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Activation of the WNT/β-catenin pathway has emerged as a potential therapeutic target in androgenetic alopecia (AGA). Methyl vanillate (MV) - a safe plant-derived ingredient - has been recently shown to activate the WNT/β-catenin signaling. Objectives Two distinct substudies were conducted. First, we designed a 6-month, uncontrolled, open-label clinical study to investigate whether topically applied MV may increase hair count and hair mass index (HMI) in female AGA. Second, we conducted a molecular study on the effect of MV on WNT10B mRNA expression in scalp biopsies of women with AGA.
A total of 20 Caucasian women (age range: 25-57 years) with AGA (Sinclair grade 1-2) were included. The research product was an alcohol-free formulation supplied in the form of a spray containing 0.2% MV as the active ingredient.
In the clinical study, hair count and HMI were found to increase at 6 months by 6% (P < 0.01) and 12% (P < 0.001), respectively, compared with baseline. No participant discontinued treatment due to adverse effects, and the overall patient satisfaction was good. At the molecular level, the topical application of the research product resulted in a 32% increase in WNT10B mRNA expression levels in the temporal scalp area (P < 0.001).
Our pilot data suggest that topical MV can increase hair count and HMI by inducing WNT10B expression in the scalp, potentially serving as a novel treatment strategy for female AGA.
To read the full-text of this research, you can request a copy directly from the authors.
... Low-level laser therapy (LLLT) also seems to improve hair regrowth in the conditions of AGA, AA, and chemotherapy-induced alopecia . There are studies demonstrating the positive effects of natural bioactive compounds on AGA [24,30,52,55,56,58,. A recently published study demonstrates that a 5-mer peptide (GLYYF; P5) has the potential to promote hair growth when topically applied . ...
... Hence, 23 the predicted target genes largely overlap. Nevertheless, miR-29s exhibit different regula- 24 tions, and thus, their functions may be different from each other . These miRNAs 25 accommodate diverse functions. ...
Androgenetic alopecia (AGA) remains an unsolved problem for the well-being of humankind, although multiple important involvements in hair growth have been discovered. Up until now, there is no ideal therapy in clinical practice in terms of efficacy and safety. Ultimately, there is a strong need for developing a feasible remedy for preventing and treating AGA. The Wnt/β-catenin signaling pathway is critical in hair restoration. Thus, AGA treatment via modulating this pathway is rational, although challenging. Dickkopf-related protein 1 (DKK1) is distinctly identified as an inhibitor of canonical Wnt/β-catenin signaling. Thus, in order to stimulate the Wnt/β-catenin signaling pathway, inhibition of DKK1 is greatly demanding. Studying DKK1-targeting microRNAs (miRNAs) involved in the Wnt/β-catenin signaling pathway may lay the groundwork for the promotion of hair growth. Bearing in mind that DKK1 inhibition in the balding scalp of AGA certainly makes sense, this review sheds light on the perspectives of miRNA-mediated hair growth for treating AGA via regulating DKK1 and, eventually, modulating Wnt/β-catenin signaling. Consequently, certain miRNAs regulating the Wnt/β-catenin signaling pathway via DKK1 inhibition might represent attractive candidates for further studies focusing on promoting hair growth and AGA therapy.
... 159 Previous studies show increased human hair growth with valproic acid 160,161 and, another Wnt/b-catenin activator, methyl vanillate. 162 Low-level laser therapy also has been shown to stimulate hair growth by activating Wnt/b-catenin signalling. 163,164 Thus, activation of the WNT/b-catenin pathway appears a promising potential therapeutic target in AGA. ...
... Among the most exciting developments in AA treatment are Janus kinase (JAK) inhibitors, a class of drugs that specifically target the enzymes inside hair follicles that maintain their dormant state in AA. 208 JAK kinase inhibitors are believed to directly stimulate follicle regeneration, promoting anagen progression follicles out of the telogen phase back into active growth. 162 Numerous studies have recently been reported with oral tofacitinib, oral baricitinib and oral ruxolitinib in AA.  Hair regrowth of 40-60% has been reported with these drugs, which have already been approved for other indications. Topical formulations of JAK inhibitors have been under investigation in AA to avoid the AEs reported with systemic JAK inhibitors such as infections, viral reactivation, bone marrow disruption, transaminase and lipid changes. ...
For many decades and until recently, medical approach to dermatologic diseases has been based on the physician's ability to recognize and treat symptoms. Nowadays, advances in the understanding of the biology of diseases and in technologies for intervening against them have allowed physicians to diagnose and treat underlying disease processes rather than simply addressing the symptoms. This means that rather than addressing ‘the disease in humans’, physicians can now address the particular pathologic (biologic, molecular) disturbance as it presents in the individual patient, i.e., physicians now can practice something much closer to ‘personalized medicine’, leading to greater benefits for the patients and the health of society in general. The deeper understanding of ultraviolet radiation, the importance of photoprotection and increased knowledge about signalling pathways of melanoma and carcinoma have led to more complete care for the dermatologic patient. The current popularity for excessive exposure to the sun, without adequate application of the appropriate photoprotection remedies, is the origin of melanoma, but also for the weakening of the structure and functions of the skin. Indeed, fragility of the skin can affect humans around the world. In the senior population, this skin fragility is accompanied by pruritus, whereas atopic dermatitis is an inflammatory disease with highest prevalence in children and adolescents. Acne, the number one reason for dermatologic consultations worldwide, increases its prevalence in adolescents and in females. Senescent alopecia affects humans after menopause and andropause. The articles in this publication present an overview of the current advanced understanding of the diagnosis and therapeutic approaches in 6 fields of dermatology – dermatopaediatry and gerontodermatology, oncodermatology, hair loss, atopic dermatitis, photoprotection and acne – and thereby serve as a useful compendium of updated information and references for all healthcare professionals who see patients with presentations of the symptoms of these diseases.
