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.

Twisted van der Waals Quantum Materials: Fundamentals, Tunability, and Applications.

Twisted van der Waals (vdW) quantum materials have emerged as a rapidly developing field of two-dimensional (2D) semiconductors. These materials establish a new central research area and provide a promising platform for studying quantum phenomena and investigating the engineering of novel optoelectronic properties such as single photon emission, nonlinear optical response, magnon physics, and topological superconductivity. These captivating electronic and optical properties result from, and can be tailored by, the interlayer coupling using moiré patterns formed by vertically stacking atomic layers with controlled angle misorientation or lattice mismatch. Their outstanding properties and the high degree of tunability position them as compelling building blocks for both compact quantum-enabled devices and classical optoelectronics. This paper offers a comprehensive review of recent advancements in the understanding and manipulation of twisted van der Waals structures and presents a survey of the state-of-the-art research on moiré superlattices, encompassing interdisciplinary interests. It delves into fundamental theories, synthesis and fabrication, and visualization techniques, and the wide range of novel physical phenomena exhibited by these structures, with a focus on their potential for practical device integration in applications ranging from quantum information to biosensors, and including classical optoelectronics such as modulators, light emitting diodes, lasers, and photodetectors. It highlights the unique ability of moiré superlattices to connect multiple disciplines, covering chemistry, electronics, optics, photonics, magnetism, topological and quantum physics. This comprehensive review provides a valuable resource for researchers interested in moiré superlattices, shedding light on their fundamental characteristics and their potential for transformative applications in various fields.

The homing of exogenous hair follicle mesenchymal stem cells into hair follicle niches.

Hair loss is a debilitating condition associated with the depletion of dermal papilla cells (DPCs), which can be replenished by dermal sheath cells (DSCs). Hence, strategies aimed at increasing the populations of DPCs and DSCs hold promise for the treatment of hair loss. In this study, we demonstrated in mice that introduced exogenous DPCs and DSCs (hair follicle mesenchymal stem cells) could effectively migrate and integrate into the dermal papilla and dermal sheath niches, leading to enhanced hair growth and prolonged anagen phases. However, the homing rates of DPCs and DSCs were influenced by various factors, including recipient mouse depilation, cell passage number, cell dose, and immune rejection. Through in vitro and in vivo experiments, we also discovered that the CXCL13/CXCR5 pathway mediated the homing of DPCs and DSCs into hair follicle niches. This study underscores the potential of cell-based therapies for hair loss by targeted delivery of DPCs and DSCs to their respective niches and sheds light on the intriguing concept that isolated mesenchymal stem cells can home back to their original niche microenvironment.

Negative Capacitance Field Effect Transistors based on Van der Waals 2D Materials.

Steep subthreshold swing (SS) is a decisive index for low energy consumption devices. However, the SS of conventional field effect transistors (FETs) has suffered from Boltzmann Tyranny, which limits the scaling of SS to sub-60 mV dec-1 at room temperature. Ferroelectric gate stack with negative capacitance (NC) is proved to reduce the SS effectively by the amplification of the gate voltage. With the application of 2D ferroelectric materials, the NC FETs can be further improved in performance and downscaled to a smaller dimension as well. This review introduces some related concepts for in-depth understanding of NC FETs, including the NC, internal gate voltage, SS, negative drain-induced barrier lowering, negative differential resistance, single-domain state, and multi-domain state. Meanwhile, this work summarizes the recent advances of the 2D NC FETs. Moreover, the electrical characteristics of some high-performance NC FETs are expressed as well. The factors which affect the performance of the 2D NC FETs are also presented in this paper. Finally, this work gives a brief summary and outlook for the 2D NC FETs.

The AR/miR-221/IGF-1 pathway mediates the pathogenesis of androgenetic alopecia.

