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This review article synthesizes relevant information about hair-follicle biology and pathobiology and summarizes the clinical presentation and management of this common condition. The impact of certain skin diseases on the lives of those affected tends to be underestimated or even dismissed as simply a “cosmetic problem.” Alopecia areata exemplifies such a condition, owing to its substantial disease burden and its often devastating effects on the patient's quality of life and self-esteem. 1 , 2 Although alopecia areata is one of the most common autoimmune diseases, the pathobiology of this chronic, relapsing hair-loss disorder is not fully understood, and the available therapies are disappointing. 3 – 6 This review summarizes the pathogenesis, clinical presentation, and management of alopecia areata and synthesizes relevant background information concerning the biologic . . .

The “thyroid–skin connection” has become a hot frontier in dermatoendocrinology. In this context, the pituitary hormone that controls thyroid hormone production, thyrotropin (TSH), caught the attention of skin researchers only after it was reported that the receptor for TSH (TSH-R) is transcribed and translated by selected cultured human skin cell populations and in normal human scalp skin in situ, introducing skin as a nonconventional, peripheral target organ for regulation by TSH. In this issue, Cianfarani et al. present corroborating evidence and raise the old question of whether intracutaneous TSH-R stimulation by autoantibodies contributes to the skin changes seen in autoimmune thyroid disease. This provides a good opportunity to define the questions to be addressed when exploring the thyroid–skin connection.

Skin epithelial stem cells operate within a complex signaling milieu that orchestrates their lifetime regenerative properties. The question of whether and how immune cells impact on these stem cells within their niche is not well understood. Here we show that skin-resident macrophages decrease in number because of apoptosis before the onset of epithelial hair follicle stem cell activation during the murine hair cycle. This process is linked to distinct gene expression, including Wnt transcription. Interestingly, by mimicking this event through the selective induction of macrophage apoptosis in early telogen, we identify a novel involvement of macrophages in stem cell activation in vivo. Importantly, the macrophage-specific pharmacological inhibition of Wnt production delays hair follicle growth. Thus, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel, additional cue that regulates their regenerative activity. This finding may have translational implications for skin repair, inflammatory skin diseases and cancer.

Hair follicles (HFs) are unique, multi-compartment, mini-organs that cycle through phases of active hair growth and pigmentation (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Anagen HFs have high demands for energy and biosynthesis precursors mainly fulfilled by aerobic glycolysis. Histochemistry reports the outer root sheath (ORS) contains high levels of glycogen. To investigate a functional role for glycogen in the HF we quantified glycogen by Periodic-Acid Schiff (PAS) histomorphometry and colorimetric quantitative assay showing ORS of anagen VI HFs contained high levels of glycogen that decreased in catagen. qPCR and immunofluorescence microscopy showed the ORS expressed all enzymes for glycogen synthesis and metabolism. Using human ORS keratinocytes (ORS-KC) and ex vivo human HF organ culture we showed active glycogen metabolism by nutrient starvation and use of a specific glycogen phosphorylase (PYGL) inhibitor. Glycogen in ORS-KC was significantly increased by incubation with lactate demonstrating a functional Cori cycle. Inhibition of PYGL significantly stimulated the ex vivo growth of HFs and delayed onset of catagen. This study defines translationally relevant and therapeutically targetable new features of HF metabolism showing that human scalp HFs operate an internal Cori cycle, synthesize glycogen in the presence of lactate and modulate their growth via PYGL activity.