... Vanillic acid, a phenolic acid, is a major component of wheat bran, which has been reported to exhibit anti-oxidative and hepatoprotective activity (Itoh et al., 2009;Amin et al., 2017). In patients with AGA, methyl vanillate with a structure similar to that of vanillic acid could promote hair growth by activating the Wnt/β-catenin pathway (Tosti et al., 2016). However, biological activity of vanillic acid in DPCs has not been investigated. ...
The hair cycle (anagen, catagen, and telogen) is regulated by the interaction between mesenchymal cells and epithelial cells in the hair follicles. The proliferation of dermal papilla cells (DPCs), mesenchymal-derived fibroblasts, has emerged as a target for the regulation of the hair cycle. Here, we show that vanillic acid, a phenolic acid from wheat bran, promotes the proliferation of DPCs via a PI3K/Akt/Wnt/β-catenin dependent mechanism. Vanillic acid promoted the proliferation of DPCs, accompanied by increased levels of cell-cycle proteins cyclin D1, CDK6, and Cdc2 p34. Vanillic acid also increased the levels of phospho(ser473)-Akt, phospho(ser780)-pRB, and phospho(thr37/46)-4EBP1 in a time-dependent manner. Wortmannin, an inhibitor of the PI3K/Akt pathway, attenuated the vanillic acid-mediated proliferation of DPCs. Vanillic acid-induced progression of the cell-cycle was also suppressed by wortmannin. Moreover, vanillic acid increased the levels of Wnt/β-catenin proteins, such as phospho(ser9)-glycogen synthase kinase-3β (GSK-3β), phospho(ser552)-β-catenin, and phospho(ser675)-β-catenin. We found that vanillic acid increased the levels of cyclin D1 and Cox-2, which are target genes of β-catenin, and these changes were inhibited by wortmannin. To investigate whether vanillic acid affects the downregulation of β-catenin by dihydrotestosterone (DHT), implicated in the development of androgenetic alopecia, DPCs were stimulated with DHT in the presence and absence of vanillic acid for 24 h. Western blotting and confocal microscopy analyses showed that the decreased level of β-catenin after the incubation with DHT was reversed by vanillic acid. These results suggest that vanillic acid could stimulate anagen and alleviate hair loss by activating the PI3K/Akt and Wnt/β-catenin pathways in DPCs.
... The deciphering of the pathogenesis of atrichia with papular lesions (MIM209500) and of hypotrichosis simplex of scalp type 1 (MIM 607479) remarkably illustrates this paradigm as it has demonstrated in a clinical setting the importance of WNT signaling for normal hair development, 5,34 which in turn has formed the basis for pilot studies of novel hair growth-promoting therapies. 35,36 Similarly, the identification of pathogenic variants in LIPH 8 and LPAR6 13 in multiple families with LAH has demarcated a new biological pathway ultimately leading to the biosynthesis of LPA 14,15 (which may possibly intersect with the WNT/βcatenin signaling pathway 16 ) and critical for the maintenance of hair growth. 37 The present study attributes to C3ORF52, a protein to date without a known function, a pivotal role in this pathway as C3ORF52 seems to be necessary for normal LPA biosynthesis (Fig. 5). ...
Localized autosomal recessive hypotrichosis (LAH) has been associated with pathogenic variants in DSG4, encoding a desmosomal protein as well as in LIPH and LPAR6, encoding respectively lipase H, which catalyzes the formation of 2-acyl-lysophosphatidic acid (LPA), and lysophosphatidic acid receptor 6, a receptor for LPA. LPA promotes hair growth and differentiation. In this study we aimed at delineating the genetic basis of LAH in patients without pathogenic variants in these three genes.
Variant analysis was conducted using exome and direct sequencing. We then performed quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunofluorescence staining, immunoblotting, enzymatic, and coimmunoprecipitation assays to evaluate the consequences of potential etiologic variants.
We identified homozygous variants in C3ORF52 in four individuals with LAH. C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The LAH-causing variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H–mediated LPA biosynthesis.
LAH can be caused by abnormal function of at least three proteins which are necessary for proper LPA biosynthesis.
... ingredient is a suspected Wnt-activator given the concomitant 32% increase in Wnt10B expression in the temporal scalp . Treatment of mice with amniotic membrane has similarly shown up regulation of anagen stimulatory signals, specifically, increased FGF7 and proliferating cell nuclear antigen. ...
Aiging is a natural part of life. Hair follicles age over time, which can lead to loss of hair follicles. This paper reviews the WNT/b-catenin pathway and the BMP Pathway to drive hair follicles from telogen the anagen. Minimizing time in the telogen phase helps to reduce the inflamatory phase that has a negative effect on stem cells necessary to initiate a new hair cycle. Medical treatments to combat hair loss are discussed and reviewed.
