Wnt1a maintains characteristics of dermal papilla cells that induce mouse hair regeneration in a 3D preculture system.
Dong Liang,Hao Haojie,Liu Jiejie,Tong Chuan,Ti Dongdong,Chen Deyun,Chen Li,Li Meirong,Liu Huiling,Fu Xiaobing,Han Weidong
Journal of tissue engineering and regenerative medicine
Hair follicle morphogenesis and regeneration depend on intensive but well-orchestrated interactions between epithelial and mesenchymal components. Therefore, an alternative strategy to reproduce the process of epithelial-mesenchymal interaction in vitro could use a 3D system containing appropriate cell populations. The 3D air-liquid culture system for reproducibly generating hair follicles from dissociated epithelial and dermal papilla (DP) cells combined with a collagen-chitosan scaffold is described in this study. Wnt-CM was prepared from the supernatant of Wnt1a-expressing bone marrow mesenchymal stem cells (BM-MSCs) that maintain the hair-inducing gene expression of DP cells. The collagen-chitosan scaffold cells (CCS cells) were constructed using a two-step method by inoculating the Wnt-CM-treated DP cells and epidermal (EP) cells into the CCS. The cells in the air-liquid culture formed dermal condensates and a proliferative cell layer in vitro. The CCS cells were able to induce hair regeneration in nude mice. The results demonstrate that Wnt-CM can maintain the hair induction ability of DP cells in expansion cultures, and this approach can be used for large-scale preparation of CCS cells in vitro to treat hair loss. Copyright © 2015 John Wiley & Sons, Ltd.
TREMendous Macrophages Inhibit Hair Growth.
Dalessandri Tim,Kasper Maria
Cell stem cell
Tissue-resident immune cells with potent sensing and effector functions are well-placed to fundamentally aid tissue homeostasis via crosstalk with stem cells. In this issue of Cell Stem Cell, Wang et al. (2019) identify a dermis-resident TREM2+ macrophage subpopulation that promotes hair follicle stem cell quiescence via cytokine-mediated JAK-STAT signaling.
Spatiotemporal antagonism in mesenchymal-epithelial signaling in sweat versus hair fate decision.
Lu Catherine P,Polak Lisa,Keyes Brice E,Fuchs Elaine
Science (New York, N.Y.)
The gain of eccrine sweat glands in hairy body skin has empowered humans to run marathons and tolerate temperature extremes. Epithelial-mesenchymal cross-talk is integral to the diverse patterning of skin appendages, but the molecular events underlying their specification remain largely unknown. Using genome-wide analyses and functional studies, we show that sweat glands are specified by mesenchymal-derived bone morphogenetic proteins (BMPs) and fibroblast growth factors that signal to epithelial buds and suppress epithelial-derived sonic hedgehog (SHH) production. Conversely, hair follicles are specified when mesenchymal BMP signaling is blocked, permitting SHH production. Fate determination is confined to a critical developmental window and is regionally specified in mice. In contrast, a shift from hair to gland fates is achieved in humans when a spike in BMP silences SHH during the final embryonic wave(s) of bud morphogenesis.
A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition.
Biehs Brian,Dijkgraaf Gerrit J P,Piskol Robert,Alicke Bruno,Boumahdi Soufiane,Peale Franklin,Gould Stephen E,de Sauvage Frederic J
Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC), residual disease persists in some patients and may contribute to relapse when treatment is discontinued. Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1-Trp53 mouse model of BCC and found that mice treated with vismodegib harbour quiescent residual tumours that regrow upon cessation of treatment. Profiling experiments revealed that residual BCCs initiate a transcriptional program that closely resembles that of stem cells of the interfollicular epidermis and isthmus, whereas untreated BCCs are more similar to the hair follicle bulge. This cell identity switch was enabled by a mostly permissive chromatin state accompanied by rapid Wnt pathway activation and reprogramming of super enhancers to drive activation of key transcription factors involved in cellular identity. Accordingly, treatment of BCC with both vismodegib and a Wnt pathway inhibitor reduced the residual tumour burden and enhanced differentiation. Our study identifies a resistance mechanism in which tumour cells evade treatment by adopting an alternative identity that does not rely on the original oncogenic driver for survival.
A Subset of TREM2 Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth.
Wang Etienne C E,Dai Zhenpeng,Ferrante Anthony W,Drake Charles G,Christiano Angela M
Cell stem cell
Hair growth can be induced from resting mouse hair follicles by topical application of JAK inhibitors, suggesting that JAK-STAT signaling is required for maintaining hair follicle stem cells (HFSCs) in a quiescent state. Here, we show that Oncostatin M (OSM), an IL-6 family cytokine, negatively regulates hair growth by signaling through JAK-STAT5 to maintain HFSC quiescence. Genetic deletion of the OSM receptor or STAT5 can induce premature HFSC activation, suggesting that the resting telogen stage is actively maintained by the hair follicle niche. Single-cell RNA sequencing revealed that the OSM source is not intrinsic to the hair follicle itself and is instead a subset of TREM2 macrophages that is enriched within the resting follicle and deceases immediately prior to HFSC activation. In vivo inhibition of macrophage function was sufficient to induce HFSC proliferation and hair cycle induction. Together these results clarify how JAK-STAT signaling actively inhibits hair growth.
Lactate dehydrogenase activity drives hair follicle stem cell activation.
Flores Aimee,Schell John,Krall Abigail S,Jelinek David,Miranda Matilde,Grigorian Melina,Braas Daniel,White Andrew C,Zhou Jessica L,Graham Nicholas A,Graeber Thomas,Seth Pankaj,Evseenko Denis,Coller Hilary A,Rutter Jared,Christofk Heather R,Lowry William E
Nature cell biology
Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.