Androgenetic alopecia (AGA) affects more than half of the adult population worldwide and is primarily caused by the binding of dihydrotestosterone (DHT) to androgen receptors (AR). However, the mechanisms by which AR affects hair follicles remain unclear. In our study, we found that miR-221 significantly suppressed hair growth and the proliferation of dermal papilla cells (DPCs) and dermal sheath cells (DSCs) in AGA patients. Interestingly, miR-221 and AR were mainly co-located in the same part of the hair follicle. Mechanistic analysis revealed that AR directly promoted the transcription of miR-221, which in turn suppressed IGF-1 expression, leading to the inactivation of the MAPK pathway in DPCs and the PI3K/AKT pathway in DSCs. In AGA patients, miR-221 expression was positively correlated with AR expression and negatively correlated with IGF-1 expression. Our findings indicate that miR-221, as a direct target of AR, plays a crucial role in the pathogenesis of AGA, making it a novel biomarker and potential therapeutic target for treating AGA.

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.

N6-methyladenosine RNA Methylation Correlates with Immune Microenvironment and Immunotherapy Response of Melanoma.

RNA methylation normally inhibits the self-recognition and immunogenicity of RNA. As such, it is likely an important inhibitor of cancer immune recognition in the tumor microenvironment, but how N6-methyladenosine (m6A) affects prognosis and treatment response remains unknown. In eight independent melanoma cohorts (1,564 patients), the modification patterns of 21 m6A gene signatures were systematically correlated with the immune cell infiltration of melanoma tumor microenvironment. m6A modification patterns for each patient were quantified using the principal component analysis method, yielding an m6Ascore that reflects the abundance of m6A RNA modifications. Two different m6A modification patterns were observed in patients with melanoma, separated into high and low m6Ascores that correlated with survival and treatment response. Low m6Ascores were characterized by an immune-inflamed phenotype, with 61.1% 5-year survival. High m6Ascores were characterized by an immune-excluded phenotype, with 52.2% 5-year survival. Importantly, lower m6Ascores correlated with more sensitive anti-PD-1 and anti-CTLA4 treatment responses, with 90% of patients with low m6Ascore responding, whereas 10% of those with high m6Ascore nonresponding (in cohort GSE63557). At single-cell and spatial transcriptome resolution, m6Ascore reflects melanoma malignant progression, immune exhaustion, and resistance to immune checkpoint blockade therapy. Hence, the m6Ascore correlates to an important facet of tumor immune escape as a tool for personalized medicine to guide immunotherapy in patients with melanoma.

Commensal microbiome promotes hair follicle regeneration by inducing keratinocyte HIF-1α signaling and glutamine metabolism.

Tissue injury induces metabolic changes in stem cells, which likely modulate regeneration. Using a model of organ regeneration called wound-induced hair follicle neogenesis (WIHN), we identified skin-resident bacteria as key modulators of keratinocyte metabolism, demonstrating a positive correlation between bacterial load, glutamine metabolism, and regeneration. Specifically, through comprehensive multiomic analysis and single-cell RNA sequencing in murine skin, we show that bacterially induced hypoxia drives increased glutamine metabolism in keratinocytes with attendant enhancement of skin and hair follicle regeneration. In human skin wounds, topical broad-spectrum antibiotics inhibit glutamine production and are partially responsible for reduced healing. These findings reveal a conserved and coherent physiologic context in which bacterially induced metabolic changes improve the tolerance of stem cells to damage and enhance regenerative capacity. This unexpected proregenerative modulation of metabolism by the skin microbiome in both mice and humans suggests important methods for enhancing regeneration after injury.

Natural Reconstruction: A Comprehensive Standardized Operating Procedure for Restoring Eyebrow Loss Due to Scarring.