Hair loss can be a psychologically devastating adverse effect of chemotherapy, but satisfactory management strategies for chemotherapy-induced alopecia remain elusive. In this Review we focus on the complex pathobiology of this side-effect. We discuss the clinical features and current management approaches, then draw upon evidence from mouse models and human hair-follicle organ-culture studies to explore the main pathobiology principles and explain why chemotherapy-induced alopecia is so challenging to manage. P53-dependent apoptosis of hair-matrix keratinocytes and chemotherapy-induced hair-cycle abnormalities, driven by the dystrophic anagen or dystrophic catagen pathway, play important parts in the degree of hair-follicle damage, alopecia phenotype, and hair-regrowth pattern. Additionally, the degree of hair-follicle stem-cell damage determines whether chemotherapy-induced alopecia is reversible. We highlight the need for carefully designed preclinical research models to generate novel, clinically relevant pointers to how this condition may be overcome.

Olfactory receptors are expressed by different cell types throughout the body and regulate physiological cell functions beyond olfaction. In particular, the olfactory receptor OR2AT4 has been shown to stimulate keratinocyte proliferation in the skin. Here, we show that the epithelium of human hair follicles, particularly the outer root sheath, expresses OR2AT4, and that specific stimulation of OR2AT4 by a synthetic sandalwood odorant (Sandalore ® ) prolongs human hair growth ex vivo by decreasing apoptosis and increasing production of the anagen-prolonging growth factor IGF-1. In contrast, co-administration of the specific OR2AT4 antagonist Phenirat ® and silencing of OR2AT4 inhibit hair growth. Together, our study identifies that human hair follicles can engage in olfactory receptor-dependent chemosensation and require OR2AT4-mediated signaling to sustain their growth, suggesting that olfactory receptors may serve as a target in hair loss therapy. Increasing evidence suggest that olfactory receptors can carry additional functions besides olfaction. Here, Chéret et al. show that stimulation of the olfactory receptor ORT2A4 by the odorant Sandalore ® stimulates growth of human scalp hair follicles ex vivo, suggesting the use of ORT2A4-targeting odorants as hair growth-promoting agents.

Novel senotherapeutics are needed to reverse aging-related skin decline. The research question addressed was whether mesoglycan, a clinically approved glycosaminoglycan formulation known to enhance perfusion, angiogenesis, and VEGF-A signaling, possesses therapeutic potential for rejuvenating photo aged human skin. To test this, we treated full-thickness photoaged facial human skin samples (mean age: 72 ± 5 years) from seven women ex vivo. The samples were treated with topical or medium-delivered mesoglycan (100, 200, and 300 µM) for 6 days under serum-free conditions that accelerate skin aging. Biomarkers associated with aging were assessed using quantitative immunohistomorphometry. Mesoglycan treatment improved key skin aging biomarkers at all doses. Compared to vehicle-treated skin, mesoglycan broadly enhanced epidermal structure and function, improved pigmentation-related markers, reduced cellular senescence, boosted mitochondrial performance and antioxidant defenses, and improved dermal matrix structure and microvasculature density. Notably, mesoglycan also upregulated VEGF-A and VEGFR2, promoting skin rejuvenation. Medium-delivered mesoglycan produced stronger overall effects, while rete ridge reappearance was observed exclusively after topical application. Mesoglycan demonstrates senotherapeutic potential in photoaged human skin, acting via complementary pathways, including VEGF-A upregulation. Although medium-delivered mesoglycan yielded the greatest biomarker improvements topical application restored rete ridges, a sign of epidermal reorganization and also significantly enhanced basement membrane structure, pigmentation, mitochondrial function and antioxidant defenses, while avoiding systemic exposure, making it the safer and more feasible route for localized skin anti-aging.