Treg-Cell Control of a CXCL5-IL-17 Inflammatory Axis Promotes Hair-Follicle-Stem-Cell Differentiation During Skin-Barrier Repair.
Mathur Anubhav N,Zirak Bahar,Boothby Ian C,Tan Madge,Cohen Jarish N,Mauro Thea M,Mehta Pooja,Lowe Margaret M,Abbas Abul K,Ali Niwa,Rosenblum Michael D
Restoration of barrier-tissue integrity after injury is dependent on the function of immune cells and stem cells (SCs) residing in the tissue. In response to skin injury, hair-follicle stem cells (HFSCs), normally poised for hair generation, are recruited to the site of injury and differentiate into cells that repair damaged epithelium. We used a SC fate-mapping approach to examine the contribution of regulatory T (Treg) cells to epidermal-barrier repair after injury. Depletion of Treg cells impaired skin-barrier regeneration and was associated with a Th17 inflammatory response and failed HFSC differentiation. In this setting, damaged epithelial cells preferentially expressed the neutrophil chemoattractant CXCL5, and blockade of CXCL5 or neutrophil depletion restored barrier function and SC differentiation after epidermal injury. Thus, Treg-cell regulation of localized inflammation enables HFSC differentiation and, thereby, skin-barrier regeneration, with implications for the maintenance and repair of other barrier tissues.
Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
Garza Luis A,Liu Yaping,Yang Zaixin,Alagesan Brinda,Lawson John A,Norberg Scott M,Loy Dorothy E,Zhao Tailun,Blatt Hanz B,Stanton David C,Carrasco Lee,Ahluwalia Gurpreet,Fischer Susan M,FitzGerald Garret A,Cotsarelis George
Science translational medicine
Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that prostaglandin D(2) synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, prostaglandin D(2) (PGD(2)), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD(2) levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD(2) receptor G protein (heterotrimeric guanine nucleotide)-coupled receptor 44 (GPR44), but not the PGD(2) receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD(2) in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD(2) as an inhibitor of hair growth in AGA and suggest the PGD(2)-GPR44 pathway as a potential target for treatment.
Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial.
Nangia Julie,Wang Tao,Osborne Cynthia,Niravath Polly,Otte Kristen,Papish Steven,Holmes Frankie,Abraham Jame,Lacouture Mario,Courtright Jay,Paxman Richard,Rude Mari,Hilsenbeck Susan,Osborne C Kent,Rimawi Mothaffar
Importance:Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial. Objectives:To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects. Design, Setting, and Participants:Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized. Interventions:Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device. Main Outcomes and Measures:The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [<50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale. Results:At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events. Conclusions and Relevance:Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects. Trial Registration:clinicaltrials.gov Identifier: NCT01986140.
Variant in Central Centrifugal Cicatricial Alopecia.
Malki Liron,Sarig Ofer,Romano Maria-Teresa,Méchin Marie-Claire,Peled Alon,Pavlovsky Mor,Warshauer Emily,Samuelov Liat,Uwakwe Laura,Briskin Valeria,Mohamad Janan,Gat Andrea,Isakov Ofer,Rabinowitz Tom,Shomron Noam,Adir Noam,Simon Michel,McMichael Amy,Dlova Ncoza C,Betz Regina C,Sprecher Eli
The New England journal of medicine
BACKGROUND:Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia among women of African ancestry. The disease is occasionally observed to affect women in families in a manner that suggests an autosomal dominant trait and usually manifests clinically after intense hair grooming. We sought to determine whether there exists a genetic basis of CCCA and, if so, what it is. METHODS:We used exome sequencing in a group of women with alopecia (discovery set), compared the results with those in a public repository, and applied other filtering criteria to identify candidate genes. We then performed direct sequencing to identify disease-associated DNA variations and RNA sequencing, protein modeling, immunofluorescence staining, immunoblotting, and an enzymatic assay to evaluate the consequences of potential etiologic mutations. We used a replication set that consisted of women with CCCA to confirm the data obtained with the discovery set. RESULTS:In the discovery set, which included 16 patients, we identified one splice site and three heterozygous missense mutations in in 5 patients (31%). (The approximate prevalence of the disease is up to 5.6%.) encodes peptidyl arginine deiminase, type III (PADI3), an enzyme that post-translationally modifies other proteins that are essential to hair-shaft formation. All three CCCA-associated missense mutations in affect highly conserved residues and are predicted to be pathogenic; protein modeling suggests that they result in protein misfolding. These mutations were found to result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased enzymatic activity - findings that support their pathogenicity. Immunofluorescence staining showed decreased expression of PADI3 in biopsy samples of scalp skin obtained from patients with CCCA. We then directly sequenced in an additional 42 patients (replication set) and observed genetic variants in 9 of them. A post hoc analysis of the combined data sets showed that the prevalence of mutation was higher among patients with CCCA than in a control cohort of women of African ancestry (P = 0.002 by the chi-square test; P = 0.006 by Fisher's exact test; and after adjustment for relatedness of persons, P = 0.03 and P = 0.04, respectively). CONCLUSIONS:Mutations in , which encodes a protein that is essential to proper hair-shaft formation, were associated with CCCA. (Funded by the Ram Family Foundation and others.).
