Retinoic acid drives hair follicle stem cell activation via Wnt/ß-catenin signalling in androgenetic alopecia.

BACKGROUND: Depletion or permanent quiescence of the hair follicle stem cell (HFSC) pool underlies pathogenesis in androgenetic alopecia (AGA). Reactivation of quiescent HFSCs is considered an efficient treatment strategy for hair loss. The retinoic acid (RA) is critical to ensure stem cell homeostasis and function. However, little is known about whether RA regulates HFSC homeostasis. We aimed to investigate the impact of RA on HFSC homeostasis and the underlying mechanisms, in order to provide new potential targets for medical therapies of AGA. METHODS: Microdissected hair follicles from the occipital and frontal scalp in AGA were obtained for RNA sequencing analysis and test. The C57BL/6 mice model in telogen was established to investigate the effect of exogenous RA. Miniaturized hair follicles from frontal scalp were incubated with or without RA in hair follicle organ culture to test the effects on hair shaft elongation, hair cycling and HFSC activities. A strategy to characterize the effect of RA on HFSC in primary culture was developed to identify novel mechanisms that control HFSC activation. A clinical study was performed to test the efficacy of RA treatment in AGA patients. RESULTS: RA signalling was inhibited in the course of AGA pathogenesis along with HFSC dysfunction. Hair regeneration was retarded in AGA miniaturized hair follicles with RA deficiency, but they tended to recover after treatment with RA. In addition, RA treatment during the telogen phase facilitated HFSC anagen entry and accelerated hair growth. Mechanistically, RA promoted hair growth by stimulating stem cells via Wnt/ß-catenin signalling and accelerating the transition from a dormant to an activated state. Furthermore, a clinical study suggested that RA has obvious advantages in the early intervention of AGA by reactivating HFSCs. CONCLUSIONS: Our study provides insights into the reactivation of HFSCs in AGA and provides potential targets for medical therapies.

Feasibility of adipose-derived therapies for hair regeneration: Insights based on signaling interplay and clinical overview.

Dermal white adipose tissue (dWAT) is a dynamic component of the skin and closely interacts with the hair follicle. Interestingly, dWAT envelops the hair follicle during anagen and undergoes fluctuations in volume throughout the hair cycle. dWAT-derived extracellular vesicles can significantly regulate the hair cycle, and this provides a theoretical basis for utilizing adipose tissue as a feasible clinical strategy to treat hair loss. However, the amount and depth of the available literature are far from enough to fully elucidate the prominent role of dWAT in modulating the hair growth cycle. This review starts by investigating the hair cycle-coupled dWAT remodeling and the reciprocal signaling interplay underneath. Then, it summarizes the current literature and assesses the advantages and limitations of clinical research utilizing adipose-derived therapies for hair regeneration.

Evaluation of a Novel Graft-Holding Solution in Hair Transplantation: A Randomized Controlled Clinical Study.

BACKGROUND: Hair transplantation has become a popular choice for alopecia treatment; however, postsurgical hair shedding still annoys both patients and surgeons. OBJECTIVE: To explore the impact of graft-holding solution on postsurgical hair shedding and testify the protective efficacy of histidine-tryptophan-ketoglutarate solution with adenosine triphosphate and deferoxamine (HTK-AD). METHODS: There were 240 patients enrolled in the study, and the follicles were placed into either HTK-AD or Ringer solution (RS). Masson staining and live/dead staining were performed to evaluate graft morphology and apoptosis levels, respectively. The between-group comparison of postsurgical graft shedding, survival rate, complications, and patient satisfaction was performed. RESULTS: Grafts in HTK-AD maintained organized dense collagen construction and higher cell viability, but those preserved in RS became soft, which hindered implantation. Histidine-tryptophan-ketoglutarate solution with adenosine triphosphate and deferoxamine significantly reduced the incidence of postsurgical hair shedding (73.81% vs 95%), delayed shedding onset, and diminished shedding amount versus RS ( p < .05) when ≥3,000 grafts were transplanted. The shedding duration was shortened, and hair regrowth started earlier in HTK-AD versus RS ( p < .05); thus, satisfaction was increased. The final survival rate showed no difference between 2 groups. CONCLUSION: Histidine-tryptophan-ketoglutarate solution with adenosine triphosphate and deferoxamine is superior to RS for hair graft preservation because it improves graft viability and alleviates postsurgical shedding.