BACKGROUND: Scarring that results in eyebrow loss is a cosmetic problem that can result in severe psychological distress. Although hair transplantation is increasingly used for eyebrow restoration, graft loss may occur, preventing achievement of desired results. Single-hair follicle transplantation, however, may be effective. The authors describe outcomes of a standardized method of eyebrow reconstruction, involving single-hair follicle transplantation combined with follicular unit extraction, in patients with absent eyebrows because of scarring. METHODS: This study was approved by the institutional ethics committee of Nanfang Hospital and all patients provided written informed consent before surgery. The medical records of patients who underwent eyebrow reconstruction from 2012 to 2019 for eyebrow loss caused by scar formation were reviewed retrospectively. Outcomes evaluated included satisfaction, graft survival rate, and long-term complications. A nine-step standardized operating procedure was established for eyebrow reconstruction in patients with eyebrow absence attributable to scarring. RESULTS: During the study period, 167 patients (205 eyebrows) underwent eyebrow reconstruction. Following the first stage of reconstruction, 95 percent of patients were highly satisfied with the density and natural appearance of their eyebrows. The average graft survival rate was 85 percent (range, 70 to 90 percent), significantly higher than the 75 percent survival rate previously reported. Fewer than 5 percent of patients underwent the second stage of reconstruction, with these patients expressing satisfaction with their outcomes. No obvious complications were observed. CONCLUSION: This standardized method may optimize outcomes in patients with eyebrow absence attributable to scarring. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Cellular Heterogeneity Facilitates the Functional Differences Between Hair Follicle Dermal Sheath Cells and Dermal Papilla Cells: A New Classification System for Mesenchymal Cells within the Hair Follicle Niche.

Mesenchymal stem cells (MSCs) are known for their self-renewal and multi-lineage differentiation potential, with these cells often being evaluated in the regulation and maintenance of specific cellular niches including those of the hair follicle. Most mesenchymal stem cells in the hair follicles are housed in the dermal papilla (DP) and dermal sheath (DS), with both niches characterized by a broad variety of cellular subsets. However, while most previous studies describing the hair follicle mesenchymal niche treated all DP and DS cells as Hair Follicle Mesenchymal Stem Cells (HF-MSCs), the high number of cellular subsets would suggest that these cells are actually too heterogenous for such a broad definition. Given this we designed this study to evaluate the differentiation processes in these cells and used this data to create a new set of classifications for DP and DS cells, dividing them into "hair follicle mesenchymal stem cells (HF-MSCs)", "hair follicle mesenchymal progenitor cells (HF-MPCs)", and "hair follicle mesenchymal functional cells (HF-MFCs)". In addition, those cells that possess self-renewal and differentiation were re-named hair follicle derived mesenchymal multipotent cells (HF-MMCs). This new classification may help to further our understanding of the heterogeneity of hair follicle dermal cells and provide new insights into their evaluation.

Ficoll density gradient sedimentation isolation of pelage hair follicle mesenchymal stem cells from adult mouse back skin: a novel method for hair follicle mesenchymal stem cells isolation.

BACKGROUND: Hair follicle mesenchymal stem cells (HF-MSCs) have great potential for cell therapy. Traditional method to isolate whisker HF-MSC is time-consuming and few in cell numbers. How to quickly and conveniently obtain a large number of HF-MSC for experimental research is a problem worth exploring. METHODS: Two-step Ficoll Density Gradient Sedimentation (FDGS) was performed to isolate pelage HF-MSC from adult mice. The characteristic of the isolated cells was identified and compared with whisker HF-MSC by immunofluorescence staining, flow cytometry, three-lineage differentiation and hair follicle reconstruction. Pelage HF-MSC and exosomes were injected into the dorsal skin of mice as well as hair follicle organ culture to explore its role in promoting hair growth. The cells and exosomes distribution were located by immunofluorescence staining. RESULTS: Isolated pelage HF-MSC expressed similar markers (ALP, Versican, NCAM, Nestin), showed similar growth pattern, possessed similar mesenchymal stem cells function and hair follicle induction ability as whisker HF-MSC. A large number of cells can be obtained with fewer mice compared to traditional method. Injected pelage HF-MSC promoted hair growth by secreting exosomes. CONCLUSION: A large number of Pelage HF-MSC can be isolated by FDGS, which can promote hair growth by secreting exosomes which may target the dermal papilla and hair matrix region of host hair follicle.