Pratt C Herbert,King Lloyd E,Messenger Andrew G,Christiano Angela M,Sundberg John P
Nature reviews. Disease primers
Alopecia areata is an autoimmune disorder characterized by transient, non-scarring hair loss and preservation of the hair follicle. Hair loss can take many forms ranging from loss in well-defined patches to diffuse or total hair loss, which can affect all hair-bearing sites. Patchy alopecia areata affecting the scalp is the most common type. Alopecia areata affects nearly 2% of the general population at some point during their lifetime. Skin biopsies of affected skin show a lymphocytic infiltrate in and around the bulb or the lower part of the hair follicle in the anagen (hair growth) phase. A breakdown of immune privilege of the hair follicle is thought to be an important driver of alopecia areata. Genetic studies in patients and mouse models have shown that alopecia areata is a complex, polygenic disease. Several genetic susceptibility loci were identified to be associated with signalling pathways that are important to hair follicle cycling and development. Alopecia areata is usually diagnosed based on clinical manifestations, but dermoscopy and histopathology can be helpful. Alopecia areata is difficult to manage medically, but recent advances in understanding the molecular mechanisms have revealed new treatments and the possibility of remission in the near future.
Clinical cosmeceutical repurposing of melatonin in androgenic alopecia using nanostructured lipid carriers prepared with antioxidant oils.
Hatem Shymaa,Nasr Maha,Moftah Noha H,Ragai Maha H,Geneidi Ahmed S,Elkheshen Seham A
Expert opinion on drug delivery
BACKGROUND:The present work aims to formulate nanostructured lipid carriers (NLCs) exhibiting high skin deposition and high inherent antioxidant potential to repurpose the use of melatonin hormone and some antioxidant oils in the treatment of androgenic alopecia (AGA). RESEARCH DESIGN AND METHODS:NLCs were characterized for their size, charge, drug entrapment, anti-oxidant potential, physical stability, in vitro release, surface morphology, and ex-vivo skin deposition. Their merits were clinically tested on patients suffering from AGA by calculating the degree of improvement, conduction of hair pull test, histometric assessment, and dermoscopic evaluation. RESULTS:Results revealed that melatonin NLCs showed nanometer size, negatively charged surface, high entrapment efficiency, and high anti-oxidant potential, in addition to sustained release for 6 h. Furthermore, NLCs displayed good storage stability and they were able to increase the skin deposition of melatonin 4.5-folds in stratum corneum, 7-folds in epidermis, and 6.8-folds in the dermis compared to melatonin solution. Melatonin NLCs displayed more clinically desirable results compared to the melatonin solution in AGA patients, manifested by increased hair density and thickness and decreased hair loss. CONCLUSIONS:The aforementioned system was shown to be a very promising treatment modality for AGA, which is worthy of futuristic experimentation.
Comparative effectiveness of low-level laser therapy for adult androgenic alopecia: a system review and meta-analysis of randomized controlled trials.
Liu Kao-Hui,Liu Donald,Chen Yu-Tsung,Chin Szu-Ying
Lasers in medical science
The purpose of this review is to explore the effectiveness of low-level laser therapy (LLLT) in the treatment of adult androgenic alopecia (AGA). A systematic search of studies on LLLT for AGA was conducted mainly in Pubmed, Embase, and Cochrane Systematic Reviews. The standardized mean difference (SMD) in the changes of hair density treated by LLLT versus sham devices was analyzed. The meta-analysis included 8 studies comprising a total of 11 double-blinded randomized controlled trials. The quantitative analysis showed a significant increase in hair density for those treated by LLLT versus sham group (SMD 1.316, 95% confidence interval, CI 0.993 to 1.639). The subgroup analysis demonstrated that LLLT increases hair growth in both genders, in both comb- and helmet-type devices, and in short- and long-term treatment course. The subgroup analysis also showed a more significant increase of hair growth for the LLLT versus sham in the low-frequency treatment group (SMD 1.555, 95% CI 1.132 to 1.978) than in the high-frequency group (SMD 0.949, 95% CI 0.644 to 1.253). The review was limited by the heterogeneity of included trials. LLLT significantly increased hair density in AGA. The meta-analysis suggests that low treatment frequency by LLLT have a better hair growth effect than high treatment frequency. LLLT represents a potentially effective treatment for AGA in both male and female. The types of LLLT devices and LLLT treatment course duration did not affect the effectiveness in hair growth.
Platelet-Rich Plasma in Androgenic Alopecia: Indications, Technique, and Potential Benefits.
Ferneini Elie M,Beauvais Daniel,Castiglione Concetta,Ferneini Moniek V
Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons
PURPOSE:The purpose of this study was to provide an overview of platelet-rich plasma (PRP) injected into the scalp for the management of androgenic alopecia. MATERIALS AND METHODS:A literature review was performed to evaluate the benefits of PRP in androgenic alopecia. RESULTS:Hair restoration has been increasing. PRP's main components of platelet-derived growth factor, transforming growth factor, and vascular endothelial growth factor have the potential to stimulate hard and soft tissue wound healing. In general, PRP showed a benefit on patients with androgenic alopecia, including increased hair density and quality. Currently, different PRP preparations are being used with no standard technique. CONCLUSION:This review found beneficial effects of PRP on androgenic alopecia. However, more rigorous study designs, including larger samples, quantitative measurements of effect, and longer follow-up periods, are needed to solidify the utility of PRP for treating patients with androgenic alopecia.
Platelet-Rich Plasma for Treating Androgenic Alopecia: A Systematic Review.
