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Immune tolerance is maintained in lymphoid organs (LOs). Despite the presence of complex immune cell networks in non-LOs, it is unknown whether self-tolerance is maintained in these tissues. We developed a technique to restrict genetic recombination to regulatory T cells (Tregs) only in skin. Selective depletion of skin Tregs resulted in T cell-mediated inflammation of hair follicles (HFs). Suppression did not rely on CTLA-4, but instead on high-affinity interleukin-2 (IL-2) receptor expression by skin Tregs, functioning exclusively in a cell-extrinsic manner. In a novel model of HF stem cell (HFSC)-driven autoimmunity, we reveal that skin Tregs immunologically protect the HFSC niche. Finally, we used spatial transcriptomics to identify aberrant IL-2 signaling at stromal-HF interfaces in a rare form of human alopecia characterized by HFSC destruction and alopecia areata. Collectively, these results reveal the fundamental biology of Tregs in skin uncoupled from the systemic pool and elucidate a mechanism of self-tolerance.

Background: Androgenetic alopecia (AGA) is common. While topical minoxidil remains the only FDA‐approved therapeutic for AGA, its efficacy is limited in stimulating clinically significant hair regrowth over the longer term. Oral minoxidil, which is used off‐label, is a promising alternative; however, its effectiveness and underlying mechanisms warrant further investigation. Aims: To elucidate the site of action and infer the physiological mechanisms underlying therapeutic responses to oral minoxidil in patients with AGA. Methods: Forty‐one patients with AGA underwent 6 months of low‐dose oral minoxidil treatment. Minoxidil sulfotransferase (SULT) activity was assayed in plucked scalp hair follicles. The primary outcome was hair growth after low‐dose oral minoxidil treatment for a minimum of 6 months, and the secondary outcome was SULT activity in hair follicles. Results: After 6 months of treatment, 26 (63.4%) patients experienced a clinical improvement in alopecia symptoms. The response rate was higher in men (19/26 [73.1%]) than in women (6/15 [40.0%]). Patients with low hair follicle SULT activity demonstrated a higher minoxidil response rate than those with high enzyme activity (85% vs. 43%, p = 0.009). Conclusions: Our findings indicate that low SULT activity within the hair follicles is associated with a favorable response to oral minoxidil therapy in patients with AGA. Further elucidation of the underlying mechanisms could significantly improve personalized therapeutic approaches through improved patient selection and the rational design of adjuvant treatments. [ABSTRACT FROM AUTHOR]

Introduction: Follicular delivery is one of the targeted drug delivery methods aiming to target the hair follicles. The accumulation and retention time of targeted drugs is enhanced when nanoparticles are used as drug carriers. Particle size is one of the important factors affecting the penetration and accumulation of particles in the hair follicles, and there is a controversy in different studies for the best particle size for follicular delivery. Mouse models are mostly used in clinical trials for dermal, transdermal, and follicular delivery studies. Also, it is essential to investigate the reliability of the results between human studies and mouse models. Methods: Curcumin-loaded nanostructured lipid carriers (NLCs), as a fluorescent agent, with three different particle size ranges were prepared using the hot homogenization method and applied topically on the mouse and human study groups. Biopsies were taken from applied areas on different days after using the formulation. The histopathology studies were done on the skin biopsies of both groups using confocal laser scanning microscopy (CLSM). We compared the confocal laser scanning microscope pictures of different groups, in terms of penetration and retention time of nanoparticles in human and mouse hair follicles. Results: The best particle size in both models was the 400 nm group but the penetration and accumulation of particles in human and mouse hair follicles were totally different even for the 400 nm group. In human studies, 400 nm particles showed good accumulation after seven days; this result can help to increase the formulation using intervals. Conclusion: The best particle size for human and mouse follicular drug delivery is around 400 nm and although mouse models are not completely suitable for follicular delivery studies, they can be used in some conditions as experimental models. [ABSTRACT FROM AUTHOR]

Oxytocin has various effects ranging from promoting labor in pregnant women to alleviating stress. Recently, we reported the hair growth-promoting effects of oxytocin in hair follicle organoids. However, its clinical application faces challenges such as rapid degradation in vivo and poor permeability due to its large molecular weight. Therefore, in this study, we investigated the effects of the oxytocin receptor (OXTR) agonists WAY267464 and LIT001 as alternatives to oxytocin on hair growth. Human dermal papilla (DP) cells were cultured in WAY267464 or LIT001-supplemented medium. The addition of WAY267464 and LIT001 increased the expression of hair growth-related genes in DP cells. We tested the hair growth-promoting effects of WAY267464 and LIT001 using hair follicle organoids in vitro and found that they significantly promoted hair follicle sprouting. Thus, our findings indicate that WAY267464 and LIT001 are potential hair growth agents and may encourage further research on the development of novel hair growth agents targeting OXTR in patients with alopecia. [ABSTRACT FROM AUTHOR]

The hair follicle can cycle throughout a lifetime, undergoing periods of growth (anagen), regression (catagen) and relative quiescence (telogen). The time that a hair follicle spends in each of these stages is crucial to determine the length of hair fibre that it produces. Perturbations in this regard can manifest in various hair diseases such as anagen effluvium, or acute and chronic telogen effluvium. The established 'dogma' when considering how many hair follicles there are in each stage has long been that the majority are in anagen (85%–90%), followed by telogen (10%–15%) and catagen (1%–2%). These values are based on various studies using different methodologies such as hair plucking, phototrichograms and histology. However, these methods have flaws when it comes to differentiating between catagen and telogen follicles. We sought to determine the catagen: telogen ratio through the ex vivo stereomicroscopic examination of hundreds of hair follicles removed from the occipital scalp of 14 Caucasian males during routine hair transplantation procedures. Using this methodology, and in agreement with a similar observation by another research group, we found that the percentage of catagen hair follicles was higher (7.5%) than telogen (3.5%) in all patients assessed. Consequently, we believe that the percentage of catagen follicles is clearly underestimated and therefore challenge the current established dogma. [ABSTRACT FROM AUTHOR]

[Display omitted] • Aldehyde dehydrogenase 2 (ALDH2) levels in human hair follicles (HFs) are significantly increased during the anagen phase. • ALDH2 expression is primarily localized in the outer root sheath of human HFs. • Activation of ALDH2 in HFs leads to anagen induction and subsequent hair shaft elongation. • ALDH2 activation triggers reactive oxygen species scavenging in HFs and upregulates β-catenin signaling. • Modulation of ALDH2 may be a promising therapeutic approach for inducing the anagen phase, providing novel insights into the impact of ALDH2 activation on HFs. Hair loss is a common phenomenon associated with various environmental and genetic factors. Mitochondrial dysfunction-induced oxidative stress has been recognized as a crucial determinant of hair follicle (HF) biology. Aldehyde dehydrogenase 2 (ALDH2) mitigates oxidative stress by detoxifying acetaldehyde. This study investigated the potential role of ALDH2 modulation in HF function and hair growth promotion. To evaluate the effects of ALDH2 activation on oxidative stress in HFs and hair growth promotion. The modulatory role of ALDH2 on HFs was investigated using an ALDH2 activator. ALDH2 expression in human HFs was evaluated through in vitro immunofluorescence staining. Ex vivo HF organ culture was employed to assess hair shaft elongation, while the fluorescence probe 2′,7′- dichlorodihydrofluorescein diacetate was utilized to detect reactive oxygen species (ROS). An in vivo mouse model was used to determine whether ALDH2 activation induces anagen. During the anagen phase, ALDH2 showed significantly higher intensity than that in the telogen phase, and its expression was primarily localized along the outer layer of HFs. ALDH2 activation promoted anagen phase induction by reducing ROS levels and enhancing reactive aldehyde clearance, which indicated that ALDH2 functions as a ROS scavenger within HFs. Moreover, ALDH2 activation upregulated Akt/GSK 3β/β-catenin signaling in HFs. Our findings highlight the hair growth promotion effects of ALDH2 activation in HFs and its potential as a promising therapeutic approach for promoting anagen induction. [ABSTRACT FROM AUTHOR]

