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Hair follicles are essential appendages of the mammalian skin, as hair performs vital functions of protection, thermoregulation and sensation. Hair follicles harbour exceptional regenerative abilities as they contain multiple somatic stem cell populations such as hair follicle stem cells (HFSCs) and melanocyte stem cells. Surrounding the stem cells and their progeny, diverse groups of cells and extracellular matrix proteins are organized to form a microenvironment (called ‘niche’) that serves to promote and maintain the optimal functioning of these stem cell populations. Recent studies have shed light on the intricate nature of the HFSC niche and its crucial role in regulating hair follicle regeneration. In this Review, we describe how the niche serves as a signalling hub, communicating, deciphering and integrating both local signals within the skin and systemic inputs from the body and environment to modulate HFSC activity. We delve into the recent advancements in identifying the cellular and molecular nature of the niche, providing a holistic perspective on its essential functions in hair follicle morphogenesis, regeneration and ageing.The regenerative abilities of mammalian hair follicles are facilitated by the proliferation of hair follicle stem cells (HFSCs), which reside in specialized niches within the skin. Recent studies shed light on how local signals and systemic inputs from the body and the environment regulate HFSC function.

Wound healing is essential to repair the skin after injury. In the epidermis, distinct stem cells (SCs) populations contribute to wound healing. However, how SCs balance proliferation, differentiation and migration to repair a wound remains poorly understood. Here, we show the cellular and molecular mechanisms that regulate wound healing in mouse tail epidermis. Using a combination of proliferation kinetics experiments and molecular profiling, we identify the gene signatures associated with proliferation, differentiation and migration in different regions surrounding the wound. Functional experiments show that SC proliferation, migration and differentiation can be uncoupled during wound healing. Lineage tracing and quantitative clonal analysis reveal that, following wounding, progenitors divide more rapidly, but conserve their homoeostatic mode of division, leading to their rapid depletion, whereas SCs become active, giving rise to new progenitors that expand and repair the wound. These results have important implications for tissue regeneration, acute and chronic wound disorders. Wound healing is essential to repair the skin after injury and distinct stem cells in the epidermis are known to contribute to the process. Here the authors perform molecular, functional and clonal analysis and reveal the individual contribution of stem cells coming from different epidermal compartments to the wound-healing process in mice.

Melanin, the most abundant skin chromophore, is produced by melanocytes and is one of the key components responsible for mediating the skin’s response to ultraviolet radiation (UVR). Because of its antioxidant, radical scavenging, and broadband UV absorbing properties, melanin reduces the penetration of UVR into the nuclei of keratinocytes. Despite its long-established photoprotective role, there is evidence that melanin may also induce oxidative DNA damage in keratinocytes after UV exposure and therefore be involved in the development of melanoma. The present work aimed at evaluating the dependence of UV-induced DNA damage on melanin content and distribution, using reconstructed human epidermis (RHE) models. Tanned and light RHE were irradiated with a 233 nm UV-C LED source at 60 mJ/cm 2 and a UV lamp at 3 mJ/cm 2 . Higher UV-mediated free radicals and DNA damage were detected in tanned RHE with significantly higher melanin content than in light RHE. The melanin distribution in the individual models can explain the lack of photoprotection. Fluorescence lifetime-based analysis and Fontana–Masson staining revealed a non-homogeneous distribution and absence of perinuclear melanin in the tanned RHE compared to the in vivo situation in humans. Extracellularly dispersed epidermal melanin interferes with photoprotection of the keratinocytes.