Mao Guangyu,Zhang Guohui,Fan Weixin
Aesthetic plastic surgery
BACKGROUND:Platelet-rich plasma (PRP) contains a variety of growth factors and proteins that can accelerate tissue repair. Androgenic alopecia is a genetic disorder characterized by atrophy of hair follicles and hair loss. At present, PRP injections for hair restoration have become a popular though controversial practice. We conducted a meta-analysis to compare the differences between patients treated with local injections of PRP and control group subjects to explore the effectiveness of PRP treatment for androgenic alopecia. MATERIALS AND METHODS:We searched PubMed, EMBASE and the Cochrane Library until Jan 2019 for human studies evaluating the efficacy of PRP for the treatment of androgenic alopecia. RESULTS:We retrieved 132 papers; 11 articles matched our inclusion criteria and comprised 262 androgenic alopecia patients. Through a meta-analysis, we found a significantly locally increased hair number per cm after PRP injections in the treatment group versus the control group (mean difference 38.75, 95% CI 22.22-55.28, P < .00001). Similarly, a significantly increased terminal hair density was found in the PRP group compared with the control group (mean difference 22.83, 95% CI 0.28-45.38, P = 0.05). CONCLUSION:Most studies suggest that subcutaneous injection of PRP is likely to reduce hair loss, increase hair diameter and density in patients with androgenic alopecia. Because of the low quality of the studies, small sample sizes, different treatment regimens and possible publication bias, the results of this meta-analysis should be interpreted with caution. Furthermore, more randomized controlled studies should be performed. LEVEL OF EVIDENCE III:This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Metabolic syndrome in androgenic alopecia.
Gopinath Hima,Upadya Gatha M
Indian journal of dermatology, venereology and leprology
BACKGROUND:Androgenic alopecia has been associated with an increased risk of coronary heart disease in various studies. The relationship between androgenic alopecia and metabolic syndrome, a known risk factor for atherosclerotic cardiovascular disease, is still poorly understood. AIM:To study the association between metabolic syndrome and early-onset androgenic alopecia. METHODS:A hospital-based analytical cross-sectional study was done on men in the age group of 18-55 years. Eighty five clinically diagnosed cases with early-onset (<35 years) androgenic alopecia of Norwood grade III or above, and 85 controls without androgenic alopecia were included. Data collected included anthropometric measurements, arterial blood pressure and history of chronic diseases. Fasting blood and lipid profile were determined. Metabolic syndrome was diagnosed as per the new International Diabetes Federation criteria. Chi-square and Student's t-test were used for statistical analysis using Statistical Package for the Social Sciences (SPSS) version 17.00. RESULTS:Metabolic syndrome was seen in 19 (22.4%) patients with androgenic alopecia and 8 (9.4%) controls (P = 0.021). Abdominal obesity, hypertension and lowered high-density lipoprotein were significantly higher in patients with androgenic alopecia versus their respective controls. LIMITATIONS:The limitations of our study include small sample size in subgroups and the lack of evidence of a temporal relationship between metabolic syndrome and androgenic alopecia. CONCLUSION:A higher prevalence of metabolic syndrome is seen in men with early-onset androgenic alopecia. Early screening for metabolic syndrome and its components is beneficial in patients with early-onset androgenic alopecia.
Low-level laser therapy for the treatment of androgenic alopecia: a review.
Darwin Evan,Heyes Alexandra,Hirt Penelope A,Wikramanayake Tongyu Cao,Jimenez Joaquin J
Lasers in medical science
There are many new low-level laser technologies that have been released commercially that claim to support hair regrowth. In this paper, we will examine the clinical trials to determine whether the body of evidence supports the use of low-level laser therapy (LLLT) to treat androgenic alopecia (AGA). A literature search was conducted through Pubmed, Embase, and Clinicaltrials.gov for clinical trials using LLLT to treat AGA. Thirteen clinical trials were assessed. Review articles were not included. Ten of 11 trials demonstrated significant improvement of androgenic alopecia in comparison to baseline or controls when treated with LLLT. In the remaining study, improvement in hair counts and hair diameter was recorded, but did not reach statistical significance. Two trials did not include statistical analysis, but showed marked improvement by hair count or by photographic evidence. Two trials showed efficacy for LLLT in combination with topical minoxidil. One trial showed efficacy when accompanying finasteride treatment. LLLT appears to be a safe, alternative treatment for patients with androgenic alopecia. Clinical trials have indicated efficacy for androgenic alopecia in both men and women. It may be used independently or as an adjuvant of minoxidil or finasteride. More research needs to be undertaken to determine the optimal power and wavelength to use in LLLT as well as LLLT's mechanism of action.
Injections of platelet-rich plasma for androgenic alopecia: A systematic review.
Picard F,Hersant B,Niddam J,Meningaud J-P
Journal of stomatology, oral and maxillofacial surgery
The aim of this literature review was to evaluate the effects of PRP injections into the scalp of patients with androgenic alopecia. A literature review was conducted using the Pubmed and Google Scholar databases with the search terms "platelet-rich plasma" or "platelet-rich fibrin" and "hair" or "alopecia" or "androgenic alopecia". The publications included had to clinically assess the efficacy of PRP injections in patients with androgenic alopecia. Out of the 32 publications retrieved, 14 publications were included, of which 3 randomized, 4 prospective controlled, 4 prospective uncontrolled and 3 retrospective studies. Seven out of 9 studies reported a significant increase of hair density ranging between 12.3 and 45.9 hairs/cm, (i.e. 19-31% hairs/cm). Four studies assessed hair loss with the traction test and found a negative result after treatment in more than 95% of patients. Regarding hair thickness, 1 study reported an increase in hair diameter of 46.4% and 1 reported an increase of 106.4% of the "Hair mass index". Overall, the use of PRP injections in patients with androgenic alopecia seems effective with respect to promoting lost hair regrowth, decreasing hair loss and increasing hair thickness. The effects appear to be progressive from the first injection session, to peak after 3 to 5 sessions and to be attenuated in the absence of further injections. No major adverse effect was reported in the 14 clinical studies.