Dermal white adipose tissue (DWAT) is a distinctive adipose depot located within the lower dermis of the skin. Its significance as an ancillary fat in skin homoeostasis has recently received increased attention. New research has revealed that DWAT responses to skin pathology and physiology changes, impacting skin development, hair cycling, defense mechanisms, and fibrotic conditions. In this review, we explore the developmental process of DWAT and the adipose commitment timing of hypodermal. We explore the development process of DWAT and its pivotal role in regulating the hair cycle. We conclude the antibacterial activity and reversible dedifferentiation of dermal adipocytes in response to skin defense. Furthermore, we underscore the potentially crucial yet underestimated anti‐fibrotic functions of DWAT‐derived adipokines and adipocyte‐myofibroblast transition. [ABSTRACT FROM AUTHOR]

Chronic skin wounds are estimated to affect 6.5 million patients in the US, at a cost of over USD 25 billion. Efforts to prevent and/or treat such wounds will result in reduced morbidity and economic losses. This project is focused on the role of vitamin D signaling in the epidermis in the control of stem cell (SC) activation and function during the initial response to the wounding of the skin, a response that, if defective, contributes to poor wound healing or cancer. In this review, I first describe the anatomy of the skin, focusing first on the epidermis, describing the different cell layers which in a spatial way also represent the differentiation process of the interfollicular epidermis (IFE) as it undergoes continuous regeneration. I then describe the other components of the skin, particularly the hair follicle (HF), which undergoes a cyclic pattern of regeneration. Adult SCs residing in these regenerative tissues play essential roles in the maintenance of these tissues. However, when the skin is wounded, the progeny of SCs from all regions of the HF and IFE contribute to the healing process by changing their initial cell fate to take on an epithelial genotype/phenotype to heal the wound. Although earlier lineage tracing studies helped to define the contributions SCs from the different niches made to wound healing, scRNAseq studies have demonstrated a considerably more nuanced picture. The role of vitamin D signaling will be introduced by reviewing the unique role played by the epidermal keratinocyte first in producing vitamin D and then in metabolizing it into its active form 1,25(OH)2D. 1,25(OH)2D is the principal ligand for the vitamin D receptor (VDR), a transcription factor that helps to mediate the genomic changes in the stem cells in their response to wounding. In these actions, the VDR is regulated by coregulators, of which the steroid receptor coactivator complexes SRC 2 and 3 and the mediator complex (MED) play essential roles. The VDR generally acts in association with other transcription factors such as p63 and β-catenin that can colocalize with the VDR in the genes it regulates. Although much remains to be understood, the role of the VDR in the stem cell response to wounding is clearly essential and quite different from its classic roles in regulating calcium metabolism, although calcium is essential for the actions of vitamin D signaling in the skin. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) innovative preservative on hair follicle activity of rat vibrissae under low temperature conditions. Methods From January 2021 to December 2023, the upper of hair follicle (UHF) from male SD rat vibrissae was used in the experiment. These UHF were equally divided into NS, IGF-1, EGF, and IGF-1+EGF preservation solutions groups. At 3, 6 and 12 hours, the cultured UHF were analyzed by hematoxylin and eosin (HE) staining and alkaline phosphatase (ALP) activity. The UHF co-cultured with NS and IGF-1+EGF for 3 hours were further transplanted into the dorsum of nude mice. After 24 hours, the transplanted UHF was taken to observe by HE staining and ALP activity. Results In vitro preservation, HE staining results indicated that the cultured UHF at 3 hours, the follicle structure and cell arrangement were normal without obvious changes. At 12 hours, only the IGF-1+EGF group had intact follicle structure and clear organization. Moreover, ALP values showed that the IGF-1+EGF group at 3, 6 and 12 hours were significantly higher than the NS group (P＜0.001). Overall, ALP activity gradually decreased over time. In vivo transplantation, HE staining results showed that the IGF-1+EGF group were structurally distinct with orderly cell arrangements, compared to the NS group. ALP values were significantly higher than NS group (P＜0.05). Conclusion The innovative preservation solutions containing IGF-1 and EGF under low temperatures, can effectively enhance the activity of UHF, and promote the success of hair follicle transplantation. [ABSTRACT FROM AUTHOR]

Background: Alopecia areata (AA), an immune-mediated disorder, is marked by temporary, nonscarring hair loss. The bulge area is protected from immune attacks by immune privilege; however, recent studies demonstrated immune cells infiltrating the bulge area. Objective: This study aims to investigate the immunohistochemical expression of the sex-determining region Y-box 9 (SOX9) and cluster of differentiation 34 (CD34) in AA patients as markers of hair follicle stem cells (HFSCs) and progenitor cells, respectively. Methods: Immunohistochemical staining of SOX9 and CD34 was applied on skin samples of 20 AA patients and 20 healthy controls. Results: SOX9 and CD34 were significantly lower in lesional samples of cases compared to perilesional and control skin biopsies. Furthermore, SOX9 level was negatively correlated with the severity of alopecia tool score (SALT score) among the studied AA patients. Moreover, lowered SOX9 expression was present in patients with recurrent attacks. Conclusions: The significant reduction of stem cell markers (SOX9 and CD34) in our studied AA cases signifies the pathological affection of HFSCs and their progeny in AA. This is thought to cause a loss of competence in generating new hair in some AA cases, which needs to be validated in further research. Limitations of the study: This study has a small sample size. [ABSTRACT FROM AUTHOR]

Androgenic alopecia (AGA) has a considerable impact on the physical and mental health of patients. Nano preparations have apparent advantages and high feasibility in the treatment of AGA. Cardamonin (CAR) has a wide range of pharmacological activities, but it has the problems of poor solubility in water and low bioavailability. There are few, if any, researches on the use of nano-loaded CAR to improve topical skin delivery of AGA. In this study, a CAR-loaded liposomal formulation (CAR@Lip and CAR@Lip Gel) was developed and characterized. The prepared CAR@Lip exhibited a uniform and rounded vesicle in size. CAR@Lip and CAR@Lip Gel can significantly improve the cumulative release of CAR. Additionally, CAR@Lip can obviously promote the proliferation and migration of human dermal papilla cells (hDPCs). Cell uptake revealed that the uptake of CAR@Lip significantly increased compared with the free drug. Furthermore, both CAR@Lip and CAR@Lip Gel groups could markedly improve the transdermal performance of CAR, and increase the topical content of the drug in the hair follicle compared with CAR. The ratchet effect of hair follicles could improve the skin penetration depth of nanoformulations. Notably, Anti-AGA tests in the mice showed that CAR@Lip and CAR@Lip Gel groups could promote hair growth, and accelerate the transition of hair follicles to the growth stage. The anti-androgen effect was revealed by regulating the expression of IGF-1, VEGF, KGF, and TGF-β, participating in SHH/Gli and Wnt/β-catenin pathways. Importantly, the nanoformulations had no obvious skin irritation. Thus, our study showed that CAR-loaded liposomal formulation has potential application in the treatment of AGA. [ABSTRACT FROM AUTHOR]