Overexpression of miR-122 promotes apoptosis of dermal papilla cells by directly targeting IGF1R in androgenetic alopecia.

Androgenetic alopecia (AGA) is the most common pattern of hair loss resulting from the effects of androgen on hair follicles. MicroRNAs (miRs) serve imperative roles in the regulation of many biological processes of hair follicles. However, the exact molecular mechanism of AGA remains to be elucidated. In the present study, we found miR-122, which is mainly recognized as a tumor suppressor, was highly overexpressed in the bulb of balding hair follicles in comparison with nonbalding ones in AGA. Moreover, miR-122 induces apoptosis of human dermal papilla cells (hDPCs) with miR-122 mimics in vitro, and the expression of insulin-like growth factor 1 receptor (IGF1R) in hDPCs was reduced following upregulation of miR-122. Mechanistically, dual-luciferase reporter assay confirmed that miR-122 directly targeted the 3'-untranslated region of IGF1R. These findings suggested that upregulation of miR-122 induces apoptosis, potentially via the repression of IGF1R in hDPCs of AGA, providing a novel insight into the potential pathological mechanism of miR-122 in AGA DPCs.

Nanoscale microenvironment engineering for expanding human hair follicle stem cell and revealing their plasticity.

BACKGROUND: Periodically regenerated hair follicles provide an excellent research model for studying tissue regeneration and stem cell homeostasis. Periodic activation and differentiation of hair follicle stem cells (HFSCs) fuel cyclical bouts of hair regeneration. HFSCs represent an excellent paradigm for studying tissue regeneration and somatic stem cell homeostasis. However, these crucial studies are hampered by the lack of a culture system able to stably expand human HFSCs and regulate their fate. RESULTS: Here, we use layer-by-layer (LbL) self-assembly with gelatin/alginate to construct a nanoscale biomimetic extracellular matrix (ECM) for an HFSC population. The LbL coating provides ECM and mechanical support for individual cells, which helps to maintain the CD200+α6+ HFSC population to a certain extent. Addition of key signal molecules (FGF-7 and VEGF-A) simulates the minimum essential components of the stem cell microenvironment, thereby effectively and stably expanding HFSCs and maintaining the CD200+α6+ HFSC population. Subsequently, BMP2 loaded to the nanocoated layer, as a slow-release signal molecule, activates BMP signaling to regulate HFSCs' fate in order to obtain a purified CD200+α6+ HFSC population. CONCLUSION: This system can minimize the microenvironment of HFSCs; thus, stably amplifying HFSCs and revealing their plasticity. Our study thus provides a new tool for studies of hair follicle reconstruction and stem cell homeostasis.

Effect of De-epithelialization on Graft Survival Rate After Follicular Unit Extraction.

BACKGROUND: To achieve a natural postoperative appearance, hair grafts are often de-epithelialized from the epidermis during follicular unit extraction (FUE). However, the effect of de-epithelialization on the survival rate of transplanted hair follicles (HFs) has not been investigated. OBJECTIVE: To investigate the effect of de-epithelialization on the survival rate of transplanted HFs. METHODS: A total of 64 male patients with androgenetic alopecia were included in this study. They were randomly divided into de-epithelialization and control groups. Organ culture was performed to assess the elongation of hair shaft and the percentage of anagen HFs in both groups. Patients were followed up postoperatively to evaluate complications, postoperative shedding, survival rates, and satisfaction. RESULTS: No significant difference in hair shaft elongation and percentage of anagen HFs was observed between both groups. The immediate postoperative satisfaction in the control group was much lower than that in the de-epithelialization group (71.25% and 100%, respectively). No significant differences in shedding rate, graft survival rate, and complications were noticed between both groups. CONCLUSION: Follicular de-epithelialization does not affect the survival rate of graft in FUE. Based on these data, de-epithelialization may improve immediate postoperative appearance and lead to a more pleasing cosmetic outcome.

Extensive Scarring Alopecia Treated Through a Single Dense-Packing Follicular Unit Extraction Megasession.