A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors.
English Robert S
Androgenic alopecia, also known as pattern hair loss, is a chronic progressive condition that affects 80% of men and 50% of women throughout a lifetime. But despite its prevalence and extensive study, a coherent pathology model describing androgenic alopecia's precursors, biological step-processes, and physiological responses does not yet exist. While consensus is that androgenic alopecia is genetic and androgen-mediated by dihydrotestosterone, questions remain regarding dihydrotestosterone's exact role in androgenic alopecia onset. What causes dihydrotestosterone to increase in androgenic alopecia-prone tissues? By which mechanisms does dihydrotestosterone miniaturize androgenic alopecia-prone hair follicles? Why is dihydrotestosterone also associated with hair growth in secondary body and facial hair? Why does castration (which decreases androgen production by 95%) stop pattern hair loss, but not fully reverse it? Is there a relationship between dihydrotestosterone and tissue remodeling observed alongside androgenic alopecia onset? We review evidence supporting and challenging dihydrotestosterone's causal relationship with androgenic alopecia, then propose an evidence-based pathogenesis model that attempts to answer the above questions, account for additionally-suspected androgenic alopecia mediators, identify rate-limiting recovery factors, and elucidate better treatment targets. The hypothesis argues that: (1) chronic scalp tension transmitted from the galea aponeurotica induces an inflammatory response in androgenic alopecia-prone tissues; (2) dihydrotestosterone increases in androgenic alopecia-prone tissues as part of this inflammatory response; and (3) dihydrotestosterone does not directly miniaturize hair follicles. Rather, dihydrotestosterone is a co-mediator of tissue dermal sheath thickening, perifollicular fibrosis, and calcification - three chronic, progressive conditions concomitant with androgenic alopecia progression. These conditions remodel androgenic alopecia-prone tissues - restricting follicle growth space, oxygen, and nutrient supply - leading to the slow, persistent hair follicle miniaturization characterized in androgenic alopecia. If true, this hypothetical model explains the mechanisms by which dihydrotestosterone miniaturizes androgenic alopecia-prone hair follicles, describes a rationale for androgenic alopecia progression and patterning, makes sense of dihydrotestosterone's paradoxical role in hair loss and hair growth, and identifies targets to further improve androgenic alopecia recovery rates: fibrosis, calcification, and chronic scalp tension.
Mechanical stretch induces hair regeneration through the alternative activation of macrophages.
Chu Szu-Ying,Chou Chih-Hung,Huang Hsien-Da,Yen Meng-Hua,Hong Hsiao-Chin,Chao Po-Han,Wang Yu-Hsuan,Chen Po-Yu,Nian Shi-Xin,Chen Yu-Ru,Liou Li-Ying,Liu Yu-Chen,Chen Hui-Mei,Lin Feng-Mao,Chang Yun-Ting,Chen Chih-Chiang,Lee Oscar K
Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Mechanical stimulations affect cell proliferation, differentiation, and migration, as well as determining tissue homeostasis and repair. By using a specially designed skin-stretching device, we discover that hair stem cells proliferate in response to stretch and hair regeneration occurs only when applying proper strain for an appropriate duration. A counterbalance between WNT and BMP-2 and the subsequent two-step mechanism are identified through molecular and genetic analyses. Macrophages are first recruited by chemokines produced by stretch and polarized to M2 phenotype. Growth factors such as HGF and IGF-1, released by M2 macrophages, then activate stem cells and facilitate hair regeneration. A hierarchical control system is revealed, from mechanical and chemical signals to cell behaviors and tissue responses, elucidating avenues of regenerative medicine and disease control by demonstrating the potential to manipulate cellular processes through simple mechanical stimulation.
Hair Cell Regeneration.
Chen Yan,Zhang Shasha,Chai Renjie,Li Huawei
Advances in experimental medicine and biology
Cochlear hair cells are mechanoreceptors of the auditory system and cannot spontaneously regenerate in adult mammals; thus hearing loss due to hair cell damage is permanent. In contrast, hair cells in nonmammalian vertebrates such as birds and in the zebrafish lateral line have the ability to regenerate after hair cell loss. Many regulatory factors, including signaling pathways, transcription factors, and epigenetic regulators, play roles in hair cell regeneration in various species. In this chapter, we review the history of hair cell regeneration research, the methods used in the study of hair cell regeneration, the properties and modulating factors of inner ear stem cells, and the re-formation of cochlear ribbon synapses and hearing function recovery.
Multifunctional Zn doped hollow mesoporous silica/polycaprolactone electrospun membranes with enhanced hair follicle regeneration and antibacterial activity for wound healing.