Stem cells underlie tissue homeostasis, but their dynamics during ageing—and the relevance of these dynamics to organ ageing—remain unknown. Here we report that the expression of the hemidesmosome component collagen XVII (COL17A1) by epidermal stem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis, and that the resulting differential expression of COL17A1 in individual stem cells generates a driving force for cell competition. In vivo clonal analysis in mice and in vitro 3D modelling show that clones that express high levels of COL17A1, which divide symmetrically, outcompete and eliminate adjacent stressed clones that express low levels of COL17A1, which divide asymmetrically. Stem cells with higher potential or quality are thus selected for homeostasis, but their eventual loss of COL17A1 limits their competition, thereby causing ageing. The resultant hemidesmosome fragility and stem cell delamination deplete adjacent melanocytes and fibroblasts to promote skin ageing. Conversely, the forced maintenance of COL17A1 rescues skin organ ageing, thereby indicating potential angles for anti-ageing therapeutic intervention. COL17A1-driven stem cell competition and symmetric cell divisions initially govern skin homeostasis, but the same mechanisms result in skin ageing later in life.

Tissue growth in the adult is an orchestrated process that often requires biological clocks to time stem cell and progenitor activity. Here, we employed the hair follicle, which cycles between growth and regression in a timely-restricted mode, to show that some components of the hair cycle clock reside within the mesenchymal niche of the hair follicle, the dermal papilla (DP), and both Fgf and Wnt signaling pathways interact within the DP to regulate the expression of these components that include Wnt agonists ( Rspondins ) and antagonists ( Dkk2 and Notum ). The levels of Wnt agonists and antagonists in the DP are progressively reduced and elevated during the growth phase, respectively. Consequently, Wnt signaling activity in the overlying epithelial progenitor cells decreases, resulting in the induction of the regression phase. Remarkably, DP properties allow Wnt activity in the DP to persist despite the Wnt-inhibiting milieu and consequently synchronize the induction and progression of the regression phase. This study provides insight into the importance of signaling crosstalk in coupling progenitors and their niche to regulate tissue growth. The underlying mechanisms regulating the mouse hair cycle remain poorly understood. Here, the authors find that Fgf and Wnt signaling pathways interact in the mesenchymal niche of the hair follicle to regulate the molecular clock that dictates the duration of hair growth.

An analysis of mouse skin reveals that super-enhancers are critical to identity, lineage commitment and plasticity of adult stem cells; dynamic super-enhancer remodelling in new niches is dependent on the levels of pioneer transcription factor SOX9, which is identified as a key regulator of super-enhancer chromatin for hair follicle stem cells. Super-enhancers and stem cell plasticity Adult stem cells are able to differentiate along a lineage and also to transiently exit their native niche while retaining their plasticity. Here, Elaine Fuchs and colleagues analyse super-enhancers and chromatin dynamics in mouse hair follicle stem cells in vivo , both during lineage progression and when the stem cells are outside their niche and exposed to a new environment. The pioneer factor SOX9 — a type of transcription factor that binds directly to condensed chromatin — is identified as a crucial regulator of the hair follicle stem cells' super-enhancers in promoting and maintaining cell fate. Adult stem cells occur in niches that balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, stem cells outside their niche often display fate flexibility 1 , 2 , 3 , 4 . Here we show that super-enhancers 5 underlie the identity, lineage commitment and plasticity of adult stem cells in vivo . Using hair follicle as a model, we map the global chromatin domains of hair follicle stem cells and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters (‘epicentres’) of transcription factor binding sites undergo remodelling upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicentres, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, hair follicle stem cells dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicentres, enabling their genes to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of hair follicle stem cell super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense transcription-factor-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states and differentiation.

The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery 1 . Although the response of epidermal cells to stretching has been studied in vitro 2 , 3 , it remains unclear how mechanical forces affect their behaviour in vivo. Here we develop a mouse model in which the consequences of stretching on skin epidermis can be studied at single-cell resolution. Using a multidisciplinary approach that combines clonal analysis with quantitative modelling and single-cell RNA sequencing, we show that stretching induces skin expansion by creating a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation. Transcriptional and chromatin profiling identifies how cell states and gene-regulatory networks are modulated by stretching. Using pharmacological inhibitors and mouse mutants, we define the step-by-step mechanisms that control stretch-mediated tissue expansion at single-cell resolution in vivo. Single-cell analysis in a mouse model of skin stretching shows that stretching causes a transient expansion bias in a population of epidermal stem cells, which is associated with chromatin remodelling and changes in transcriptional profiles.