Restoration of appearance for women after aesthetic eyelash transplantation using a novel eyelash resection technique.

BACKGROUND: Hair transplantation based on the follicular unit extraction provides a new opportunity to improve the appearance of patients with congenital sparse eyelashes. However, disparity between transplanted grafts and original eyelashes and the physiological characteristics of upper eyelid skin cause difficulties with this technique and result in low satisfaction. Removal of unsatisfactory eyelashes is indispensable for restoration of appearance and a second transplantation. Unfortunately, existing methods for hair removal have variable success rates, and hairs frequently regrow. OBJECTIVE: This article introduces an effective method to remove unsatisfactory eyelashes in patients with congenital sparse eyelashes who have undergone eyelash transplantation. METHODS: We used a new technique, which involves resection of eyelashes with a composite strip, to remove unsatisfactory eyelashes in patients who underwent eyelash transplantation. The demographic and clinical characteristics of patients were recorded. Outcomes evaluated included patient satisfaction, hair regrowth, and long-term complications. RESULTS: From 2017 to 2021, 10 patients (20 sides) underwent eyelash removal. All patients were highly satisfied with the outcomes. Unsatisfactory eyelashes were thoroughly removed, and none regrew during 1 year of follow-up. No complications were observed. CONCLUSION: Strip composite eyelash excision is a safe and effective method for patients who have undergone unsatisfactory eyelash transplantation.

Filament Engineering of Two-Dimensional h-BN for a Self-Power Mechano-Nociceptor System.

The switching variability caused by intrinsic stochasticity of the ionic/atomic motions during the conductive filaments (CFs) formation process largely limits the applications of diffusive memristors (DMs), including artificial neurons, neuromorphic computing and artificial sensory systems. In this study, a DM device with improved device uniformity based on well-crystallized two-dimensional (2D) h-BN, which can restrict the CFs formation from three to two dimensions due to the high migration barrier of Ag+ between h-BN interlayer, is developed. The BN-DM has potential arrayable feature with high device yield of 88%, which can be applied for building a reservoir computing system for digital pattern recognition with high accuracy rate of 96%, and used as an artificial nociceptor to sense the external noxious stimuli and mimic the important biological nociceptor properties. By connecting the BN-DM to a self-made triboelectric nanogenerator (TENG), a self-power mechano-nociceptor system, which can successfully mimic the important nociceptor features of "threshold", "relaxation" and "allodynia" is designed.

Reconfigurable 2D WSe2 -Based Memtransistor for Mimicking Homosynaptic and Heterosynaptic Plasticity.

The mimicking of both homosynaptic and heterosynaptic plasticity using a high-performance synaptic device is important for developing human-brain-like neuromorphic computing systems to overcome the ever-increasing challenges caused by the conventional von Neumann architecture. However, the commonly used synaptic devices (e.g., memristors and transistors) require an extra modulate terminal to mimic heterosynaptic plasticity, and their capability of synaptic plasticity simulation is limited by the low weight adjustability. In this study, a WSe2 -based memtransistor for mimicking both homosynaptic and heterosynaptic plasticity is fabricated. By applying spikes on either the drain or gate terminal, the memtransistor can mimic common homosynaptic plasticity, including spiking rate dependent plasticity, paired pulse facilitation/depression, synaptic potentiation/depression, and filtering. Benefitting from the multi-terminal input and high adjustability, the resistance state number and linearity of the memtransistor can be improved by optimizing the conditions of the two inputs. Moreover, the device can successfully mimic heterosynaptic plasticity without introducing an extra terminal and can simultaneously offer versatile reconfigurability of excitatory and inhibitory plasticity. These highly adjustable and reconfigurable characteristics offer memtransistors more freedom of choice for tuning synaptic weight, optimizing circuit design, and building artificial neuromorphic computing systems.