... 38 Likewise, methyl vanillate treatment resulted in a 6% increase in hair count and 12% increase in hair mass index. 39 The same is true for comparisons of this study against our previous efficacy trial of SO extract, where participants were also from a different ethnic background (Japanese). Nevertheless, an improvement in shed hair after MTP3 treatment was evident compared to our previous trial of FGF5-inhibiting SO extract: 80% reduction in hair fall at day 112 for the MTP3-treated groups vs. 68% at 4 months. ...
There are very few effective, scientifically validated treatments with known mechanisms of action for treatment of hair loss in both men and women. Fibroblast growth factor 5 (FGF5) is an important factor in the irreversible transition from anagen to catagen, and inhibition of FGF5 prolongs anagen phase and reduces hair loss.
We aimed to screen botanically derived molecules for FGF5 inhibitory activity in vitro and assess efficacy in a clinical setting.
We screened for FGF5 inhibitory efficacy via a novel 2-step in vitro pipeline consisting of an engineered FGF5 responsive cell line, followed by an activated dermal papillae (DP) cell method. Efficacy in a clinical setting was assessed in a randomized, single-blind, placebo-controlled trial against early- to mid-stage pattern hair loss in men and women.
We observed FGF5 inhibitory activity for a number of compounds from the monoterpenoid family, many showing greater inhibitory efficacy than our previously reported crude plant extracts. Evaluation of a lead candidate in a clinical study over 112 days showed a significant improvement in anagen:telogen (AT) ratio (p = 0.002), reduced hair fall (p = 0.007) and improved visual grading (p = 0.004). Scientifically matched photography on a subgroup of randomly chosen participants highlighted significant improvement in hair density, with increases evident in all tested participants compared to baseline.
Isolates from the monoterpenoid family displayed efficacy in FGF5 inhibition in vitro. A topical formulation containing a leading isolate significantly improved AT ratio, reduced hair fall and increased apparent hair density in the tested population of men and women.
Lagerstroemia indica (L. indica) is reported to have diverse biological activities including anti-inflammatory, anti-cancer, neuro-regulatory, antidiabetic and antioxidant activity.
The purpose of the present study is to examine the potential of hair growth promotion and/or hair loss prevention by L. indica extract.
The effects of L. indica on hair growth have been studied in human hair follicle dermal papillary (hHFDP) cells and follicular organ culture ex vivo by cell proliferation assay, PCR, western blot analysis and reporter gene activity assay. Moreover, a clinical trial was conducted in healthy volunteers.
L. indica significantly promoted the proliferation of hHFDP cells, which was associated with increased expression of TCF/LEF, VEGF and Gli1 mRNA, and inhibition of STAT6 and Smad2 mRNA. Treatment with L. indica also increased the TCF/LEF reporter gene activity but downregulated the SBE- and STAT6-luciferase activities. The expression of total β-catenin, CDK4 and CDK2 were elevated, while that of STAT6 and SMAD2/3 was suppressed upon treatment with L. indica. In human hair follicles organ culture, L. indica significantly inhibited hair follicular degeneration. The clinical trial showed a statistically significant rise in total hair count in test group (n=24) after 24 weeks of applying the hair tonic enriched with L. indica (141.46 ± 21.27 number/cm2 , p < 0.05).
We suggest that L. indica extract prevents hair loss as well as stimulate hair growth by regulating the Wnt-β-catenin, JAK3-STAT6 and TGF-β1-Smad signaling pathways, and may be further developed as a novel functional cosmetic for preventing hair loss.
Androgenetic Alopecia (AGA) is by far the most common cause of hair loss in men, and its high prevalence has been reported in detail for many decades . Several different terms in international medical bibliography have been suggested by several authors, such as androgenic alopecia, male pattern baldness, androgen-dependent alopecia, common baldness, and genetic hair loss. However, the term “Androgenetic Alopecia” is considered the most appropriate since it summarizes the etiology of the condition, with the term “andro-” referring to the hormonal and “-genetic”, implying the inherited parameter of its pathogenesis.
Secondary hair follicles (SHFs) in the Angora rabbit exhibit classic cyclic hair development, but the multiple molecular signals involved in hair cycling are yet to be explored in detail. In the present study, we investigated the expression pattern, methylation and histone H3 acetylation status of Wnt10b, as a molecular signal participating in hair cycling, during the SHF cycle in the Angora rabbit. Expression of Wnt10b at the anagen phase was significantly higher than that at both the telogen and catagen phases, suggesting that Wnt10b might serve as a critical activator during cyclic transition of SHFs. Methylation frequency of the fifth CpG site (CpG5‐175 bp) in CpG islands at the anagen phase was lower than that at both the catagen and telogen phases. The methylation status of the CpG5 site was negatively correlated with Wnt10b expression. This indicated that the methylation of CpG5 might participate in Wnt10b transcriptional suppression in SHFs. Furthermore, histone H3 acetylation status in the regions‐256~−11 bp and 98 ~ 361 bp were significantly lower at both the catagen and telogen phases than at the anagen phase. The histone H3 acetylation level was significantly positively correlated with Wnt10b expression. This confirmed that histone acetylation was likely involved in upregulating Wnt10b transcription in SHFs. Additionally, potential binding to the transcription factors ZF57 and HDBP was predicted within the CpG5 site. In conclusion, our findings reveal the epigenetic mechanism of Wnt10b transcription and provide a new insight into epigenetic regulation during the SHF cycle in the Angora rabbit.