Zhang Yu,Chang Mengling,Bao Feng,Xing Min,Wang Endian,Xu Qing,Huan Zhiguang,Guo Feng,Chang Jiang
Due to the complexity of the skin tissue structure, the regeneration of the entire skin, including skin appendages such as hair follicles, is a big challenge. In addition, skin trauma is often accompanied by bacterial infections that delay the wound healing. Therefore, developing wound dressings, which promote hair follicle regeneration and inhibit bacterial infection in the wound healing process, is of great clinical significance. In this study, Zn doped hollow mesoporous silica nanospheres (HMZS) were synthesized by a sol-gel method and a novel wound healing dressing was prepared by incorporation of drug ciprofloxacin hydrochloride (CiH)-loaded Zn containing mesoporous silica nanospheres (CiH-HMZS) into polycaprolactone (PCL) electrospun fibers. The CiH-HMZS/P nano-composite electrospun fibers exhibit the ability to promote angiogenesis and skin regeneration by releasing Si ions, and the activity to enhance hair follicle regeneration and inhibit bacterial growth by releasing zinc ions and achieve the synergistic antibacterial effect with both Zn ions and CiH in low concentrations. Thus, the CiH-HMZS/P nano-composite membrane is a promising multi-functional wound healing material for inhibiting bacterial growth in infected wounds and enhancing skin wound healing including hair follicle regeneration.
Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells.
Lei Mingxing,Schumacher Linus J,Lai Yung-Chih,Juan Wen-Tau,Yeh Chao-Yuan,Wu Ping,Jiang Ting-Xin,Baker Ruth E,Widelitz Randall Bruce,Yang Li,Chuong Cheng-Ming
Proceedings of the National Academy of Sciences of the United States of America
Organoids made from dissociated progenitor cells undergo tissue-like organization. This in vitro self-organization process is not identical to embryonic organ formation, but it achieves a similar phenotype in vivo. This implies genetic codes do not specify morphology directly; instead, complex tissue architectures may be achieved through several intermediate layers of cross talk between genetic information and biophysical processes. Here we use newborn and adult skin organoids for analyses. Dissociated cells from newborn mouse skin form hair primordia-bearing organoids that grow hairs robustly in vivo after transplantation to nude mice. Detailed time-lapse imaging of 3D cultures revealed unexpected morphological transitions between six distinct phases: dissociated cells, cell aggregates, polarized cysts, cyst coalescence, planar skin, and hair-bearing skin. Transcriptome profiling reveals the sequential expression of adhesion molecules, growth factors, Wnts, and matrix metalloproteinases (MMPs). Functional perturbations at different times discern their roles in regulating the switch from one phase to another. In contrast, adult cells form small aggregates, but then development stalls in vitro. Comparative transcriptome analyses suggest suppressing epidermal differentiation in adult cells is critical. These results inspire a strategy that can restore morphological transitions and rescue the hair-forming ability of adult organoids: () continuous PKC inhibition and () timely supply of growth factors (IGF, VEGF), Wnts, and MMPs. This comprehensive study demonstrates that alternating molecular events and physical processes are in action during organoid morphogenesis and that the self-organizing processes can be restored via environmental reprogramming. This tissue-level phase transition could drive self-organization behavior in organoid morphogenies beyond the skin.
Stem cell plasticity enables hair regeneration following Lgr5 cell loss.
Hoeck Joerg D,Biehs Brian,Kurtova Antonina V,Kljavin Noelyn M,de Sousa E Melo Felipe,Alicke Bruno,Koeppen Hartmut,Modrusan Zora,Piskol Robert,de Sauvage Frederic J
Nature cell biology
Under injury conditions, dedicated stem cell populations govern tissue regeneration. However, the molecular mechanisms that induce stem cell regeneration and enable plasticity are poorly understood. Here, we investigate stem cell recovery in the context of the hair follicle to understand how two molecularly distinct stem cell populations are integrated. Utilizing diphtheria-toxin-mediated cell ablation of Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5) stem cells, we show that killing of Lgr5 cells in mice abrogates hair regeneration but this is reversible. During recovery, CD34 (CD34 antigen) stem cells activate inflammatory response programs and start dividing. Pharmacological attenuation of inflammation inhibits CD34 cell proliferation. Subsequently, the Wnt pathway controls the recovery of Lgr5 cells and inhibition of Wnt signalling prevents Lgr5 cell and hair germ recovery. Thus, our study uncovers a compensatory relationship between two stem cell populations and the underlying molecular mechanisms that enable hair follicle regeneration.
Hair regeneration using adipose-derived stem cells.
Jin Su-Eon,Sung Jong-Hyuk
Histology and histopathology
Adipose-derived stem cells (ASCs) have been used in tissue repair and regeneration. Recently, it was reported that ASC transplantation promotes hair growth in animal experiments, and a conditioned medium of ASCs (ASC-CM) induced the proliferation of hair-compositing cells in vitro. However, ASCs and their conditioned medium have shown limited effectiveness in clinical settings. ASC preconditioning is one strategy that can be used to enhance the efficacy of ASCs and ASC-CM. Therefore, we highlighted the functional role of ASCs in hair cycle progression and also the advantages and disadvantages of their application in hair regeneration. In addition, we introduced novel ASC preconditioning methods to enhance hair regeneration using ASC stimulators, such as vitamin C, platelet-derived growth factor, hypoxia, and ultraviolet B.
Hair Follicle and Sebaceous Gland De Novo Regeneration With Cultured Epidermal Stem Cells and Skin-Derived Precursors.