Abstract Oxytocin has various effects ranging from promoting labor in pregnant women to alleviating stress. Recently, we reported the hair growth-promoting effects of oxytocin in hair follicle organoids. However, its clinical application faces challenges such as rapid degradation in vivo and poor permeability due to its large molecular weight. Therefore, in this study, we investigated the effects of the oxytocin receptor (OXTR) agonists WAY267464 and LIT001 as alternatives to oxytocin on hair growth. Human dermal papilla (DP) cells were cultured in WAY267464 or LIT001-supplemented medium. The addition of WAY267464 and LIT001 increased the expression of hair growth-related genes in DP cells. We tested the hair growth-promoting effects of WAY267464 and LIT001 using hair follicle organoids in vitro and found that they significantly promoted hair follicle sprouting. Thus, our findings indicate that WAY267464 and LIT001 are potential hair growth agents and may encourage further research on the development of novel hair growth agents targeting OXTR in patients with alopecia.

Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single-cell RNA sequencing, we uncovered both direct and indirect paths by which resident SG progenitors ordinarily differentiate into sebocytes, including transit through a Krt5+PPARγ+ transitional basal cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair-follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR2 signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.

Trichofolliculoma is a rare benign, hamartomatous adnexal tumour of the skin. Aetiology seems to be unclear. It is usually seen in adults, with no gender predilection. The most commonly involved sites are the face and scalp. It appears as a papule or nodule with small protruding hairs, which is a classic feature of the tumour. It has unique diagnostic and histopathological features that help in making a definitive diagnosis. Here, we report an exemplary case of an adult male patient aged 45 years with a gradual progressive diffuse swelling on the left side of the face for 1.5 years. Clinically, it was diagnosed as a sebaceous cyst, but after the biopsy histopathological evaluation was performed, and the diagnosis was confirmed as trichofolliculoma.

Ectodermal organs, such as hair follicles, originate from simple epithelial and mesenchymal sheets through a complex developmental process driven by interactions between these cell types. This process involves dermal condensation, placode formation, bud morphogenesis, and organogenesis, and all of these processes require intricate interactions among various tissues. Recent research has emphasized the crucial role of reciprocal and dynamic interactions between cells and the extracellular matrix (ECM), referred to as the "dynamic duo", in the development of ectodermal organs. These interactions provide spatially and temporally changing biophysical and biochemical cues within tissues. Using the hair follicle as an example, this review highlights two types of cell–ECM adhesion units—focal adhesion-type and hemidesmosome-type adhesion units—that facilitate communication between epithelial and mesenchymal cells. This review further explores how these adhesion units, along with other cell–ECM interactions, evolve during hair follicle development and regeneration, underscoring their importance in guiding both developmental and regenerative processes. [Display omitted] • Dynamic cell-ECM interactions guide hair follicle development and regeneration. • Focal adhesions and hemidesmosomes are key ECM adhesion units in hair follicles. • Basement membrane mediates epithelial and mesenchymal mechanochemical interactions. [ABSTRACT FROM AUTHOR]

Skin stem cells (SCs) play a pivotal role in supporting tissue homeostasis. Several types of SCs are responsible for maintaining and regenerating skin tissue. These include bulge SCs and others residing in the interfollicular epidermis, infundibulum, isthmus, sebaceous glands, and sweat glands. The emergence of skin SCs commences during embryogenesis, where multipotent SCs arise from various precursor populations. These early events set the foundation for the diverse pool of SCs that will reside in the adult skin, ready to respond to tissue repair and regeneration demands. A network of molecular cues regulates skin SC behavior, balancing quiescence, self-renewal, and differentiation. The disruption of this delicate equilibrium can lead to SC exhaustion, impaired wound healing, and pathological conditions such as skin cancer. The present review explores the intricate mechanisms governing the development, activation, and differentiation of skin SCs, shedding light on the molecular signaling pathways that drive their fate decisions and skin homeostasis. Unraveling the complexities of these molecular drivers not only enhances our fundamental knowledge of skin biology but also holds promise for developing novel strategies to modulate skin SC fate for regenerative medicine applications, ultimately benefiting patients with skin disorders and injuries.

Skin, the largest organ in the human body, is a crucial protective barrier that plays essential roles in thermoregulation, sensation, and immune defence. This complex organ undergoes intricate processes of development. Skin development initiates during the embryonic stage, orchestrated by molecular cues that control epidermal specification, commitment, stratification, terminal differentiation, and appendage growth. Key signalling pathways are integral in coordinating the development of the epidermis, hair follicles, and sweat glands. The complex interplay among these pathways is vital for the appropriate formation and functionality of the skin. Disruptions in multiple molecular pathways can give rise to a spectrum of skin diseases, from congenital skin disorders to cancers. By delving into the molecular mechanisms implicated in developmental processes, as well as in the pathogenesis of diseases, this narrative review aims to present a comprehensive understanding of these aspects. Such knowledge paves the way for developing innovative targeted therapies and personalised treatment approaches for various skin conditions.

Ming Cheng,1,2 Cong Ma,1– 3 Hong-Duo Chen,1,2 Yan Wu,1,2 Xue-Gang Xu1,2 1Department of Dermatology, The First Hospital of China Medical University, Shenyang, 110000, People’s Republic of China; 2Key Laboratory of Immunodermatology, Ministry of Education and NHC; National Joint Engineering Research Center for Theranostics of Immunological Skin Diseases, Shenyang, 110000, People’s Republic of China; 3Department of Dermatology and Sexually Transmitted Diseases, The First Hospital of Inner Mongolia University for Nationalities, Tongliao, 028000, People’s Republic of ChinaCorrespondence: Xue-Gang Xu; Yan Wu, Department of Dermatology, The First Hospital of China Medical University, Shenyang, 110000, People’s Republic of China, Email xuxuegang2749290@163.com; jlwuyan@126.comAbstract: Alopecia is considered a widespread yet troubling health issue, with limited treatment options. As membranous structures derived from cells carrying proteins, nucleic acids and lipids, exosomes functionally medicate intercellular communication and alter the responses of recipient cells, resulting in disease restraint or promotion. Exosomes have broad prospects in diagnosis and treatment of diseases. Studies using animal models and at the cellular level have clearly shown that exosomes from several types of cells, including dermal papilla cells and mesenchymal stem cells, have a notable capacity to promote hair growth, suggesting that exosomes may provide a new option to treat alopecia. Here, we present a thorough review of the most recent progress in the application of exosomes to hair growth.Keywords: exosome, hair follicle, alopecia