Alopecia or hair loss is a worldwide unisex dermatological problem which affects aesthetic lifestyle qualities in humans. In recent years, drug discovery for hair loss has gained significant pharmaceutical research attention. Synthetic drugs such as minoxidil, oral finasteride, anthralin cream and ketoconazole based antifungal shampoos are some of the commercially available product formulations for hair loss treatment. As these products are mostly chemically derived, their long-term exposure to the skin could result in various side effects and skin disorders. Since traditional medicine relies on herbs to treat alopecia, in recent times, different species of herbs are being extracted to generate functional bioactive chemicals as active ingredients to treat hair loss. These biologically derived phytochemicals may offer improved long-term biocompatibility with the skin. This chapter presents an overview of various phytochemicals with anti-alopecia properties and discusses their modes of action. Additionally, the efficiency of flavonoids, which is a major phytochemical constituent of several herbs and a potential 5α reductase enzyme inhibitor, as a potential drug for alopecia treatment is also discussed.
Androgenetic alopecia (AGA) affects predisposed men and women and is characterized by nonscarring progressive miniaturization of the hair follicle accompanied by shortening of the anagen phase, leading to a gradual conversion of terminal hairs into vellus hairs with a pattern distribution. The etiology of AGA is multifactorial and polygenetic. Male androgenetic alopecia, also known as male pattern hair loss (MPHL), is clearly an androgen-dependent condition, and although the mode of inheritance is uncertain, a genetic predisposition is observed. In female androgenetic alopecia, also known as female pattern hair loss (FPHL), the role of androgens is still uncertain. It is more frequent in Caucasians than in Asians and Africans, and the prevalence increases with age.
Introduction: In the past thirty years, only two drugs have received FDA approval for the treatment of androgenetic alopecia reflecting a lack of success in unraveling novel targets for pharmacological intervention. However, as our knowledge of hair biology improves, new signaling pathways and organogenesis processes are being uncovered which have the potential to yield more effective therapeutic modalities.
Areas covered: This review focuses on potential targets for drug development to treat hair loss. The physiological processes underlying the promise of regenerative medicine to recreate new functional hair follicles in bald scalp are also examined.
Expert opinion: The discovery of promising new targets may soon enable treatment options that modulate the hair cycle to preserve or extend the growth phase of the hair follicle. This could also enable stimulation of progenitor cells and morphogenic pathways to reactivate miniaturized follicles in bald scalp or leverage the potential of wound healing and embryogenic development as an emerging paradigm to generate new hair follicles in barren skin.
Wnt10b is a member of Wnt family that plays a variety of roles in biological functions, including those in the development of hair follicles. To investigate the effect of Wnt10b on hair growth in the Angora rabbit and to determine the underlying molecular mechanism, we cultured dermal papilla (DP) cells with exogenous Wnt10b in vitro. We observed the expressions of downstream critical gene β‐catenin and lymphoid enhancer‐binding factor 1 (LEF1) in Wnt/β‐catenin pathway. The levels of β‐catenin mRNA and protein were higher in the Wnt10b group of DP cells than in the Control group, and the mRNA level of LEF1 in the Wnt10b group was higher than in the Control group. Moreover, translocation of β‐catenin from cytoplasm to nucleus was activated in the Wnt10b group. Furthermore, the mRNA levels of the hair follicle‐regulatory genes, insulin‐like growth factor‐1 (IGF‐1) and alkaline phosphatase (ALP), and the protein activity of ALP was also upregulated in the Wnt10b group compared to their corresponding levels in the Control group. These data suggest that Wnt10b could activate the canonical Wnt/β‐catenin signalling pathway to induce DP cells in the Angora rabbit. In addition, the proliferation of DP cells was significantly promoted when cultured with Wnt10b for 48 and 72 hr, suggesting that Wnt10b plays a pivotal role in the proliferation and maintenance of DP cells in vitro. In conclusion, this study demonstrates that Wnt10b may promote hair follicle growth in Angora rabbit through the canonical Wnt/β‐catenin signalling pathway that promotes the proliferation of DP cells.
Pattern hair loss is the most common form of hair loss in both women and men. Male pattern hair loss, also termed male androgenetic alopecia (M-AGA), is an androgen-dependent trait that is predominantly genetically determined. Androgen-mediated mechanisms are probably involved in FPHL in some women but the evidence is less strong than in M-AGA; and other non-androgenic pathways, including environmental influences, may contribute to the aetiology. Genome-wide association studies (GWASs) have identified several genetic loci for M-AGA and have provided better insight into the underlying biology. However, the role of heritable factors in female pattern hair loss (FPHL) is largely unknown. Recently published studies have been restricted to candidate gene approaches and could not clearly identify any susceptibility locus/gene for FPHL but suggest the aetiology differs substantially from that of M-AGA. Hypotheses about possible pathomechanisms of FPHL as well as the results of the genetic studies performed to date are summarized. This article is protected by copyright. All rights reserved.