Wang Xiaoxiao,Wang Xusheng,Liu Jianjun,Cai Ting,Guo Ling,Wang Shujuan,Wang Jinmei,Cao Yanpei,Ge Jianfeng,Jiang Yuyang,Tredget Edward E,Cao Mengjun,Wu Yaojiong
Stem cells translational medicine
: Stem cell-based organ regeneration is purported to enable the replacement of impaired organs in the foreseeable future. Here, we demonstrated that a combination of cultured epidermal stem cells (Epi-SCs) derived from the epidermis and skin-derived precursors (SKPs) was capable of reconstituting functional hair follicles and sebaceous glands (SG). When Epi-SCs and SKPs were mixed in a hydrogel and implanted into an excisional wound in nude mice, the Epi-SCs formed de novo epidermis along with hair follicles, and SKPs contributed to dermal papilla in the neogenic hair follicles. Notably, a combination of culture-expanded Epi-SCs and SKPs derived from the adult human scalp were sufficient to generate hair follicles and hair. Bone morphogenetic protein 4, but not Wnts, sustained the expression of alkaline phosphatase in SKPs in vitro and the hair follicle-inductive property in vivo when SKPs were engrafted with neonatal epidermal cells into excisional wounds. In addition, Epi-SCs were capable of differentiating into sebocytes and formed de novo SGs, which excreted lipids as do normal SGs. Thus our results indicate that cultured Epi-SCs and SKPs are sufficient to generate de novo hair follicles and SGs, implying great potential to develop novel bioengineered skin substitutes with appendage genesis capacity. SIGNIFICANCE:In postpartum humans, skin appendages lost in injury are not regenerated, despite the considerable achievement made in skin bioengineering. In this study, transplantation of a combination of culture-expanded epidermal stem cells and skin-derived progenitors from mice and adult humans led to de novo regeneration of functional hair follicles and sebaceous glands. The data provide transferable knowledge for the development of novel bioengineered skin substitutes with epidermal appendage regeneration capacity.
Noncoding dsRNA induces retinoic acid synthesis to stimulate hair follicle regeneration via TLR3.
Kim Dongwon,Chen Ruosi,Sheu Mary,Kim Noori,Kim Sooah,Islam Nasif,Wier Eric M,Wang Gaofeng,Li Ang,Park Angela,Son Wooyang,Evans Benjamin,Yu Victoria,Prizmic Vicky P,Oh Eugene,Wang Zixiao,Yu Jianshi,Huang Weiliang,Archer Nathan K,Hu Zhiqi,Clemetson Nashay,Nelson Amanda M,Chien Anna,Okoye Ginette A,Miller Lloyd S,Ghiaur Gabriel,Kang Sewon,Jones Jace W,Kane Maureen A,Garza Luis A
How developmental programs reactivate in regeneration is a fundamental question in biology. We addressed this question through the study of Wound Induced Hair follicle Neogenesis (WIHN), an adult organogenesis model where stem cells regenerate de novo hair follicles following deep wounding. The exact mechanism is uncertain. Here we show that self-noncoding dsRNA activates the anti-viral receptor toll like receptor 3 (TLR3) to induce intrinsic retinoic acid (RA) synthesis in a pattern that predicts new hair follicle formation after wounding in mice. Additionally, in humans, rejuvenation lasers induce gene expression signatures for dsRNA and RA, with measurable increases in intrinsic RA synthesis. These results demonstrate a potent stimulus for RA synthesis by non-coding dsRNA, relevant to their broad functions in development and immunity.
Sericin hydrogels promote skin wound healing with effective regeneration of hair follicles and sebaceous glands after complete loss of epidermis and dermis.
Qi Chao,Xu Luming,Deng Yan,Wang Guobin,Wang Zheng,Wang Lin
Full-thickness skin injury affects millions of people worldwide each year. It often leads to scar formation and loss of skin appendages even after clinical treatment. The majority of wound dressings currently used cannot achieve scarless skin regeneration with complete recovery of appendages such as hair follicles and sebaceous glands. Functional regeneration of these skin appendages is a great challenge. However, we achieved this goal by the successful development and utilization of a photo-crosslinkable sericin hydrogel (SMH) as a new type of wound dressing for repairing full-thickness skin injury. SMH implanted in a mouse full-thickness skin injury model promoted scarless wound healing with effective regeneration of hair follicles and sebaceous glands. By employing techniques of molecular biology, biochemistry, and in vivo cell tracing, we revealed the underlying repair mechanisms: SMH inhibited inflammation, stimulated angiogenesis during healing process, prevented scar tissue formation via regulating the expressions of TGF-β1 and TGF-β3, and recruited mesenchymal stem cells to injury sites for regeneration of skin appendages. Collectively, in this study, we developed a sericin-based hydrogel as a wound dressing for full-thickness skin injury repair, uncovered the functional roles of sericin hydrogels in promoting scarless skin regeneration along with effective recovery of skin appendages, and thus unveiled sericin's potential for skin wound healing.
iNOS inhibits hair regeneration in obese diabetic (ob/ob) mice.
Sasaki Mari,Shinozaki Shohei,Morinaga Hironobu,Kaneki Masao,Nishimura Emi,Shimokado Kentaro
Biochemical and biophysical research communications
Previous studies have shown that androgenic alopecia is associated with metabolic syndrome and diabetes. However, the detailed mechanism whereby diabetes causes alopecia still remains unclear. We focused on the inflammatory response that is caused by diabetes or obesity, given that inflammation is a risk factor for hair loss. Inducible nitric oxide synthase (iNOS) is known to be upregulated under conditions of acute or chronic inflammation. To clarify the potential role of iNOS in diabetes-related alopecia, we generated obese diabetic iNOS-deficient (ob/ob; iNOS-KO mice). We observed that ob/ob; iNOS-KO mice were potentiated for the transition from telogen (rest phase) to anagen (growth phase) in the hair cycle compared with iNOS-proficient ob/ob mice. To determine the effect of nitric oxide (NO) on the hair cycle, we administered an iNOS inhibitor intraperitoneally (compound 1400 W, 10 mg/kg) or topically (10% aminoguanidine) in ob/ob mice. We observed that iNOS inhibitors promoted anagen transition in ob/ob mice. Next, we administered an NO donor (S-nitrosoglutathione, GSNO), to test whether NO has the telogen elongation effects. The NO donor was sufficient to induce telogen elongation in wild-type mice. Together, our data indicate that iNOS-derived NO plays a role in telogen elongation under the inflammatory conditions associated with diabetes in mice.