Yan Ji,1 Haorong Li,1 Jiguo Li,2 Guangqiang Yang,1 Wenli Zhang,1 Yan Shen,1 Bohui Xu,3 Jianping Liu,1 Jingyuan Wen,4 Wenting Song1 1Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Nanjing Miaobang Meiye Enterprise Management Co, LTD, Nanjing, People’s Republic of China; 3School of Pharmacy, Nantong University, Nantong, 226001, People’s Republic of China; 4School of Pharmacy, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, New ZealandCorrespondence: Wenting Song, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, People’s Republic of China, Email songwenting908@163.com Jingyuan Wen, School of Pharmacy, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, New Zealand, Email j.wen@auckland.ac.nzPurpose: Acne vulgaris is a chronic inflammatory skin disorder centered on hair follicles, making hair follicle-targeted delivery of anti-acne drugs a promising option for acne treatment. However, current researches have only focused on the delivering to healthy hair follicles, which are intrinsically different from pathologically clogged hair follicles in acne vulgaris.Patients and Methods: Azelaic acid (AZA) micro/nanocrystals with different particle sizes were prepared by wet media milling or high-pressure homogenization. An experiment on AZA micro/nanocrystals delivering to healthy hair follicles was carried out, with and without the use of physical enhancement techniques. More importantly, it innovatively designed an experiment, which could reveal the ability of AZA micro/nanocrystals to penetrate the constructed clogged hair follicles. The anti-inflammatory and antibacterial effects of AZA micro/nanocrystals were evaluated in vitro using a RAW264.7 cell model stimulated by lipopolysaccharide and a Cutibacterium acnes model. Finally, both the anti-acne effects and skin safety of AZA micro/nanocrystals and commercial products were compared in vivo.Results: In comparison to commercial products, 200 nm and 500 nm AZA micro/nanocrystals exhibited an increased capacity to target hair follicles. In the combination group of AZA micro/nanocrystals and ultrasound, the ability to penetrate hair follicles was further remarkably enhanced (ER value up to 9.6). However, toward the clogged hair follicles, AZA micro/nanocrystals cannot easily penetrate into by themselves. Only with the help of 1% salicylic acid, AZA micro/nanocrystals had a great potential to penetrate clogged hair follicle. It was also shown that AZA micro/nanocrystals had anti-inflammatory and antibacterial effects by inhibiting pro-inflammatory factors and Cutibacterium acnes. Compared with commercial products, the combination of AZA micro/nanocrystals and ultrasound exhibited an obvious advantage in both skin safety and in vivo anti-acne therapeutic efficacy.Conclusion: Hair follicle-targeted delivery of AZA micro/nanocrystals provided a satisfactory alternative in promoting the treatment of acne vulgaris.Keywords: acne vulgaris, azelaic acid, hair follicle, micro/nanocrystals, targeted delivery

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Cashmere goats possess two types of hair follicles, with the secondary hair follicles producing valuable cashmere fiber used for textiles. The growth of cashmere exhibits a seasonal pattern arising from photoperiod change. Transcription factors play crucial roles during this process. The transcription factor, cold-shock domain, containing C2 (Csdc2) plays a crucial role in modulating cell proliferation and differentiation. Our preceding research indicated that the expression of Csdc2 changes periodically during anagen to telogen. However, the mechanisms of Csdc2 in regulating SHF growth remain unclear. Here, we found that the knockdown of Csdc2 inhibits the proliferation of dermal papilla cells. ChIP-Seq analysis showed that Csdc2 had a unique DNA binding motif in SHFs. Through conjoint analysis of ChIP-Seq and RNA-Seq, we revealed a total of 25 candidate target genes of Csdc2. Notably, we discovered a putative Csdc2 binding site within roundabout guidance receptor 2 (Robo2) on chromosome 1 of the goat genome. Furthermore, qRT-PCR and dual-luciferase reporter assay confirmed Csdc2's positive regulatory influence on Robo2. These findings expand the research field of hair follicle transcriptional regulatory networks, offering insights into molecular breeding strategies to enhance cashmere production in goats. [ABSTRACT FROM AUTHOR]

Androgenic alopecia (AGA) is the most common type of alopecia and its treatments involve drugs that have various adverse effects and are not completely effective. Radiofrequency-based therapies (RF) are an alternative for AGA treatment. Although there is increasing clinical evidence of the effectiveness of RF for alopecia, its effects at the tissue and cellular level have not been studied in detail. The objective of this study was to analyze ex vivo the potential effect of RF currents used in capacitive resistive electrical transfer (CRET) therapy on AGA. Hair follicles (HFs) were donated by patients with AGA and treated with CRET. AGA-HFs were exposed in vitro to intermittent 448 kHz electric current in subthermal conditions. Cell proliferation (Ki67), apoptosis (TUNEL assay), differentiation (β-catenin), integrity (collagen and MMP9), thickness of the epidermis surrounding HF, proportion of bulge cells and melanoblasts in AGA-HF were analyzed by immunohistochemistry. CRET increased proliferation and decreased death of different populations of AGA-HF cells. In addition, the melanoblasts increased in bulge and the epidermis surrounding the hair follicle thickened. These results support the effectiveness of RF-based therapies for the treatment of alopecia. However, clinical trials are necessary to know the true effectiveness of CRET therapy and other RF therapies for AGA treatment. [ABSTRACT FROM AUTHOR]

Sheep body size can directly reflect the growth rates and fattening rates of sheep and is also an important index for measuring the growth performance of meat sheep. Inner Mongolia Cashmere Goat is a local excellent breed of cashmere and meat dual-purpose, which is a typical heterogeneous indumentum. The hair follicles cycle through periods of vigorous growth (anagen), a regression caused by apoptosis (catagen), and relative rest (telogen). At present, it is not clear which genes affect the cycle transformation of hair follicles and unclear how proteins impact the creation and expansion of hair follicles. we using multi-omics joint analysis methodologies to investigated the possible pathways of transformation and apoptosis in goat hair follicles. The results showed that 917,1,187, and 716 proteins were specifically expressed in anagen, catagen andtelogen. The result of gene ontology (GO) annotation showed that differentially expressed proteins (DEPs) are in different growth cycle periods, and enriched GO items are mostly related to the transformation of cells and proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment result indicated that the apoptosis process has a great impact on hair follicle's growth cycle. The results of the protein interaction network of differential proteins showed that the ribosomal protein family (RPL4, RPL8, RPS16, RPS18, RPS2, RPS27A, RPS3) was the core protein in the network. The results of combined transcriptome and proteomics analysis showed that there were 16,34, and 26 overlapped DEGs and DEPs in the comparison of anagen VS catagen, catagen VS telogen and anagen VS telogen, of which API5 plays an important role in regulating protein and gene expression levels. We focused on API5 and Ribosomal protein and found that API5 affected the apoptosis process of hair follicles, and ribosomal protein was highly expressed in the resting stage of hair follicles. They are both useful as molecular marker candidate genes to study hair follicle growth and apoptosis, and they both have an essential function in the cycle transition process of hair follicles. The results of this study may provide a theoretical basis for further research on the growth and development of hair follicles in Inner Mongolian Cashmere goats. [ABSTRACT FROM AUTHOR]

