Distinct types of stem cell divisions determine organ regeneration and aging in hair follicles.

Hair follicles, mammalian mini-organs that grow hair, miniaturize during aging, leading to hair thinning and loss. Here we report that hair follicle stem cells (HFSCs) lose their regenerative capabilities during aging owing to the adoption of an atypical cell division program. Cell fate tracing and cell division axis analyses revealed that while HFSCs in young mice undergo typical symmetric and asymmetric cell divisions to regenerate hair follicles, upon aging or stress, they adopt an atypical 'stress-responsive' type of asymmetric cell division. This type of division is accompanied by the destabilization of hemidesmosomal protein COL17A1 and cell polarity protein aPKCλ and generates terminally differentiating epidermal cells instead of regenerating the hair follicle niche. With the repetition of these atypical divisions, HFSCs detach from the basal membrane causing their exhaustion, elimination and organ aging. The experimentally induced stabilization of COL17A1 rescued organ homeostasis through aPKCλ stabilization. These results demonstrate that distinct stem cell division programs may govern tissue and organ aging.

Precision Medicine and the Practice of Trichiatry: Adapting the Concept.

Evidence-based medicine (EBM) aims for the ideal that healthcare professionals make conscientious, explicit, and judicious use of the best available evidence gained from the scientific method to clinical decision-making. It seeks to assess the strength of the evidence for benefits of diagnostic tests and treatments, using techniques from science, engineering, and statistics, such as the systematic review of medical literature, meta-analysis, risk-benefit analysis, and randomized controlled trials. The limited success rate of EBM therapies suggests that the complex nature of hair loss may be inadequately served by the present levels of evidence, and that physicians treating hair loss may have fallen short of adequately researching a robust evidence to underpin their practices. Against this backdrop, the concept of precision medicine (PM) is evolving. PM refers to the customization of medical care to the patient's individual characteristics based on the patient's genetic background and other molecular or cellular analysis, while classifying patients into subpopulations that differ in their susceptibility to a particular medical condition, in the biology or prognosis of those medical conditions, or in their response to a specific treatment. With the advances in hair research, the powerful tools of molecular biology and genetics, and innovative technologies, we have the robust scientific data and tools to adapt the concept of PM to the practice of trichiatry. Finally, databases pertaining to the development and efficacy of PM must be analyzed and be used to form the basis of evidence-based personalized trichiatry.

Trichologist, Dermatotrichologist, or Trichiatrist? A Global Perspective on a Strictly Medical Discipline.

Few dermatologic problems carry as much emotional overtones as the complaint of hair loss. The best way to alleviate the distress related to hair loss is to effectively treat it. In fact, one of the oldest medical professions is the Egyptian physician who specialized on diseases of the head. And yet, from ancient Egypt down to modern times, human hair has been the object of superstition and mystery. Remarkably and despite the genuine advances in effective medical treatments, hair cosmetics, and surgical procedures, phony hair loss solutions continue to be marketed with an amazing success. In 1860, a quasi-scientific interest in hair loss and hair care originated in a London barbershop and became known as trichology, with the Institute of Trichologists being founded. Other corporations successively followed internationally, but it was only in 2010 that the term dermatotrichologist was proposed for board-certified dermatologists dealing with the scientific study of the hair and scalp, in contrast to the trichologist who is rather associated with laity and cosmetics than with medical professionalism, or - worse - offers opportunities to possible imposters with a primary commercial interest. The new term "trichiatrist" is proposed, literally meaning the "medical treatment of the hair," to designate the strictly medical professional dealing with the hair and scalp in health and disease. Trichiatrists differ from trichologists by virtue of being physicians. The quality and stringency of their graduate medical training is identical to that of other physicians.

Guidelines for the diagnosis and treatment of male-pattern and female-pattern hair loss, 2017 version.

Male-pattern hair loss (MPHL, androgenetic alopecia) is a slowly progressive form of alopecia which begins after puberty. In 2010, we published the first Japanese edition of guidelines for the diagnosis and treatment of MPHL. It achieved the original goal of providing physicians and patients in Japan with evidence-based information for choosing efficacious and safe therapy for MPHL. Subsequently, new therapeutic drugs and treatment methods have been developed, and women's perception of MPHL has undergone change and the term "female-pattern hair loss (FPHL)" is becoming more common internationally. Thus, here we report a revised version of the 2010 guidelines aimed at both MPHL and FPHL. In these guidelines, finasteride 1 mg daily, dutasteride 0.5 mg daily and topical 5% minoxidil twice daily for MPHL, and topical 1% minoxidil twice daily for FPHL, are recommended as the first-line treatments. Self-hair transplantation, irradiation by light-emitting diodes and low-level lasers, and topical application of adenosine for MPHL are recommended, whereas prosthetic hair transplantation and oral administration of minoxidil should not be performed. Oral administration of finasteride or dutasteride are contraindicated for FPHL. In addition, we have evaluated the effectiveness of topical application of carpronium chloride, t-flavanone, cytopurine, pentadecane and ketoconazole, and wearing a wig. Unapproved topical application of bimatoprost and latanoprost, and emerging hair regeneration treatments have also been addressed. We believe that the revised guidelines will improve further the diagnostic and treatment standards for MPHL add FPHL in Japan.

Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis.

Hair thinning and loss are prominent aging phenotypes but have an unknown mechanism. We show that hair follicle stem cell (HFSC) aging causes the stepwise miniaturization of hair follicles and eventual hair loss in wild-type mice and in humans. In vivo fate analysis of HFSCs revealed that the DNA damage response in HFSCs causes proteolysis of type XVII collagen (COL17A1/BP180), a critical molecule for HFSC maintenance, to trigger HFSC aging, characterized by the loss of stemness signatures and by epidermal commitment. Aged HFSCs are cyclically eliminated from the skin through terminal epidermal differentiation, thereby causing hair follicle miniaturization. The aging process can be recapitulated by Col17a1 deficiency and prevented by the forced maintenance of COL17A1 in HFSCs, demonstrating that COL17A1 in HFSCs orchestrates the stem cell-centric aging program of the epithelial mini-organ.

HSL Attenuates the Follicular Oxidative Stress and Enhances the Hair Growth in ob/ob Mice.

SUMMARY: We demonstrated enhanced hair regeneration following topical administration of N-(3-oxododecanoyl)-l-homoserine lactone (HSL) in ob/ob mice. The ob/ob mice showed delayed hair regeneration (more than 6 wk) after depilation, which rapidly induced transition to anagen in the hair cycle in wild-type mice. Vehicle and HSL solutions were applied to the depilated dorsal skin of ob/ob mice. The depilated skin of the HSL-treated mice was fully covered with hair, whereas no macroscopic alteration was observed in vehicle-treated group by the fourth week after depilation. Oxidative stress was drastically decreased and the expression of the antioxidative enzymes PON1 and PON3 was increased in the HSL-treated skin with highly proliferative anagen follicles. These results suggest that HSL is a candidate therapeutic agent for alopecia in metabolic syndrome.

Polymorphic CAG repeat numbers in the androgen receptor gene of female pattern hair loss patients.

Female pattern hair loss (FPHL) is frequently referred to as female androgenetic alopecia (FAGA). However, the role of androgen in this type of hair loss remains uncertain. We previously reported greater therapeutic efficacy of finasteride in Japanese male androgenetic alopecia (MAGA) patients in cases where the CAG repeats of the androgen receptor (AR) gene were short. To examine the correlation between CAG repeat numbers and the therapeutic efficacy of finasteride in FPHL patients, the efficacy of finasteride (1 mg/day) was evaluated macroscopically. Because women have two X-chromosomes, the shorter and longer CAG repeat numbers were analyzed in 37 Japanese FPHL patients, then the correlation of these factors was statistically analyzed by anova. No statistical significance in terms of the differences in CAG repeat numbers was detected among the four groups classified on the basis of the efficacy of finasteride. From these results, it may be concluded that the efficacy of this medicine in each FPHL patient cannot be predicted by the CAG repeat numbers in the AR gene.

Androgen receptor co-activator Hic-5/ARA55 as a molecular regulator of androgen sensitivity in dermal papilla cells of human hair follicles.

Androgen site-specifically affects human hair growth after puberty through androgen receptors in the dermal papilla, which transactivate target genes acting in conjunction with co-activators. To examine the regulation of androgen sensitivity in hair follicles, we focused on androgen receptor co-activator Hic-5/ARA55. Its interaction with transfected androgen receptor in beard dermal papilla cells was confirmed with mammalian two-hybrid assays. The semiquantitative reverse transcriptase-polymerase chain reaction showed that Hic-5/ARA55 mRNA expression was high in dermal papilla cells from the beard and bald frontal scalp but low in cells from the occipital scalp. To determine whether Hic-5/ARA55 mRNA level correlates with its endogenous activity, we studied the effect of dominant negative Hic-5/ARA55 on transfected androgen receptor transactivation induced by R1881 using mouse mammary tumor virus-luciferase assays. We found that it suppressed the transactivation by 64.5 and 71.4% in dermal papilla cells from the beard and bald frontal scalp, respectively, whereas it showed no significant effect in cells from the occipital scalp. Our findings suggest that Hic-5/ARA55 is a molecular regulator for androgen sensitivity in human hair follicles.