Activation of Wnt/Beta-catenin signalling in adult mouse epidermis leads to expansion of the stem cell compartment and redirects keratinocytes in the interfollicular epidermis and sebaceous glands (SGs) to differentiate along the hair follicle (HF) lineages. Here we demonstrate that during epidermal development and homeostasis there is reciprocal activation of the androgen receptor (AR) and Beta-catenin in cells of the HF bulb. AR activation reduced Beta-catenin-dependent transcription, blocked Beta-catenin induced induction of HF growth and prevented Beta-catenin-mediated conversion of SGs into HFs. Conversely, AR inhibition enhanced the effects of Beta-catenin activation, promoting HF proliferation and differentiation, culminating in the formation of benign HF tumours and complete loss of SG identity. We conclude that AR signalling plays a key role in epidermal stem cell fate selection by modulating responses to Beta-catenin in adult mouse skin.
Androgenetic alopecia (AGA) is one of the commonest reasons for dermatological consultation. Over the last few years our understanding of the pathophysiology of AGA has improved and this has paved way for better diagnostic and therapeutic options. Recent research has dwelled on the role of stem cells in the pathophysiology of AGA and has also identified newer genetic basis for the condition. Dermoscopy/trichoscopy has emerged as a useful diagnostic tool for AGA. While the major treatment options continue to be topical minoxidil, systemic Finasteride and hair transplantations, newer modalities are under investigation. Specific diagnostic and treatment recommendations have also been developed on evidence based principles. This article reviews the recent concepts in relation to AGA. With regards to the pathophysiology we have tried to stress on recent knowledge of the molecular and genetic basis of AGA. We have emphasized on an evidence based approach for treatment and diagnosis.
The Wnt/β-catenin pathway is a potential target for development of anabolic agents to treat osteoporosis because of its role in osteoblast differentiation and bone formation. However, there is no clinically available anti-osteoporosis drug that targets this Wnt/β-catenin pathway. In this study, we screened a library of aqueous extracts of 350 plants and identified Hovenia dulcis Thunb (HDT) extract as a Wnt/β-catenin pathway activator. HDT extract induced osteogenic differentiation of calvarial osteoblasts without cytotoxicity. In addition, HDT extract increased femoral bone mass without inducing significant weight changes in normal mice. In addition, thickness and area of femoral cortical bone were also significantly increased by the HDT extract. Methyl vanillate (MV), one of the ingredients in HDT, also activated the Wnt/β-catenin pathway and induced osteoblast differentiation in vitro. MV rescued trabecular or cortical femoral bone loss in the ovariectomized mice without inducing any significant weight changes or abnormality in liver tissue when administrated orally. Thus, natural HDT extract and its ingredient MV are potential anabolic agents for treating osteoporosis.
A signal first arising in the dermis to initiate the development of hair follicles has been described for many decades. Wnt is the earliest signal known to be intimately involved in hair follicle induction. However, it is not clear whether the inductive signal of Wnt arises intradermally or intraepidermally. Whether Wnt acts as the first dermal signal to initiate hair follicle development also remains unclear. Here we report that Wnt production mediated by Gpr177, the mouse Wls ortholog, is essential for hair follicle induction. Gpr177, encoding a multipass transmembrane protein, regulates Wnt sorting and secretion. Cell type-specific abrogation of the signal reveals that only epidermal, but not dermal, production of Wnt is required. An intraepidermal Wnt signal is necessary and sufficient for hair follicle initiation. However, the subsequent development depends on reciprocal signaling crosstalk of epidermal and dermal cells. Wnt signals within the epidermis and dermis and crossing between the epidermis and dermis have distinct roles and specific functions in skin development. This study not only defines the cell type responsible for Wnt production, but also reveals a highly dynamic regulation of Wnt signaling at different steps of hair follicle morphogenesis. Our findings uncover a mechanism underlying hair follicle development orchestrated by the Wnt pathway.Journal of Investigative Dermatology advance online publication, 29 November 2012; doi:10.1038/jid.2012.407.
Wnt proteins are secreted molecules that play multiple roles during hair follicle development and postnatal hair cycling. Wntless (Wls) is a cargo protein required for the secretion of various Wnt ligands. However, its role during hair follicle development and hair cycling remains unclear. Here, we examined the expression of Wls during hair follicle induction and postnatal hair cycling. We also conditionally deleted Wls with K14-cre to investigate its role in hair follicle induction. K14-cre;Wls(c/c) mice exhibited abnormal hair follicle development, which is possibly caused by impaired canonical Wnt signaling. Meanwhile, Wnt5a is also expressed in embryonic epidermis, but Wnt5a null mice showed no significant defect in embryonic hair follicle morphogenesis. Therefore, Wls may regulate hair follicle induction by mediating the Wnt/β-catenin pathway.
Hair follicles periodically undergo regeneration. The balance between activators and inhibitors may determine the time required for telogen hair follicles to reenter anagen. We previously reported that Wnt10b (wingless-type mouse mammary tumor virus integration site family member 10b) could promote the growth of hair follicles in vitro. To unveil the roles of Wnt10b in hair follicle regeneration, we established an in vivo mouse model using intradermal injection. On the basis of this model, we found that Wnt10b could induce the biological switch of hair follicles from telogen to anagen when overexpressed in the skin. The induced hair follicles expressed structure markers and could cycle normally into catagen. Conversely, anagen onset was abrogated by the knockdown of Wnt10b with small interfering RNA (siRNA). The Wnt10b aberrant expression data suggest that it is one of the activators of hair follicle regeneration. The β-catenin protein is translocated to the nucleus in Wnt10b-induced hair follicles. The biological effects of Wnt10b were abrogated when β-catenin expression was downregulated with siRNA. These data revealed that Wnt10b might induce hair follicle regeneration in vivo via the enhanced activation of the canonical Wnt signaling pathway. To our knowledge, our data provide previously unreported insights into the regulation of hair follicle cycling and provide potential therapeutic targets for hair follicle-related diseases.Journal of Investigative Dermatology advance online publication, 26 July 2012; doi:10.1038/jid.2012.235.
Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA), a GSK3β inhibitor that activates the Wnt/β-catenin pathway, to promote hair re-growth in vitro and in vivo.
Methodology/ Principal Findings
Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP). VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/β-catenin pathway, whereas minoxidil (MNX), a drug commonly used to treat alopecia, did not significantly affect the Wnt/β-catenin pathway. VPA analogs and other GSK3β inhibitors that activate the Wnt/β-catenin pathway such as 4-phenyl butyric acid, LiCl, and BeCl2 also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice.
Our findings indicate that small molecules that activate the Wnt/β-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth.
Dermal fibroblasts are required for structural integrity of the skin and for hair follicle development. Uniform Wnt signaling activity is present in dermal fibroblast precursors preceding hair follicle initiation, but the functional requirement of dermal Wnt signaling at early stages of skin differentiation and patterning remains largely uncharacterized. We show in mice that epidermal Wnt ligands are required for uniform dermal Wnt signaling/β-catenin activity and regulate fibroblast cell proliferation and initiation of hair follicle placodes. In the absence of dermal Wnt signaling/β-catenin activity, patterned upregulation of epidermal β-catenin activity and Edar expression are absent. Conversely, forced activation of β-catenin signaling leads to the formation of thickened dermis, enlarged epidermal placodes and dermal condensates that result in prematurely differentiated enlarged hair follicles. These data reveal functional roles for dermal Wnt signaling/β-catenin in fibroblast proliferation and in the epidermal hair follicle initiation program.
The mammalian hair follicle is a complex 'mini-organ' thought to form only during development; loss of an adult follicle is considered permanent. However, the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits, mice and even humans fifty years ago. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles. These remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in skin, and that this provides a window for manipulation of hair follicle neogenesis by Wnt proteins. These findings suggest treatments for wounds, hair loss and other degenerative skin disorders.
Fewer than 45% of women go through life with a full head of hair. Female pattern hair loss is the commonest cause of hair loss in women and prevalence increases with advancing age. Affected women may experience psychological distress and impaired social functioning. In most cases the diagnosis can be made clinically and the condition treated medically. While many women using oral antiandrogens and topical minoxidil will regrow some hair, early diagnosis and initiation of treatment is desirable as these treatments are more effective at arresting progression of hair loss than stimulating regrowth. Adjunctive nonpharmacological treatment modalities such as counseling, cosmetic camouflage and hair transplantation are important measures for some patients. The histology of female pattern hair loss is identical to that of male androgenetic alopecia. While the clinical pattern of the hair loss differs between men, the response to oral antiandrogens suggests that female pattern hair loss is an androgen dependant condition, at least in the majority of cases. Female pattern hair loss is a chronic progressive condition. All treatments need to be continued to maintain the effect. An initial therapeutic response often takes 12 or even 24 months. Given this delay, monitoring for treatment effect through clinical photography or standardized clinical severity scales is helpful.
The formation of the hair follicle and its cyclical growth, quiescence, and regeneration depend on reciprocal signaling between its epidermal and dermal components. The dermal organizing center, the dermal papilla (DP), regulates development of the epidermal follicle and is dependent on signals from the epidermis for its development and maintenance. GFP specifically expressed in DP cells of a transgenic mouse was used to purify this population and study the signals required to maintain it. We demonstrate that specific Wnts, but not Sonic hedgehog (Shh), maintain anagen-phase gene expression in vitro and hair inductive activity in a skin reconstitution assay.
Purpose of review:
The authors will review the current literature on efficacy and safety of 5-alpha reductase inhibitors (5αRIs) for androgenetic alopecia (AGA).
The 5αRI finasteride and dutasteride are effective in treating AGA and promoting hair regrowth. 5αRI can be given orally, topically and more recently through mesotherapy. However, there has been an increasing concern about permanent sexual adverse events such as impotence and infertility. Most of these reports are published as case reports, and two studies reporting persistent sexual side-effects after discontinuation of finasteride had serious method limitations, as patients were recruited from a website. To our knowledge, permanent sexual adverse events have yet to be published in higher quality studies, such as randomized controlled trials. Although patients treated with 5αRIs have an increased incidence of sexual adverse events, these events decrease if discontinued or over time with continued therapy.
Sexual side-effects are uncommon and resolve spontaneously in most patients even without discontinuing therapy. Significant effort is underway to find delivery systems that optimize delivery and reduce systemic absorption of topical 5αRs including hydroxypropyl chitosan and liposomal and nanoparticulate systems.
WNT-β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.
Androgenic alopecia (AGA) is the major type of scalp hair loss affecting 60 - 70% of the population worldwide. It is caused by two potent androgens, namely testosterone (T) and 5α-dihydrotestosterone (5α-DHT). Till date, only two FDA-approved synthetic drugs, minoxidil and finasteride, are used to cure AGA with only 35 and 48% success, respectively; therefore, a search for new drug based on the mechanism of androgens action is still needed.