Androgenetic alopecia (AGA) is a highly prevalent condition in contemporary society. The conventional treatment of minoxidil tincture is hindered by issues such as skin irritation caused by ethanol, non-specific accumulation in hair follicles, and short retention due to its liquid form. Herein, we have developed a novel minoxidil-incorporated engineered exosomes biopotentiated hydrogel (Gel@MNs) that has the capability to modulate the perifollicular microenvironment for the treatment of AGA. Leveraging the exceptional skin penetration abilities of flexible liposomes and the targeting properties of exosomes, the encapsulated minoxidil can be effectively delivered to the hair follicles. In comparison to free minoxidil, Gel@MNs demonstrated accelerated hair regeneration in an AGA mouse model without causing significant skin irritation. This was evidenced by an increase in both the number and size of hair follicles within the dermal layer, enhanced capillary formation surrounding the follicles, and the regulation of the transition of hair follicle cells from the telogen phase to the anagen growth phase. Therefore, this safe and microenvironment-modifying hybrid exosome-embedded hydrogel shows promising potential for clinical treatment of AGA. [ABSTRACT FROM AUTHOR]

Hair follicle development and hair growth are regulated by multiple factors and multiple signalling pathways. The hair follicle, as an important skin appendage, is the basis for hair growth, and it has the functions of safeguarding the body, perceiving the environment and regulating body temperature. Hair growth undergoes a regular hair cycle, including anagen, catagen and telogen. A small amount of physiological shedding of hair occurs under normal conditions, always in a dynamic equilibrium. Hair loss occurs when the skin or hair follicles are stimulated by oxidative stress, inflammation or hormonal disorders that disrupt the homeostasis of the hair follicles. Numerous researches have indicated that oxidative stress is an important factor causing hair loss. Here, we summarize the signalling pathways and intervention mechanisms by which oxidative stress affects hair follicle development and hair growth, discuss existing treatments for hair loss via the antioxidant pathway and provide our own insights. In addition, we collate antioxidant natural products promoting hair growth in recent years and discuss the limitations and perspectives of current hair loss prevention and treatment. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced alopecia (CIA) represents one of the most severe side effects of chemotherapy, which forces some patients to reject cancer treatment. The exact pathophysiological mechanisms of CIA are not clearly understood, which makes it difficult to discover efficient preventive or therapeutic procedures for this adverse effect. N-acetylcysteine (NAC) has a strong antioxidant activity as it stimulates glutathione synthesis and acts as an oxygen radical scavenger. The current study tried to investigate the efficacy of NAC in preserving biochemical parameters and hair follicle structure against cyclophosphamide (CYP) administration. In total, 40 adult female C57BL/6 mice were induced to enter anagen by depilation (day 0) and divided into four groups: group I (control), group II (CYP) received a single dose of CYP [150 mg/kg body weight (B.W.)/intraperitoneal injection (IP)] at day 9, group III (CYP & NAC) received a single dose of CYP at day 9 as well as NAC (500 mg/kg B.W./day/IP) from day 6–16, and group IV (NAC) received NAC from day 6–16. CYP administration in group II induced an increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), histological hair follicle dystrophy, disruption of follicular melanogenesis, overexpression of p53, and loss of ki67 immunoreactivity. NAC coadministration in group III reversed CYP-induced alterations in the biochemical parameters and preserved hair follicle structure, typical follicular melanin distribution as well as normal pattern of p53 and ki67 expression. These findings indicated that NAC could be used as an efficient and safe therapeutic option for hair loss induced by chemotherapy. [ABSTRACT FROM AUTHOR]

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

The molecular mechanisms allowing hair follicles to periodically activate their stem cells (HFSCs) are incompletely characterized. Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice have delayed anagen onset, with increased DNA damage and diminished HFSC proliferation. Open chromatin regions form near cell cycle progression and DNA damage repair genes in Irx5-/- HFSCs. DNA damage repair factor BRCA1 is an IRX5 downstream target. Inhibition of FGF kinase signaling partially rescues the anagen delay in Irx5-/- mice, suggesting that the Irx5-/- HFSC quiescent phenotype is partly due to failure to suppress Fgf18 expression. Interfollicular epidermal stem cells also show decreased proliferation and increased DNA damage in Irx5-/-mice. Consistent with a role for IRX5 as a promoter of DNA damage repair, we find that IRX genes are upregulated in many cancer types and that there is a correlation between IRX5 and BRCA1 expression in breast cancer.

Xiaofan Jin,1 Xiuzu Song2 1Zhejiang University School of Medicine, Department of Dermatology, Hangzhou Third People’s Hospital, Affiliated Hangzhou Dermatology Hospital, Hangzhou, People’s Republic of China; 2Department of Dermatology, Hangzhou Third People’s Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Xiuzu Song, Department of Dermatology, Hangzhou Third People’s Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Westlake Ave 38, Hangzhou, 310009, People’s Republic of China, Email songxiuzu@sina.comAbstract: Autophagy is recognized as a crucial regulatory process, instrumental in the removal of senescent, dysfunctional, and damaged cells. Within the autophagic process, lysosomal digestion plays a critical role in the elimination of impaired organelles, thus preserving fundamental cellular metabolic functions and various biological processes. Mitophagy, a targeted autophagic process that specifically focuses on mitochondria, is essential for sustaining cellular health and energy balance. Therefore, a deep comprehension of the operational mechanisms and implications of autophagy and mitophagy is vital for disease prevention and treatment. In this context, we examine the role of autophagy and mitophagy during hair follicle cycles, closely scrutinizing their potential association with hair loss. We also conduct a thorough review of the regulatory mechanisms behind autophagy and mitophagy, highlighting their interaction with hair follicle stem cells and dermal papilla cells. In conclusion, we investigate the potential of manipulating autophagy and mitophagy pathways to develop innovative therapeutic strategies for hair loss.Keywords: hair follicle, mitophagy, dermal papilla cell, hair follicle stem cell, alopecia

Abstract Background While rabbits are used as models in skin irritation tests, the presence of irregular patches and thickening on the dorsal skin can affect precise evaluation. In this study, genes associated with patchiness or non-patchiness on the dorsal skin of New Zealand rabbits were investigated to identify potential regulators of the patchiness phenotype. Results The results showed that parameters associated with hair follicles (HFs), such as HF density, skin thickness, and HF depth, were augmented in rabbits with the patchiness phenotype relative to the non-patchiness phenotype. A total of 592 differentially expressed genes (DEGs) were identified between the two groups using RNA-sequencing. These included KRT72, KRT82, KRT85, FUT8, SOX9, and WNT5B. The functions of the DEGs were investigated by GO and KEGG enrichment analyses. A candidate gene, KRT82, was selected for further molecular function verification. There was a significant positive correlation between KRT82 expression and HF-related parameters, and KRT82 overexpression and knockdown experiments with rabbit dermal papilla cells (DPCs) showed that it regulated genes related to skin and HF growth and development. Investigation of single nucleotide polymorphisms (SNPs) in the exons and promoter region of KRT82 identified four SNPs in the promoter region but none in the exons. The G.-631G > T, T.-696T > C, G.-770G > T and A.-873 A > C alleles conformed to the Hardy − Weinberg equilibrium, and three identified haplotypes showed linkage disequilibrium. Luciferase reporter assays showed that the core promoter region of KRT82 was located in the − 600 to − 1200 segment, in which the four SNPs were located. Conclusions The morphological characteristics of the patchiness phenotype were analyzed in New Zealand rabbits and DEGs associated with this phenotype were identified by RNA-sequencing. The biological functions of the gene KRT82 associated with this phenotype were analyzed, and four SNPs were identified in the promoter region of the gene. These findings suggest that KRT82 may be a potential biomarker for the breeding of experimental New Zealand rabbits.