BACKGROUND: Follicular unit extraction (FUE) is becoming more popular in hair restoration. However, its potential for treating extensive scarring alopecia is unknown. METHODS: Patients with scarring alopecia larger than 100 cm2 were enrolled from 2015 to 2018. After assessing scar quality regarding vascularity, pliability, and thickness, dense-packing megasession (DPM)-FUE was performed on high-quality recipient sites. Patients were followed up at 1 week and 12 months postoperatively to evaluate complications, survival rates of grafts, and patient satisfactions. Cases of nonscarring alopecia were reviewed as controls. RESULTS: Fifty-two scarring alopecia and 55 nonscarring alopecia patients were enrolled. The mean scar area was 120 cm2, and the procedure required an average of 8 operative hours, with no difference between groups (p > .05). Graft amount and postoperative complications were similar as well (p > .05). The survival rate in scarring alopecia was lower than that in the control but was still 85% (p < .05). Follow-up photographs showed effective scar camouflage after DPM-FUE. Most patients were very satisfied with the final results (p > .05). CONCLUSION: DPM-FUE is a safe and effective treatment for extensive scarring alopecia.

Comparison of low-level light therapy and combination therapy of 5% minoxidil in the treatment of female pattern hair loss.

This study was conducted in order to compare the safety and efficacy of LLLT, 5% minoxidil, and combination therapy in the treatment of FPHL. A randomized controlled trial was developed to study the effect of LLLT on FPHL using a device called iHelmet®, which is equipped with 200 5mW laser diode source (650 nm) arrays. Ninety Ludwig's types II-III FPHL patients were randomly divided into 3 groups: LLLT group (A), 5% minoxidil group (B), and combination group(C). Hair density, hair diameter, and scalp oil-secretion were detected to evaluate the treatment effect. Significant improvement of hair density and hair diameter was observed in all stages of FPHL after treatment. Oil-secretion of the three groups was decreased after treatment. The effectiveness of reducing oil-secretion in LLLT group and combination group was higher than minoxidil group (P < 0.05). For improving hair diameter and hair density, combination group was better than LLLT and minoxidil groups. No side effects were reported. Our study illustrated that LLLT is a safe and effective treatment for FPHL. Besides, LLLT can significantly improve its efficacy when used in combination with 5% minoxidil.

The effectiveness of combination therapies for androgenetic alopecia: A systematic review and meta-analysis.

Androgenetic alopecia (AGA) is the most common type of baldness affecting both men and women. Studies investigating combination therapies for AGA reported greater efficacy than monotherapy but without rigorous examination. The authors performed a meta-analysis and systemic review to further verify the evidence. To evaluate the effectiveness of three common combination therapies of minoxidil with finasteride, low-level laser light therapy (LLLT) or microneedling versus minoxidil monotherapy. We conducted a systematic review of randomized controlled trials (RCTs) of combination therapies consisting of topical minoxidil for AGA through April 2020. Quality assessment and data analysis were performed by Review Manager 5.3. Fifteen studies met the inclusion criteria involving a total of 1172 AGA patients. We conducted meta-analysis for three groups of combined treatment separately, and all were superior to monotherapy in terms of global photographic assessment (P < .05). Combination of LLLT or microneedling with minoxidil also showed significant increase in hair count (P < .05) compared to monotherapy. The present study suggests that combination therapy could be an effective, safe and promising option for the treatment of AGA. However, more RCTs are needed to further investigate and confirm the efficacy of combined treatment.

Evaluating the Satisfaction of Patients Undergoing Hair Transplantation Surgery Using the FACE-Q Scales.