Recent Progress in the Understanding of the Effect of Sympathetic Nerves on Hair Follicle Growth.

Clinical observation and experimental studies have long suggested that the perifollicular nerves have nutritional and regulatory effects on the growth, development, and physiological cycle of hair follicles (HFs), even though the concrete mechanism remains obscure. Recently, with the progress of immunohistochemistry and molecular biology techniques, more innovation has been made in the study of the follicular sympathetic nerves and its nerve-effect factor norepinephrine affecting hair follicle stem cells. This review highlights the progress in the regulation of the sympathetic nervous system toward the growth of HFs.

Stacked Two-Dimensional MXene Composites for an Energy-Efficient Memory and Digital Comparator.

Two-dimensional MXene has enormous potential for application in industry and academia owing to its surface hydrophilicity and excellent electrochemical properties. However, the application of MXene in optoelectronic memory and logical computing is still facing challenges. In this study, an optoelectronic resistive random access memory (RRAM) based on silver nanoparticles (Ag NPs)@MXene-TiO2 nanosheets (AMT) was prepared through a low-cost and facile hydrothermal oxidation process. The fabricated device exhibited a typical bipolar switching behavior and controllable SET voltage. Furthermore, we successfully demonstrated a 4-bit in-memory digital comparator with AMT RRAMs, which can replace five logic gates in a traditional approach. The AMT-based digital comparator may open the door for future integrated functions and applications in optoelectronic data storage and simplify the complex logic operations.

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.

Bacteria induce skin regeneration via IL-1ß signaling.

Environmental factors that enhance regeneration are largely unknown. The immune system and microbiome are attributed roles in repairing and regenerating structure but their precise interplay is unclear. Here, we assessed the function of skin bacteria in wound healing and wound-induced hair follicle neogenesis (WIHN), a rare adult organogenesis model. WIHN levels and stem cell markers correlate with bacterial counts, being lowest in germ-free (GF), intermediate in conventional specific pathogen-free (SPF), and highest in wild-type mice, even those infected with pathogenic Staphylococcus aureus. Reducing skin microbiota via cage changes or topical antibiotics decreased WIHN. Inflammatory cytokine IL-1ß and keratinocyte-dependent IL-1R-MyD88 signaling are necessary and sufficient for bacteria to promote regeneration. Finally, in a small trial, a topical broad-spectrum antibiotic also slowed skin wound healing in adult volunteers. These results demonstrate a role for IL-1ß to control morphogenesis and support the need to reconsider routine applications of topical prophylactic antibiotics.

Human acellular amniotic membrane incorporating exosomes from adipose-derived mesenchymal stem cells promotes diabetic wound healing.

BACKGROUND: Diabetic wounds threaten the health and quality of life of patients and their treatment remains challenging. ADSC-derived exosomes have shown encouraging results in enhancing diabetic wound healing. However, how to use exosomes in wound treatment effectively is a problem that needs to be addressed at present. METHODS: A diabetic mouse skin wound model was established. ADSC-derived exosomes (ADSC-Exos) were isolated, and in vitro application of exosomes was evaluated using human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs). After preparation and characterization of a scaffold of human acellular amniotic membrane (hAAM) loaded with ADSC-Exos in vitro, they were transplanted into wounds in vivo and wound healing phenomena were observed by histological and immunohistochemical analyses to identify the wound healing mechanism of the exosome-hAAM composites. RESULTS: The hAAM scaffold dressing was very suitable for the delivery of exosomes. ADSC-Exos enhanced the proliferation and migration of HDFs and promoted proliferation and tube formation of HUVECs in vitro. In vivo results from a diabetic skin wound model showed that the hAAM-Exos dressing accelerated wound healing by regulating inflammation, stimulating vascularization, and promoting the production of extracellular matrix. CONCLUSION: Exosome-incorporated hAAM scaffolds showed great potential in promoting diabetic skin wound healing, while also providing strong evidence for the future clinical applications of ADSC-derived exosomes.