Traidit Thianthanyakij,1,2,* Yinghui Zhou,1,* Mengyi Wu,3,* Yuting Zhang,4 Jui-Ming Lin,1 Yan Huang,4 Yuou Sha,1 Jiayi Wang,1 Sirapath Peter Kong,2 Jinran Lin,1 Qingmei Liu,1 Wenyu Wu1,5,6 1Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, 200040, People’s Republic of China; 2Faculty of Medicine, Thammasat University (Rangsit Campus), Pathumthani, 12120, Thailand; 3Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China; 4State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, People’s Republic of China; 5Department of Dermatology, Jing’an District Central Hospital, Shanghai, 200040, People’s Republic of China; 6Academy for Engineering and Technology, Fudan University, Shanghai, 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingmei Liu; Wenyu Wu, Email liuqing.mei@163.com; wenyu_wu@fudan.edu.cnBackground: Existing research links oxidative stress and inflammation to hair loss. Salvianolic acid B (SAB) is known for its anti-oxidative, anti-inflammatory, and other beneficial pharmacological properties.Objective: To assess the efficacy of SAB in modulating hair growth.Methods: In vivo experiments were conducted using C57BL/6 mice to evaluate the effects of SAB on hair and skin parameters. The study involved ex vivo analysis of human hair follicles (HFs) for hair shaft length and hair growth cycle assessment. In vitro, human dermal papilla cells (hDPCs) were cultured with SAB, and their proliferation, protection against H2O2-induced oxidative damage, and gene/protein expression alterations were examined using various analytical techniques, including Real-Time Cell Analysis (RTCA), DCFH-DA Assay, RNA-seq, and KEGG pathway analysis.Results: SAB treatment in mice significantly improved hair growth and vascularization by day 21. In human HFs, SAB extended hair shaft length and delayed the transition to the catagen phase. SAB-treated hDPCs showed a notable decrease in the expression of oxidation-antioxidation-related genes and proteins, including reduced phosphorylation levels of ERK and p38.Conclusion: The study indicates that SAB promotes hDPC proliferation and offers protection against oxidative stress, highlighting its potential as a therapeutic agent for enhancing hair growth and treating hair loss.Keywords: salvianolic acid B, hair growth, hair cycle, hair follicle, dermal papilla cells

The hair follicle (HF) is a significant skin appendage whose primary function is to produce the hair shaft. HFs are a non-renewable resource; skin damage or follicle closure may lead to permanent hair loss. Advances in biomaterials and biomedical engineering enable the feasibility of manipulating the HF-associated cell function for follicle reconstruction via rational design. The regeneration of bioengineered HF addresses the issue of limited resources and contributes to advancements in research and applications in hair loss treatment, HF development, and drug screening. Based on these requirements, this review summarizes the basic and recent advances in hair follicle regulation, including four components: acquisition of stem cells, signaling pathways, materials, and engineering methods. Recent studies have focused on efficiently combining these components and reproducing functionality, which would boost fabrication in HF rebuilding ex vivo, thereby eliminating the obstacles of transplantation into animals to promote mature development.

Whole-genome bisulfite sequencing was used to study epigenetic differences in hair follicles from Inner Mongolia Albas cashmere goats during long and short photoperiods. Results showed earlier anagen entry in short photoperiod. Genome-wide cytosine methylation was 3.23%, with CG, CHG, and CHH methylation rates at 48.00%, 0.19%, and 0.17%, respectively. Methylation was higher for CG than for CHG and CHH, and higher for introns than exons and downstream regions. Both groups had similar levels of CG, CHG, and CHH methylation, but CHH methylation levels differed slightly between photoperiods. A total of 9,700 differentially methylated regions (DMRs) and 4,187 genes (DMGs) were identified. Gene Ontology (GO) and KEGG analyses revealed significant enrichment in 67 GO terms and 41 signaling pathways related to circadian rhythms, bringing new insights in the role of DNA methylation in cashmere growth and development.

Hair follicles (HFs) are stem-cell-rich mammalian mini-organs that can undergo cyclic regenerations over the life span of the organism. The cycle of a HF consists of three consecutive phases: anagen-the active proliferation phase, catagen-the degeneration phase, and telogen-the resting phase. While HFs undergo irreversible degeneration during catagen, recent experimental research on mice shows that when anagen HFs are subject to ionizing radiation (IR), they undergo a transient degeneration, followed by a nearly full regeneration that makes the HFs return to homeostatic state. The mechanisms underlying these IR-induced HF regenerative dynamics and the catagen degenerative dynamics, remain unknown. In this work, we develop an ODE type cell differentiation population model to study the control mechanisms of HF regeneration. The model is built based on current theoretical knowledge in biology and mathematically formulated using feedback mechanisms. Model parameters are calibrated to IR experimental data, and we then provide modeling results with both deterministic ODE simulations and corresponding stochastic simulations. We perform stability and bifurcation analyses on the ODE model, which reveal that for anagen HFs, a low spontaneous apoptosis rate secures the stability of the HF homeostatic steady state, allowing the HF to regenerate even when subject to strong IR. On the other hand, the irreversible degeneration during catagen results from both strong spontaneous apoptosis rate and strong apoptosis feedback. Lastly, we perform sensitivity analysis to identify key parameters in the model to validate these hypotheses.

The dermis and epidermis, crucial structural layers of the skin, encompass appendages, hair follicles (HFs), and intricate cellular heterogeneity. However, an integrated spatiotemporal transcriptomic atlas of embryonic skin has not yet been described and would be invaluable for studying skin‐related diseases in humans. Here, single‐cell and spatial transcriptomic analyses are performed on skin samples of normal and hairless fetal pigs across four developmental periods. The cross‐species comparison of skin cells illustrated that the pig epidermis is more representative of the human epidermis than mice epidermis. Moreover, Phenome‐wide association study analysis revealed that the conserved genes between pigs and humans are strongly associated with human skin‐related diseases. In the epidermis, two lineage differentiation trajectories describe hair follicle (HF) morphogenesis and epidermal development. By comparing normal and hairless fetal pigs, it is found that the hair placode (Pc), the most characteristic initial structure in HFs, arises from progenitor‐like OGN+/UCHL1+ cells. These progenitors appear earlier in development than the previously described early Pc cells and exhibit abnormal proliferation and migration during differentiation in hairless pigs. The study provides a valuable resource for in‐depth insights into HF development, which may serve as a key reference atlas for studying human skin disease etiology using porcine models. [ABSTRACT FROM AUTHOR]