Up-to-date Clinical Trials of Hair Regeneration Using Conditioned Media of Adipose-Derived Stem Cells in Male and Female Pattern Hair Loss.
Shin Hyoseung,Won Chong Hyun,Chung Woon-Kyung,Park Byung-Soon
Current stem cell research & therapy
BACKGROUND:The primary roles of mesenchymal stem cells (MSCs) are to maintain the stem cell niche, facilitate recovery after injury, and ensure healthy aging and the homeostasis of organ and tissues. MSCs have recently emerged as a new therapeutic option for hair loss. OBJECTIVE:Since adipose-derived stem cells (ADSCs) are the most accessible sources of MSCs, ADSCbased hair regeneration is investigated. Besides replacing degenerated cells in affected organs, ADSCs exhibit their beneficial effects through the paracrine actions of various cytokines and growth factors. RESULTS:Several laboratory experiments and animal studies have shown that ADSC-related proteins can stimulate hair growth. In addition, we introduce our clinical pilot studies using conditioned media of ADSCs for pattern hair loss in men and women. CONCLUSION:We believe that conditioned media of ADSCs represents a promising alternative therapeutic strategy for hair loss. We also discuss practical therapeutic challenges and the direction of future research.
Activation of mTORC1 Signaling is Required for Timely Hair Follicle Regeneration from Radiation Injury.
Wang Wei-Hung,Chien Ting-Han,Fan Sabrina Mai-Yi,Huang Wen-Yen,Lai Shih-Fan,Wu June-Tai,Lin Sung-Jan
Transit amplifying cells (TACs) are highly proliferative in nature and tend to be sensitive to ionizing radiation. Due to the abundance of TACs that support the elongation of hair shafts, growing hair follicles are highly sensitive to radiation injury. How hair follicles repair themselves after radiation injury is unclear. In this study, we observed that in 4 Gy irradiated mice, hair follicle dystrophy was induced with apoptosis-driven loss of hair matrix cells, which are the TACs that fuel hair growth. The dystrophy was repaired within 96 h without significant hair loss, indicating that a regenerative attempt successfully restored the TAC population to resume anagen growth. Soon after irradiation, mTORC1 signaling was activated in the TAC compartment and its activation was maintained until the regeneration process was completed. Inhibition of mTORC1 by rapamycin treatment increased radiation-induced cell apoptosis, reduced cell proliferation and delayed restoration of Wnt signaling in the hair matrix after radiation injury, leading to prolonged dystrophy and hair loss. These results demonstrate that mTORC1 signaling is activated after irradiation and is required for timely regeneration of the TAC pool of hair follicles, so that hair growth can resume after radiation injury.
Hair follicle stem cell proliferation, Akt and Wnt signaling activation in TPA-induced hair regeneration.
Qiu Weiming,Lei Mingxing,Zhou Ling,Bai Xiufeng,Lai Xiangdong,Yu Yu,Yang Tian,Lian Xiaohua
Histochemistry and cell biology
Regeneration of hair follicles relies on activation of hair follicle stem cells during telogen to anagen transition process in hair cycle. This process is rigorously controlled by intrinsic and environmental factors. 12-o-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter, accelerates reentry of hair follicles into anagen phase. However, it is unclear that how TPA promotes the hair regeneration. In the present study, we topically applied TPA onto the dorsal skin of 2-month-old C57BL/6 female mice to examine the activity of hair follicle stem cells and alteration of signaling pathways during hair regeneration. We found that refractory telogen hair follicles entered anagen prematurely after TPA treatment, with the enhanced proliferation of CD34-positive hair follicle stem cells. Meanwhile, we observed Akt signaling was activated in epidermis, hair infundibulum, bulge and hair bulb, and Wnt signaling was also activated after hair follicle stem cells proliferation. Importantly, after overexpression of DKK1, a specific Wnt signaling inhibitor, the accelerated reentry of hair follicles into anagen induced by TPA was abolished. Our data indicated that TPA-induced hair follicle regeneration is associated with activation of Akt and Wnt/β-catenin signaling.
Engineering the niche for hair regeneration - A critical review.
Nilforoushzadeh Mohammad Ali,Zare Mehrak,Zarrintaj Payam,Alizadeh Effat,Taghiabadi Ehsan,Heidari-Kharaji Maryam,Amirkhani Mohammad Amir,Saeb Mohammad Reza,Mozafari Masoud
Nanomedicine : nanotechnology, biology, and medicine
Recent progress in hair follicle regeneration and alopecia treatment necessitates revisiting the concepts and approaches. In this sense, there is a need for shedding light on the clinical and surgical therapies benefitting from nanobiomedicine. From this perspective, this review attempts to recognize requirements upon which new hair therapies are grounded; to underline shortcomings and opportunities associated with recent advanced strategies for hair regeneration; and most critically to look over hair regeneration from nanomaterials and pluripotent stem cell standpoint. It is noteworthy that nanotechnology is able to illuminate a novel path for reprogramming cells and controlled differentiation to achieve the desired performance. Undoubtedly, this strategy needs further advancement and a lot of critical questions have yet to be answered. Herein, we introduce the salient features, the hurdles that must be overcome, the hopes, and practical constraints to engineer stem cell niches for hair follicle regeneration.