BACKGROUND: It is necessary to evaluate a successful cosmetic procedure from the patients' perspective. FACE-Q is a patient-reported outcome scale for patients undergoing cosmetic procedures. However, currently there are no FACE-Q scales used in the field of hair transplant surgery. This article aims to apply FACE-Q scales to evaluate the satisfaction of patients undergoing hair transplantation surgery. METHODS: FACE-Q scales were modified to contain both preoperative and 6-month postoperative self-assessment, including baseline preoperative information of patients (such as age, family history of alopecia, Hamilton' alopecia grade),preoperative self-assessment (satisfaction with appearance, the preoperative visual age, expected visual age) and postoperative self-assessment (satisfaction with appearance, postoperative visual age, satisfaction with decision, psychological well-being and social function). Besides, early life impact and recovery early symptoms were also re-evaluated. RESULTS: The mean difference between the 6-month satisfaction with appearance and baseline scores showed a significant increase of 29.62 (baseline, 46.97; 6-month, 76.59; P < 0.001) and patients perceived they appeared 5.81 years younger after surgery (P < 0.001). Postoperative satisfaction with appearance has no significant relevance with gender (P = 0.460), age (P = 0.529), marriage (P = 0.811) or family history of alopecia (P = 0.641). However, income (P = 0.003), educational level (P = 0.003), the purpose of hair transplantation (P = 0.018) and early life impact (P = 0.002) were shown to have a significant impact on satisfaction with appearance. CONCLUSIONS: The FACE-Q scales are a valid and reliable patient-reported outcome tool for patients undergoing hair transplantation and can be widely used to evaluate the satisfaction of patients undergoing such surgery. LEVEL OF EVIDENCE IV: 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 .

Evaluation Indicators of Aesthetic Effects on Hair Transplantation.

Hair transplantation involves the transplantation of hair, beard, eyebrows, eyelashes, and pubic hair. Based on our experience, the aesthetic result of hair transplantation mainly relies on 4 indicators, including selection of the donor site, direction and angle of grafted hairs, density, and survival rate of implanted hair follicles. We believe that good results can be achieved as long as attention is paid to the above 4 points.

Recipient site scalp necrosis: A rare postoperative complication of hair transplantation.

BACKGROUND: Recipient area scalp necrosis is considered a potential complication of hair transplantation, but has rarely been reported. A small number of patients have developed scalp necrosis after hair transplantation with the widely used Follicular unit excision (FUE) technique. There are no guidelines to prevent and manage this complication. The aim of this study was to provide an insight into the pathogenesis, prevention, and management of scalp necrosis following hair transplantation. METHODS: From 2012 to 2021, among more than 10 000 patients who underwent hair transplantation, only three developed scalp necrosis in our clinical experience, besides, one patient transferred to our hospital because of scalp necrosis after undergoing hair transplantation. According to the disease etiology and patients' symptom, a combination of wound management and antimicrobial therapy was employed. This study was approved by the institutional ethics committee of Nanfang Hospital. RESULTS: Of the four patients, three received timely treatment and had a good prognosis. Necrosis became confined and healed within 2-3 weeks. Grafts in the lesion area partially survived. In case 4, due to improper treatment at the early stage, the lesion developed extensively and deeply, which not only delayed wound healing, but also resulted in complete loss of grafts. CONCLUSION: Preoperative prophylaxis, timely diagnosis, and immediate treatment of scalp necrosis can prevent serious complications and reduce morbidity after hair transplantation.

A randomized controlled trial on hair follicular-derived microtissue for promoting wound healing and alleviating postoperative complications after hair transplantation.

BACKGROUND: Hair transplantation, particularly through follicular unit extraction (FUE), can lead to postoperative complications, such as numbness, itching, and pain in donor areas, primarily because of delayed wound healing. Efficient management of donor-site healing is crucial to mitigate these complications and improve overall patient outcomes. OBJECTIVE: This study aimed to assess the efficacy of hair follicular-derived microtissue (HFMT) in promoting wound healing and alleviating postoperative complications in donor areas after FUE hair transplantation. METHODS: Perifollicular tissue obtained during the trimming phase of hair transplantation was processed into HFMT and analyzed for its properties using histological and molecular techniques. In a single-blind, split-scalp study involving 98 participants, Group A received HFMT or mupirocin, whereas Group B received HFMT or no treatment. Dermatoscopic images were captured postoperatively, and visual analog scale scores were used to evaluate pain, itching, and numbness. RESULTS: HFMT-treated donor sites in Group A demonstrated a significantly higher wound closure ratio on postoperative day 3 than mupirocin-treated sites. Pain scores for HFMT-treated sites were consistently lower on postoperative days 3, 5, and 7. Similar trends were observed for itching scores. Group B exhibited outcomes comparable with Group A. CONCLUSION: The application of HFMT homogenates effectively accelerated wound healing and alleviated donor-site complications after FUE hair transplantation.