This narrative review aims to examine the therapeutic potential and mechanism of action of plant extracts in preventing and treating alopecia (baldness). We searched and selected research papers on plant extracts related to hair loss, hair growth, or hair regrowth, and comprehensively compared the therapeutic efficacies, phytochemical components, and modulatory targets of plant extracts. These studies showed that various plant extracts increased the survival and proliferation of dermal papilla cells in vitro, enhanced cell proliferation and hair growth in hair follicles ex vivo, and promoted hair growth or regrowth in animal models in vivo. The hair growth-promoting efficacy of several plant extracts was verified in clinical trials. Some phenolic compounds, terpenes and terpenoids, sulfur-containing compounds, and fatty acids were identified as active compounds contained in plant extracts. The pharmacological effects of plant extracts and their active compounds were associated with the promotion of cell survival, cell proliferation, or cell cycle progression, and the upregulation of several growth factors, such as IGF-1, VEGF, HGF, and KGF (FGF-7), leading to the induction and extension of the anagen phase in the hair cycle. Those effects were also associated with the alleviation of oxidative stress, inflammatory response, cellular senescence, or apoptosis, and the downregulation of male hormones and their receptors, preventing the entry into the telogen phase in the hair cycle. Several active plant extracts and phytochemicals stimulated the signaling pathways mediated by protein kinase B (PKB, also called AKT), extracellular signal-regulated kinases (ERK), Wingless and Int-1 (WNT), or sonic hedgehog (SHH), while suppressing other cell signaling pathways mediated by transforming growth factor (TGF)-β or bone morphogenetic protein (BMP). Thus, well-selected plant extracts and their active compounds can have beneficial effects on hair health. It is proposed that the discovery of phytochemicals targeting the aforementioned cellular events and cell signaling pathways will facilitate the development of new targeted therapies for alopecia. [ABSTRACT FROM AUTHOR]

The hair follicle is a dynamic mini-organ that has specialized cycles and architectures with diverse cell types to form hairs. Previous studies for several decades have investigated morphogenesis and signaling pathways during embryonic development and adult hair cycles in both mouse and human skin. In particular, hair follicle stem cells and mesenchymal niches received major attention as key players, and their roles and interactions were heavily revealed. Although resident and circulating immune cells affect cellular function and interactions in the skin, research on immune cells has mainly received attention on diseases rather than development or homeostasis. Recently, many studies have suggested the functional roles of diverse immune cells as a niche for hair follicles. Here, we will review recent findings about immune niches for hair follicles and provide insight into mechanisms of hair growth and diseases. [ABSTRACT FROM AUTHOR]

In our series of studies, the changes in the skin characteristics of mice caused by aging were investigated in correlation with the stem cells for keratinocytes and melanocytes in the natural hair cycle until middle age. The aim of the present review was to investigate these characteristics of hair follicles (HFs) at older age and complete the analysis of these changes as a study throughout the mouse lifetime. In addition, stem cells for keratinocytes and melanocytes were evaluated for changes in skin characteristics caused by aging. Postnatal day 200 (P200) appears to be the age of complete maturation of skin and the onset of aging with regard to HFs. Keratin 15-positive keratinocyte stem cells complete their localization as a quantitatively sufficient amount of progenitor in the hair bulge region and orchestrate the regeneration of hairs in every anagen phase thereafter. Although their frequency is low, an unusual structure of HFs, curved HFs, appear for the first time at P200. Thereafter, abnormal hair curvature continues to increase throughout life. In contrast, HF characteristics derived from melanocytes begin to show a high frequency of hypopigmented hair bulbs at P200 and appear to lead to a significant increase in the number of white hairs. Curved HFs and white hairs were considered biomarkers of aging in mice. The number of tyrosinase-related protein 2-positive melanocyte stem cells in the hair bulge is extremely low and may be one cause underlying not only the induction of melanocyte-derived characteristics by aging but possibly also that of keratinocyte-derived characteristics. These results provide insight into the mechanisms of the actions of stem cells on hair regeneration through the aging process. [ABSTRACT FROM AUTHOR]

Melanocyte stem cells (MSCs), melanocyte lineage‐specific skin stem cells derived from the neural crest, are observed in the mammalian hair follicle, the epidermis or the sweat gland. MSCs differentiate into mature melanin‐producing melanocytes, which confer skin and hair pigmentation and uphold vital skin functions. In controlling and coordinating the homeostasis, repair and regeneration of skin tissue, MSCs play a vital role. Decreased numbers or impaired functions of MSCs are closely associated with the development and therapy of many skin conditions, such as hair graying, vitiligo, wound healing and melanoma. With the advancement of stem cell technology, the relevant features of MSCs have been further elaborated. In this review, we provide an exhaustive overview of cutaneous MSCs and highlight the latest advances in MSC research. A better understanding of the biological characteristics and micro‐environmental regulatory mechanisms of MSCs will help to improve clinical applications in regenerative medicine, skin pigmentation disorders and cancer therapy. Key points: This review provides a concise summary of the origin, biological characteristics, homeostatic maintenance and therapeutic potential of cutaneous MSCs.The role and potential application value of MSCs in skin pigmentation disorders are discussed.The significance of single‐cell RNA sequencing, CRISPR‐Cas9 technology and practical models in MSCs research is highlighted. [ABSTRACT FROM AUTHOR]

Background: Androgenetic alopecia (AGA) is a prevalent genetic condition that can affect both male and female, and is considered the most frequent form of hair loss. Traditional scales and methods of classifying AGA are basically qualitative. Objective: This work aims to propose a quantitative scale to classify AGA in order to assist hair transplantation surgery. Methods: Based on whole hairless and thinning areas that needs to receive follicular units in a hair transplantation procedure, basic equations to support the scale are proposed. Additionally, the study involves simulations that apply the classification system and compare its results with those of qualitative methods. Results: The PRECISE scale utilizes a range of 0–10, using 30 cm2 as the measured standard of a bald area. For hair transplantation, 1500 follicular units (FU) are recommended for each score in the PRECISE scale. Technological and manual methods to measure the hairless and thinning areas are presented and discussed. This new quantitative classification, combined with different and complementary methods of measurement of hairless and thinning areas endorse the understanding of the clinical condition by the patient and the planning of a surgery procedure. Conclusion: The developed PRECISE scale brings a different way of classifying Androgenetic alopecia (AGA), through an essentially quantitative evaluation. It can be used to elaborate the best strategy for the hair transplantation surgery and to improve the outcomes. Level of Evidence V: 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. [ABSTRACT FROM AUTHOR]

The remarkable regenerative ability of the skin, governed by complex molecular mechanisms, offers profound insights into the skin repair processes and the pathogenesis of various dermatological conditions. This understanding, derived from studies in human skin and various model systems, has not only deepened our knowledge of skin regeneration but also facilitated the development of skin substitutes in clinical practice. Recent research highlights the crucial role of lymphatic vessels in skin regeneration. Traditionally associated with fluid dynamics and immune modulation, these vessels are now recognized for interacting with skin stem cells and coordinating regeneration. This Mini Review provides an overview of recent advancements in basic and translational research related to skin regeneration, focusing on the dynamic interplay between lymphatic vessels and skin biology. Key highlights include the critical role of stem cell-lymphatic vessel crosstalk in orchestrating skin regeneration, emerging translational approaches, and their implications for skin diseases. Additionally, the review identifies research gaps and proposes potential future directions, underscoring the significance of this rapidly evolving research arena. [ABSTRACT FROM AUTHOR]

