the tail and facial area after birth. The affected skin was histologically reminiscent of the epidermis in human common skin disease ‘psoriasis’. LIG‐1 was expressed in basal cells of the epidermis and outer root sheath cells of hair follicles in mice. Interestingly, the LIG‐1 expression was apparently down‐regulated in the psoriatic lesions, suggesting that LIG‐1 inversely correlates with proliferative ability of epidermal keratinocytes.

Molecular basis of androgenetic alopecia: From androgen to paracrine mediators through dermal papilla

Androgenetic alopecia (AGA) is characterized by vellus transformation of scalp hairs, corresponding to hair follicle miniaturization during repeated hair cycles with shortened anagen phase. This phenomenon is mediated mainly by androgen. Then, the multi-step molecular pathway of androgen can be involved in the pathogenesis of AGA. The expression of type II 5α-reductase is higher in dermal papilla cells from AGA and beard than those from other sites. On the other hand, type I 5α-reductase expression is relatively low. Next, hormone binding assays and RT-PCR demonstrated that androgen receptor (AR) expression is significantly higher in bald dermal papilla cells than non-bald cells. Additionally, AR coactivator Hic-5/ARA55 is highly expressed in dermal papilla cells of hair follicles from androgen-sensitive sites such as AGA and beard. Collectively, the enhanced expression of type II 5α-reductase, AR and Hic-5/ARA55 can upregulate sensitivity to androgen of dermal papilla cells in AGA. Furthermore, in the coculture of AR-overexpressing human dermal papilla cells from AGA and normal human keratinocytes, R1881 suppresses keratinocyte growth through androgen-inducible TGF-β1, indicating that TGF-β1 is one of the key players in pathogenesis of AGA. TGF-β2 and DKK-1 has been reported to be androgen-induced suppressor of growth of follicular epithelial cells. We expect that more pathogenic mediators will be identified in the future, enabling easier understanding of AGA pathogenesis and providing new therapeutic targets from aspect of andrology.

Possible role of coexpression of CD9 with membrane-anchored heparin-binding EGF-like growth factor and amphiregulin in cultured human keratinocyte growth.

CD9 is a protein with 4 transmembrane domains, and functions as a cell surface antigen. We have previously reported that CD9 functions as an up‐regulator of membrane‐anchored heparin‐binding EGF‐like growth factor (proHB‐EGF) activity, which is a potent mitogen as well as a soluble HB‐EGF. Anti‐CD9 antibodies can neutralize the juxtacrine activity of proHB‐EGF when both CD9 and proHB‐EGF are coexpressed. We demonstrated here: (1) the CD9 gene was transcribed and translated in the cultured human keratinocytes; (2) anti‐CD9 antibody inhibited the approximately 50% growth of human keratinocytes in culture; (3) CD9 was coprecipitated with proHB‐EGF and membrane‐anchored amphiregulin (proAR), and (4) the transient coexpression of CD9 with proHB‐EGF or proAR in mouse L cells up‐regulated their juxtacrine growth factor activities. These results suggest that CD9 would make a heterodimer and/or trimer complex with proHB‐EGF and proAR, and might cooperate with proHB‐EGF and proAR for human keratinocyte growth in a juxtacrine manner. J. Cell. Physiol. 171:291–298, 1997.

Dermoscopic findings in frontal fibrosing alopecia: report of four cases

Background  Frontal fibrosing alopecia (FFA) is characterized by frontotemporal hair recession and eyebrow loss and by a histopathology identical to lichen planopilaris. Differential diagnosis from other types of alopecia, including alopecia areata (AA), is necessary in some cases.

Trichoscopy for common hair loss diseases: Algorithmic method for diagnosis

In recent years, the usefulness of trichoscopy (scalp dermoscopy) has been reported for hair loss diseases. Here, characteristic trichoscopic features of common hair loss diseases are described using a DermLite II pro or Epilight eight. Characteristic trichoscopic features of alopecia areata are black dots, tapering hairs (exclamation mark hairs), broken hairs, yellow dots and short vellus hairs. In androgenetic alopecia (AGA), hair diameter diversity (HDD), perifollicular pigmentation/peripilar sign and yellow dots are trichoscopically observed. In all cases of AGA and female AGA, HDD more than 20%, which corresponds to vellus transformation, can be seen. In cicatricial alopecia (CA), the loss of orifices, a hallmark of CA, and the associated changes including perifollicular erythema or scale and hair tufting were observed. Finally, an algorithmic method for trichoscopic diagnosing is proposed.

Pulse corticosteroid therapy for alopecia areata: study of 139 patients.

Background/Aim: Recent reports of pulse corticosteroid therapy for alopecia areata (AA) show its efficacy for patients with a history of ≤1 year but not for recalcitrant cases or alopecia totalis/universalis. The purpose of this study was to evaluate the efficacy and safety of pulse corticosteroid therapy for recent-onset AA patients. Method: A total of 139 severe AA patients aged >15 years were included in this study. The duration from the onset of active hair loss was within 12 months for 125 (89.9%) of those patients. Results: Of the patients, 72.7% had hair loss on >50% of their scalp area. Among the recent-onset group (duration of AA ≤6 months), 59.4% were good responders (>75% regrowth of alopecia lesions), while 15.8% with >6 months duration showed a good response. Recent-onset AA patients with less severe disease (≤50% hair loss) responded at a rate of 88.0%, but only 21.4% of recent-onset patients with 100% hair loss responded. No serious adverse effects were observed.

What causes alopecia areata

The pathobiology of alopecia areata (AA), one of the most frequent autoimmune diseases and a major unsolved clinical problem, has intrigued dermatologists, hair biologists and immunologists for decades. Simultaneously, both affected patients and the physicians who take care of them are increasingly frustrated that there is still no fully satisfactory treatment. Much of this frustration results from the fact that the pathobiology of AA remains unclear, and no single AA pathogenesis concept can claim to be universally accepted. In fact, some investigators still harbour doubts whether this even is an autoimmune disease, and the relative importance of CD8+ T cells, CD4+ T cells and NKGD2+ NK or NKT cells and the exact role of genetic factors in AA pathogenesis remain bones of contention. Also, is AA one disease, a spectrum of distinct disease entities or only a response pattern of normal hair follicles to immunologically mediated damage? During the past decade, substantial progress has been made in basic AA‐related research, in the development of new models for translationally relevant AA research and in the identification of new therapeutic agents and targets for future AA management. This calls for a re‐evaluation and public debate of currently prevalent AA pathobiology concepts. The present Controversies feature takes on this challenge, hoping to attract more skin biologists, immunologists and professional autoimmunity experts to this biologically fascinating and clinically important model disease.

Androgen actions on the human hair follicle: perspectives

Androgens stimulate beard growth but suppress hair growth in androgenetic alopecia (AGA). This condition is known as ‘androgen paradox’. Human pilosebaceous units possess enough enzymes to form the active androgens testosterone and dihydrotestosterone. In hair follicles, 5α‐reductase type 1 and 2, androgen receptors (AR) and AR coactivators can regulate androgen sensitivity of dermal papillae (DP). To regulate hair growth, androgens stimulate production of IGF‐1 as positive mediators from beard DP cells and of TGF‐β1, TGF‐β2, dickkopf1 and IL‐6 as negative mediators from balding DP cells. In addition, androgens enhance inducible nitric oxide synthase from occipital DP cells and stem cell factor for positive regulation of hair growth in beard and negative regulation of balding DP cells. Moreover, AGA involves crosstalk between androgen and Wnt/β‐catenin signalling. Finally, recent data on susceptibility genes have provided us with the impetus to investigate the molecular pathogenesis of AGA.