Autophagy induces hair follicle stem cell activation and hair follicle regeneration by regulating glycolysis.

BACKGROUND: Hair follicle stem cells (HFSCs) typically remain quiescent and are activated only during the transition from telogen to anagen to ensure that the hair follicle enters a new cycle. The metabolic behavior of stem cells in tissues is regulated by macroautophagy/autophagy, and changes in HFSC metabolism directly affect their activation and maintenance. However, the role of autophagy in the regulation of HFSC metabolism and function remains unclear. METHODS: Back skin samples were obtained from mice at different hair follicle cycle stages, and immunofluorescence staining was used to monitor autophagy in HFSCs. Mouse and human hair follicles were treated with rapamycin (Rapa, an autophagy activator) or 3-methyladenine (3-MA, an autophagy inhibitor). The effects of autophagy on the hair follicle cycle and HFSC were investigated by imaging, cell proliferation staining, and HFSC-specific marker staining. The influence and mechanism of autophagy on HFSC metabolism were explored using RNA sequencing, real-time polymerase chain reaction, immunohistochemical staining, and detection of lactate and glucose concentrations. Finally, the influence of autophagy-induced glycolysis on HFSC and the hair follicle cycle was verified by stem cell characteristics and in vivo functional experiments. RESULTS: Autophagy in HFSC was highest during the transition from telogen to anagen. Inhibiting autophagy with 3-MA led to early entry into catagen and prolonged telogen, whereas Rapa promoted autophagy and hair growth. Autophagy activated HFSC by increasing the expression and activity of HFSC lactate dehydrogenase (Ldha), thereby transforming HFSC metabolism into glycolysis. Inhibition of Ldha expression counteracted the effects of autophagy. CONCLUSIONS: Autophagy activated HFSC by promoting the transition from HFSC metabolism to glycolysis, ultimately initiating the hair follicle cycle and promoting hair growth.

Minimal Invasive Removal of Leukotrichia and Hair Transplantation: A Two-step Surgery in the Treatment of Stable Follicular Vitiligo.

BACKGROUND: Follicular vitiligo is a distinct subtype of vitiligo characterized by the selective destruction of the follicular melanocytic reservoir. The treatment of follicular vitiligo-associated leukotrichia has always been a clinical challenge. METHODS: Twenty participants with stable follicular vitiligo were recruited between 2020 to 2021 and accepted two-stage surgery. In stage one, an incision around the vitiligo lesion was performed to subcutaneously dissect and scrape the leukotrichia. In stage two, healthy follicles obtained from the occipital donor site were transplanted into the vitiligo area. Follow-up examinations were conducted for a year postoperatively by the camera and dermatoscope to observe the growth state, the color and the surviving number of the transplanted hairs. Besides, the satisfaction of the patients was recorded to evaluate the potential surgical improvement. RESULTS: Twenty patients with stable follicular vitiligo underwent two-stage surgery and their mean age was 29 years old. The transplanted hair grew with natural texture as expected. The average survival rate of the transplanted hair follicles was 93.8%. No recurrence of leukotrichia showed up in the recipient area. No complications were observed and the postoperative scars in the recipient area were entirely covered by black hair. All patients were satisfied with the resulting cosmetic appearance. CONCLUSIONS: Minimally invasive removal of leukotrichia combined with hair transplantation might be an appropriate surgical option for stable follicular vitiligo to create natural and stable pigmented hair.

A clinical trial of treating androgenic alopecia with mesenchymal stem cell suspension derived from autologous hair follicle.