Relevant literature was reviewed to identify current therapeutic targets and treatments for AGA. The potential targets are classified into three categories: i) 5α-reductase; ii) androgen receptor and iii) growth-factor-producing genes related to hair growth.
Relevant assay systems using the right targets are required in order to obtain specific and effective drugs for AGA treatment. It is unlikely that single targeted agents will be sufficient for treating AGA, and therefore, it would be a challenge to obtain compounds with multiple activities.
Androgenetic alopecia (AGA) is one of the most common chronic problems seen by dermatologists worldwide. It is characterized by progressive hair loss, especially of scalp hair, and has distinctive patterns of loss in women versus men, but in both genders the central scalp is most severely affected. It often begins around puberty and is known to effect self-esteem and the individual's quality of life. In contrast to the high prevalence of AGA, approved therapeutic options are limited. In addition to the scarce pharmacologic treatments, there are numerous nonprescription products claimed to be effective in restoring hair in androgenetic alopecia.
The purpose of this paper is to review published medical and non-medical treatments for male and female AGA using the American College of Physicians evidence assessment methods. MEDLINE, EMBASE and Cochrane Library were searched for systematic reviews, randomized controlled trials, open studies, case reports and relevant studies of the treatment of male and female AGA. The relevant articles were classified according to grade and level of evidence.
The medical treatments with the best level of evidence classification for efficacy and safety for male AGA are oral finasteride and topical minoxidil solution. For female AGA, topical minoxidil solution appears to be the most effective and safe treatment. The medical treatments corresponding to the next level of evidence quality are some commonly used therapeutic non-FDA-approved options including oral and topical anti-hormonal treatments. Surgical treatment of follicular unit hair transplantation is an option in cases that have failed medical treatment although there is high variation in outcomes.
Some articles, especially those concerning traditional herbs claimed to promote hair regrowth, were published in non-English, local journals.
An assessment of the evidence quality of current publications indicates that oral finasteride (for men only) and topical minoxidil (for men and women) are the best treatments of AGA.
Valproic acid (VPA), a widely used anticonvulsant, inhibits glycogen synthase kinase 3β and activates the Wnt/β-catenin pathway, which is associated with hair growth cycle and anagen induction. To assess the efficacy of topical VPA for treating androgenetic alopecia (AGA), we performed a randomized, double-blind, placebo-controlled clinical trial. Male patients with moderate AGA underwent treatment with either VPA (sodium valproate, 8.3%) or placebo spray for 24 weeks. The primary end-point for efficacy was the change in hair count during treatment, which was assessed by phototrichogram analysis. Of the 40 patients enrolled in the study, 27 (n = 15, VPA group; n = 12, placebo group) completed the entire protocol with good compliance. No statistical differences in age, hair loss duration and total hair count at baseline were found between the groups. The mean change in total hair count was significantly higher in the VPA group than in the placebo group (P = 0.047). Both groups experienced mostly mild and self-limited adverse events, but their differences in prevalence rates were similar between the two groups (P = 0.72). A subject treated with topical VPA developed ventricular tachycardia, but it did not seem to be related to the VPA spray. Topical VPA increased the total hair counts of our patients; therefore, it is a potential treatment option for AGA.
β-Catenin, the transducer of Wnt signaling, is critical for the development and growth of hair follicles. In the absence of Wnt signals, cytoplasmic β-catenin is phosphorylated by glycogen synthase kinase (GSK)-3 and then degraded. Therefore, inhibition of GSK-3 may enhance hair growth via β-catenin stabilization. Valproic acid is an anticonvulsant and a mood-stabilizing drug that has been used for decades. Recently, valproic acid was reported to inhibit GSK-3β in neuronal cells, but its effect on human hair follicles remains unknown.
To determine the effect of VPA on human hair growth.
We investigated the effect of VPA on cultured human dermal papilla cells and outer root sheath cells and on an in vitro culture of human hair follicles, which were obtained from scalp skin samples of healthy volunteers. Anagen induction by valproic acid was evaluated using C57BL/6 mice model.
Valproic acid not only enhanced the viability of human dermal papilla cells and outer root sheath cells but also promoted elongation of the hair shaft and reduced catagen transition of human hair follicles in organ culture model. Valproic acid treatment of human dermal papilla cells led to increased β-catenin levels and nuclear accumulation and inhibition of GSK-3β by phosphorylation. In addition, valproic acid treatment accelerated the induction of anagen hair in 7-week-old female C57BL/6 mice.
Valproic acid enhanced human hair growth by increasing β-catenin and therefore may serve as an alternative therapeutic option for alopecia.
To properly assess the progression and treatment response of alopecia, one must measure the changes in hair mass, which is influenced by both the density and diameter of hair. Unfortunately, a convenient device for hair mass evaluation had not been available to dermatologists until the recent introduction of the cross-section trichometer, which directly measures the cross-sectional area of an isolated bundle of hair.
We sought to evaluate the accuracy and sensitivity of the HairCheck(®) device, a commercial product derived from the original cross-section trichometer.
Bundles of surgical silk and human hair were used to evaluate the ability of the HairCheck(®) device to detect and measure small changes in the number and diameter of strands, and bundle weight.
Strong correlations were observed between the bundle's cross-sectional area, displayed as the numeric Hair Mass Index (HMI), the number of strands, the silk/hair diameter, and the bundle dry weight.