Skin stem cells can regenerate epidermal appendages; however, hair follicles (HF) lost as a result of injury are barely regenerated. Here we show that macrophages in wounds activate HF stem cells, leading to telogen–anagen transition (TAT) around the wound and de novo HF regeneration, mostly through TNF signalling. Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose-dependent induction of HF neogenesis by TNF, which is consistent with TNF-induced AKT signalling in epidermal stem cells in vitro . TNF-induced β-catenin accumulation is dependent on AKT but not Wnt signalling. Inhibition of PI3K/AKT blocks depilation-induced HF TAT. Notably, Pten loss in Lgr5 + HF stem cells results in HF TAT independent of injury and promotes HF neogenesis after wounding. Thus, our results suggest that macrophage-TNF-induced AKT/β-catenin signalling in Lgr5 + HF stem cells has a crucial role in promoting HF cycling and neogenesis after wounding. Hair can be regenerated after skin wounding. Here the authors show that inflammatory macrophages produce TNF that activates Wnt signalling in hair follicle stem cells to drive this hair regeneration after wound repair in mice.

Human skin comprises stratified squamous epithelium and dermis with various stromal cells and the extracellular matrix (ECM). The basement membrane (BM), a thin layer at the top of the dermis, serves as a unique niche for determining the fate of epidermal stem cells (EpSCs) by transmitting physical and biochemical signals to establish epidermal cell polarity and maintain the hierarchical structure and function of skin tissue. However, how stem cell niches maintain tissue homeostasis and control wound healing by regulating the behavior of EpSCs is still not completely understood. In this study, a hierarchical skin proteome map is constructed using spatial quantitative proteomics combined with decellularization, laser capture microdissection, and mass spectrometry. The specific functions of different structures of normal native skin tissues or tissues with a dermatologic disease are analyzed in situ. Transforming growth factor-beta (TGFβ)-induced protein ig-h3 (TGFBI), an ECM glycoprotein, in the BM is identified that could enhance the growth and function of EpSCs and promote wound healing. Our results provide insights into the way in which ECM proteins facilitate the growth and function of EpSCs as part of an important niche. The results may benefit the clinical treatment of skin ulcers or diseases with refractory lesions that involve epidermal cell dysfunction and re-epithelialization block in the future. Ling Leng et al. construct a hierarchical skin proteome map and identify an extracellular matrix glycoprotein TGFBI, which is located in basement membrane and could enhance the growth and function of epidermal stem cells and promote wound healing.

Tissue stem cells are generated from a population of embryonic progenitors through organ-specific morphogenetic events 1 , 2 . Although tissue stem cells are central to organ homeostasis and regeneration, it remains unclear how they are induced during development, mainly because of the lack of markers that exclusively label prospective stem cells. Here we combine marker-independent long-term 3D live imaging and single-cell transcriptomics to capture a dynamic lineage progression and transcriptome changes in the entire epithelium of the mouse hair follicle as it develops. We found that the precursors of different epithelial lineages were aligned in a 2D concentric manner in the basal layer of the hair placode. Each concentric ring acquired unique transcriptomes and extended to form longitudinally aligned, 3D cylindrical compartments. Prospective bulge stem cells were derived from the peripheral ring of the placode basal layer, but not from suprabasal cells (as was previously suggested 3 ). The fate of placode cells is determined by the cell position, rather than by the orientation of cell division. We also identified 13 gene clusters: the ensemble expression dynamics of these clusters drew the entire transcriptional landscape of epithelial lineage diversification, consistent with cell lineage data. Combining these findings with previous work on the development of appendages in insects 4 , 5 , we describe the ‘telescope model’, a generalized model for the development of ectodermal organs in which 2D concentric zones in the placode telescope out to form 3D longitudinally aligned cylindrical compartments. Live imaging and single-cell transcriptomics of mouse hair follicles reveal their development from 2D concentric zones in the placode to 3D longitudinal compartments, one of which is a stem cell compartment.