BACKGROUND: Androgenic alopecia (AGA) is characterized by progressive hair follicle miniaturization, and novel treatments are needed to intervene in the miniaturization process. We aimed to evaluate the efficacy, safety, effectiveness, and effective population of autologous hair follicle mesenchymal stem cell therapy for the treatment of advanced AGA in Chinese people. METHODS: 50 patients ranging from 25 to 45 years old, with an average age of 32 ± 1.24 years were included. None of them had ever used minoxidil, finasteride, or other drugs to promote hair growth. Healthy hair follicles were extracted from the occipital area and treated to obtain hair follicle mesenchymal stem cells suspensions. The recipient sites were divided into two groups. Nine points were injected in a 1 cm 2 area, and 100 µl of solution containing either 1 × 10 5 cells or normal saline was injected at each point. The follow-up duration was 9 months. Observers were blinded to patient groupings and measurements. RESULTS: An increased proportion of terminal hair and hair shaft diameter was observed in the experimental group at 1 month; the effect lasted until 3 months. The hair thickening effect of advanced miniaturized hair follicles with hair shaft diameter less than 60 µm was more notable than that above 60 µm. None of the patients experienced any obvious side effects. CONCLUSIONS: Hair follicle mesenchymal stem cells were effective in the treatment of Chinese advanced AGA, and a hair shaft diameter of 60µm can be used as a key index to predict the effectiveness of the therapy.

Efficacy of Platelet-Rich Plasma plus Basic Fibroblast Growth Factor on the Treatment of Androgenic Alopecia.

BACKGROUND: Studies have identified platelet-rich plasma (PRP) as a novel adjuvant therapy in androgenetic alopecia (AGA). However, the efficacy of PRP still needs to be improved. The purpose of this study was to assess the efficacy of PRP plus basic fibroblast growth factor (PRPF) for the treatment of AGA. METHODS: This was a prospective randomized, double-blind, placebo-controlled, half-head study. Eighty patients whose AGA was staged Norwood-Hamilton stages III to VII or Ludwig stages I to III were enrolled in the study from February of 2019 to September of 2019. Patients were divided randomly into two groups of 40 patients each and were given the following treatment: group 1, PRPF was injected in the right half and the left half with placebo; group 2, PRPF was injected in the right half and the left half with PRP. The treatment was processed three times, 1 month apart. Hair growth parameters were evaluated by trichoscope monthly until the sixth month of the study. Patient satisfaction, hair pull test, and side effects were recorded during follow-up. RESULTS: Of the 80 patients included in the study, 47 were men and 33 were women with a mean age of 28.96 ± 4.82 years (range, 21 to 46 years). Both PRP and PRPF showed positive improvement ( P < 0.05) on hair count, terminal hair, and anagen hair after the treatment. Efficacy of PRPF revealed a significant improvement ( P < 0.05) in hair count, terminal hair, vellus hair, and anagen hair versus PRP. There was no statistical difference among any of the parameters in the placebo group. CONCLUSION: PRPF can be a safe and valuable form of AGA treatment, and has proven to be more effective than PRP. CLINICAL RELEVANCE STATEMENT: Hybrid therapy of PRP with relative growth factors, such as basic fibroblast growth factor, have prominent efficacy on treatment of AGA. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Hair follicle extraction combined with an expanded scalp flap for facial organ reconstruction.

BACKGROUND: Use of scalp skin for facial organ reconstruction represents a mainstream procedure for organ reconstruction. In most cases, adequate amounts of skin can be obtained by using tissue expanders, but harvesting sufficient scalp tissue in patients with low hairlines is challenging. Hair follicular unit extraction (FUE) is one approach to resolve this problem. With FUE, hair follicles are removed from the scalp skin, which can then be prepared as a donor site to obtain sufficient amounts of hairless skin. OBJECTIVES: To evaluate the safety and efficacy of FUE when combined with an expanded scalp flap for facial organ reconstruction. MATERIAL AND METHODS: Patients with low hairlines requiring facial organ reconstruction were selected for this study. The area of skin extension and hair removal were determined prior to surgery, a process which was performed in three stages. Stage I consisted of hair follicle removal using the FUE technique at the donor site. Stage II involved expander implantation using water injections. In Stage III facial organ reconstruction was completed. RESULTS: With the use of the FUE technique, hair follicles from the donor scalp were thoroughly removed and the donor scalp tissue was successfully expanded. Postoperatively, no evident scar formation at the reconstruction site or contracture of the expanded flap was observed. All patients were satisfied with the outcome of their reconstruction procedure. CONCLUSION: FUE provides a means for hair follicle removal from the donor site and can be employed to achieve a safe and effective procedure for facial reconstruction in patients with low hairlines.