HMI strongly correlated with the number and diameter of silk/hair, and the weight of the bundle, suggesting that it can serve as a valid indicator of hair mass. We have given the name cross-section trichometry (CST) to the methodology of obtaining the HMI using the HairCheck(®) system. CST is a simple modality for the quantification of hair mass, and may be used as a convenient and useful tool to clinically assess changes in hair mass caused by thinning, shedding, breakage, or growth in males and females with progressive alopecia or those receiving alopecia treatment.
Androgenetic alopecia (AGA) is the most common form of hair loss, however current treatment options are limited and moderately effective. In the past few years, there has been an increased interest in deciphering the molecular mechanisms responsible for this disorder, which has opened the possibility of novel treatments that promise to not only stimulate hair growth, but also to induce formation of new hair follicles.
The future holds more effective topical treatments with less systemic side effects (such as topical 5-alfa-reductase inhibitors), prostaglandin analogs and antagonists, medications which act through the Wnt signaling pathway, stem cells for hair regeneration, platelet-rich plasma (PRP) and more effective ways of transplanting hair. A comprehensive search was made using PubMed, GoogleScholar and Clinicaltrial.gov using different combination of key words, which included AGA treatment, new treatments for AGA, Wnt pathway, prostaglandins, PRP and stem cells for hair regrowth.
In the near future, treatments with topical 5-alfa-reductase inhibitors and prostaglandin agonists or antagonists are expected. More evidence is needed to verify the efficacy of PRP. Although hair follicle bioengineering and multiplication is a fascinating and promising field, it is still a long way from being available to clinicians.
The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future.
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.
Wnt/beta-catenin and NF-kappaB signaling mechanisms provide central controls in development and disease, but how these pathways intersect is unclear. Using hair follicle induction as a model system, we show that patterning of dermal Wnt/beta-catenin signaling requires epithelial beta-catenin activity. We find that Wnt/beta-catenin signaling is absolutely required for NF-kappaB activation, and that Edar is a direct Wnt target gene. Wnt/beta-catenin signaling is initially activated independently of EDA/EDAR/NF-kappaB activity in primary hair follicle primordia. However, Eda/Edar/NF-kappaB signaling is required to refine the pattern of Wnt/beta-catenin activity, and to maintain this activity at later stages of placode development. We show that maintenance of localized expression of Wnt10b and Wnt10a requires NF-kappaB signaling, providing a molecular explanation for the latter observation, and identify Wnt10b as a direct NF-kappaB target. These data reveal a complex interplay and interdependence of Wnt/beta-catenin and EDA/EDAR/NF-kappaB signaling pathways in initiation and maintenance of primary hair follicle placodes.
Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator beta-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate beta-catenin stability, from Wnt receptors to the cytoplasmic beta-catenin destruction complex, and nuclear machinery that mediates beta-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.
Hair follicle morphogenesis is initiated by a dermal signal that induces the development of placodes in the overlying epithelium. To determine whether WNT signals are required for initiation of follicular development, we ectopically expressed Dickkopf 1, a potent diffusible inhibitor of WNT action, in the skin of transgenic mice. This produced a complete failure of placode formation prior to morphological or molecular signs of differentiation, and blocked tooth and mammary gland development before the bud stage. This phenotype indicates that activation of WNT signaling in the skin precedes, and is required for, localized expression of regulatory genes and initiation of hair follicle placode formation.
Hair loss or hair thinning is a common complaint in clinical dermatology, and patients seeking advice for hair loss are not necessarily bald. Because the effects of treatment attempts are hard to measure, there is need for a sensitive tool to monitor hair loss and treatment responses. Such a method must be able to analyze the biologic parameters of hair growth, which are: (i) hair density (n per cm2); (ii) hair diameter (microm); (iii) hair growth rate (mm per day); and (iv) anagen/telogen ratio. Herein we present the TrichoScan as a method that combines epiluminescence microscopy with automatic digital image analysis for the measurement of human, and potentially animal hair, in situ. The TrichoScan is able to analyze all four parameters of hair growth with a so-called intraclass correlation of approximately 91% within the same TrichoScan operator and an intraclass correlation of approximately 97% for different TrichoScan operators. The application of the technique is demonstrated by comparing the hair parameters in individuals without apparent hair loss, men with untreated androgenetic alopecia, and men after treatment with finasteride (1 mg per day). We were able to detect a significant increase in hair counts and cumulative hair thickness 3 and 6 mo after treatment. Advantages of the TrichoScan are that it can be used for clinical studies to compare placebo versus treatment, to compare different capacities of hair growth promoting substances, to study androgenetic alopecia and other forms of diffuse hair loss, and to study the effects of drugs and laser treatment on hypertrichosis and hirsutism.
Dermal papilla cells of the hair follicle can be maintained in an active, hair-inducing state in vitro when cocultured with cells secreting Wnt3a. By inducing cultured dermal papilla cells to secrete Wnt themselves, we demonstrate that this activity is a direct effect of Wnt signaling to dermal papilla cells. We further demonstrate that the effects of Wnt3a are exerted through activation of the beta-catenin signal transduction pathway and do not require alternative Wnt transduction cascades. Once dermal papilla cells have lost hair-inducing properties in vitro, neither treatment with Wnt nor expression of a truncated and activating form of beta-catenin is sufficient to restore these properties to the cultured cells.
Piraccini BM, Alessandrini A. Androgenetic alopecia. G
Ital Dermatol Venereol 2014; 149: 15-24.