BACKGROUND: Autophagy has become a rapidly developing research hotspot in the biomedical fields. Many researchers are actively exploring the molecular regulatory mechanism of autophagy in a variety of diseases. However, the role of autophagy in hair growth is still unknown. OBJECTIVE: To review the current research progress and application value of autophagy in hair growth and regeneration, to understand the role of autophagy in hair growth, to explore the pathogenesis of autophagy in pathological hair loss, and to provide new ideas for the study of drugs for hair loss. METHODS: Using “hair follicle growth, hair growth, hair regeneration, autophagy associated proteins, autophagy activity, autophagy associated genes, autophagy” as Chinese search terms and “hair growth, hair follicle, hair regeneration, autophagy” as English search terms, PubMed and CNKI databases were searched. The research progress on autophagy, hair growth and the role of autophagy in hair growth in and outside China in recent years was reviewed and summarized. Articles incompatible with the subject content of the paper were excluded. Finally, 78 articles were included for the result analysis. RESULTS AND CONCLUSION: (1) Autophagy is a normal metabolic process in eukaryotes with complex molecular mechanisms and functional properties, which is beneficial to cell survival and cell death. (2) Alopecia-related diseases are associated with changes in autophagy activity, which can regulate hair growth cycle. Knockout or overexpression of autophagy-related genes can change the state of hair growth. Multiple autophagy related signaling pathways have been found to be related to hair follicle growth. Activators or inhibitors of autophagy can be used to treat or prevent hair loss. [ABSTRACT FROM AUTHOR]

Purpose: This study investigates in silico the contribution of the hair follicle to the overall dermal permeability of small molecules, as published experimental work provides inconclusive information on whether the follicular route favours the permeation of hydrophobic or hydrophilic permeants. Method: A study is conducted varying physico-chemical parameters of permeants such as lipophilicity, molecular weight and protein binding. The simulated data is compared to published experimental data to discuss how those properties can modulate the contribution of the hair follicle to the overall dermal permeation. Results: The results indicate that the contribution of the follicular route to dermal permeation can range from negligible to notable depending on the combination of lipophilic/hydrophilic properties of the substance filling the follicular route and the permeant. Conclusion: Characterisation of the substance filling the follicular route is required for analysing the experimental data of dermal permeation of small molecules, as changes between in vivo and in vitro due to handling of samples and cessation of vital functions can modify the contribution of the follicular route to overall dermal permeation, hence hindering data interpretation. [ABSTRACT FROM AUTHOR]

Abstract is missing (Short communication)

Demodex mites are commensal parasites of hair follicles (HFs). Normally asymptomatic, inflammatory outgrowth of mites can accompany malnutrition, immune dysfunction, and aging, but mechanisms restricting Demodex outgrowth are not defined. Here, we show that control of mite HF colonization in mice required group 2 innate lymphoid cells (ILC2s), interleukin-13 (IL-13), and its receptor, IL-4Ra-IL-13Ra1. HF-associated ILC2s elaborated IL-13 that attenuated HFs and epithelial proliferation at anagen onset; in their absence, Demodex colonization led to increased epithelial proliferation and replacement of gene programs for repair by aberrant inflammation, leading to the loss of barrier function and HF exhaustion. Humans with rhinophymatous acne rosacea, an inflammatory condition associated with Demodex, had increased HF inflammation with decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a key role for skin ILC2s and IL-13, which comprise an immune checkpoint that sustains cutaneous integrity and restricts pathologic infestation by colonizing HF mites.

Polyunsaturated fatty acids (PUFAs) are used as traditional remedies to treat hair loss, but the mechanisms underlying their beneficial effects are not well understood. Here, we explored the role of PUFA metabolites generated by the cytochrome P450/soluble epoxide hydrolase (sEH) pathway in the regulation of the hair follicle cycle. Histological analysis of the skin from wild-type and sEH-/- mice revealed that sEH deletion delayed telogen to anagen transition, and the associated activation of hair follicle stem cells. Interestingly, EdU labeling during the late anagen stage revealed that hair matrix cells from sEH-/- mice proliferated at a greater rate which translated into increased hair growth. Similar effects were observed in in vitro studies using hair follicle explants, where a sEH inhibitor was also able to augment whisker growth in follicles from wild-type mice. sEH activity in the dorsal skin was not constant but altered with the cell cycle, having the most prominent effects on levels of the linoleic acid derivatives 12,13-epoxyoctadecenoic acid (12,13-EpOME), and 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME). Fitting with this, the sEH substrate 12,13-EpOME significantly increased hair shaft growth in isolated anagen stage hair follicles, while its diol; 12,13-DiHOME, had no effect. RNA sequencing of isolated hair matrix cells implicated altered Wnt signaling in the changes associated with sEH deletion. Taken together, our data indicate that the activity of the sEH in hair follicle changes during the hair follicle cycle and impacts on two stem cell populations, i.e., hair follicle stem cells and matrix cells to affect telogen to anagen transition and hair growth.

Abstract Considerable global demand exists for the development of novel drugs for the treatment of alopecia. A recent report demonstrated that oxytocin promotes hair growth activity in human dermal papilla (DP) cells; however, its application in drugs or cosmetic products is challenging because rapid degradation and relatively large molecular weight prevent long-term topical administration on the scalp. Here, we examined cinnamic acid, a small molecule activator for oxytocin receptor (OXTR) expression. Treatment with cinnamic acid led to upregulation of OXTR and trichogenic gene expression in human DP cells. Furthermore, inhibition of OXTR with an antagonist, L-371,257, suppressed hair growth-related gene expression in DP cells. These findings suggest that cinnamic acid enhances the hair growth ability of DP cells via oxytocin signaling. Additionally, we tested the hair growth-promoting effects of cinnamic acid using hair follicle organoids in vitro and observed that cinnamic acid significantly promoted the growth of hair peg-like sprouting. These promising results may be useful for developing hair growth-promoting products targeting oxytocin.

Abstract Background Thymosin beta family has a significant role in promoting hair regeneration, but which type of T cells play a key role in this process has not been deeply studied. This research aimed to find out the subtypes of T cell that play key role in hair regeneration mediated by thymosin beta 15 (Tβ15). Methods Ready-to-use adenovirus expressing mouse Tmsb15b (thymosin beta 15 overexpression, Tβ15 OX) and lentivirus-Tβ15 short hairpin RNA (Tβ15 sh) were used to evaluate the role of Tβ15 in hair regeneration and development. The effect of Th22 cells on hair regeneration was further studied by optimized Th22-skewing condition medium and IL-22 binding protein (IL-22BP, an endogenous antagonist of IL-22, also known as IL-22RA2) in both ex vivo culture C57BL/6J mouse skin and BALB/c nude mice transplanted with thymus organoid model. Results The results show that Tβ15, the homologous of Tβ4, can promote hair regeneration by increasing the proliferation activity of hair follicle cells. In addition, high-level expression of Tβ15 can not only increase the number of Th22 cells around hair follicles but also accelerate the transformation of hair follicles to maturity. Consistent with the expected results, when the IL-22BP inhibitor was used to interfere with Th22, the process of hair regeneration was blocked. Conclusions In conclusion, Th22 is the key effector cell of Tβ15 inducing hair regeneration. Both Tβ15 and Th22 may be the potential drug targets for hair regeneration.