Hair greying is a visible sign of aging that affects everyone. The loss of hair color is due to the loss of melanin, a pigment found in the skin, eyes and hair. Research in mice suggests stress may accelerate hair greying, but there is no definitive research on this in humans. This is because there are no research tools to precisely map stress and hair color over time. But, just like tree rings hold information about past decades, and rocks hold information about past centuries, hairs hold information about past months and years. Hair growth is an active process that happens under the skin inside hair follicles. It demands lots of energy, supplied by structures inside cells called mitochondria. While hairs are growing, cells receive chemical and electrical signals from inside the body, including stress hormones. It is possible that these exposures change proteins and other molecules laid down in the growing hair shaft. As the hair grows out of the scalp, it hardens, preserving these molecules into a stable form. This preservation is visible as patterns of pigmentation. Examining single-hairs and matching the patterns to life events could allow researchers to look back in time through a person’s biological history. Rosenberg et al. report a new way to digitize and measure small changes in color along single human hairs. This method revealed that some white hairs naturally regain their color, something that had not been reported in a cohort of healthy individuals before. Aligning the hair pigmentation patterns with recent reports of stress in the hair donors’ lives showed striking associations. When one donor reported an increase in stress, a hair lost its pigment. When the donor reported a reduction in stress, the same hair regained its pigment. Rosenberg et al. mapped hundreds of proteins inside the hairs to show that white hairs contained more proteins linked to mitochondria and energy use. This suggests that metabolism and mitochondria may play a role in hair greying. To explore these observations in more detail Rosenberg et al. developed a mathematical model that simulates the greying of a whole head of hair over a lifetime, an experiment impossible to do with living people. The model suggested that there might be a threshold for temporary greying; if hairs are about to go grey anyway, a stressful event might trigger that change earlier. And when the stressful event ends, if a hair is just above the threshold, then it could revert back to dark. The new method for measuring small changes in hair coloring opens up the possibility of using hair pigmentation patterns like tree rings. This could track the influence of past life events on human biology. In the future, monitoring hair pigmentation patterns could provide a way to trace the effectiveness of treatments aimed at reducing stress or slowing the aging process. Understanding how ‘old’ white hairs regain their ‘young’ pigmented state could also reveal new information about the malleability of human aging more generally.

Autophagy plays a crucial role in health and disease, regulating central cellular processes such as adaptive stress responses, differentiation, tissue development, and homeostasis. However, the role of autophagy in human physiology is poorly understood, highlighting a need for a model human organ system to assess the efficacy and safety of strategies to therapeutically modulate autophagy. As a complete, cyclically remodelled (mini-)organ, the organ culture of human scalp hair follicles (HFs), which, after massive growth (anagen), spontaneously enter into an apoptosis-driven organ involution (catagen) process, may provide such a model. Here, we reveal that in anagen, hair matrix keratinocytes (MKs) of organ-cultured HFs exhibit an active autophagic flux, as documented by evaluation of endogenous lipidated Light Chain 3B (LC3B) and sequestosome 1 (SQSTM1/p62) proteins and the ultrastructural visualization of autophagosomes at all stages of the autophagy process. This autophagic flux is altered during catagen, and genetic inhibition of autophagy promotes catagen development. Conversely, an anti-hair loss product markedly enhances intrafollicular autophagy, leading to anagen prolongation. Collectively, our data reveal a novel role of autophagy in human hair growth. Moreover, we show that organ-cultured scalp HFs are an excellent preclinical research model for exploring the role of autophagy in human tissue physiology and for evaluating the efficacy and tissue toxicity of candidate autophagy-modulatory agents in a living human (mini-)organ.

Here, we have explored the involvement of innate lymphoid cells-type 1 (ILC1) in the pathogenesis of alopecia areata (AA), because we found them to be significantly increased around lesional and non-lesional HFs of AA patients. To further explore these unexpected findings, we first co-cultured autologous circulating ILC1-like cells (ILC1lc) with healthy, but stressed, organ-cultured human scalp hair follicles (HFs). ILClc induced all hallmarks of AA ex vivo: they significantly promoted premature, apoptosis-driven HF regression (catagen), HF cytotoxicity/dystrophy, and most important for AA pathogenesis, the collapse of the HFs physiological immune privilege. NKG2D-blocking or IFNγ-neutralizing antibodies antagonized this. In vivo, intradermal injection of autologous activated, NKG2D+/IFNγ-secreting ILC1lc into healthy human scalp skin xenotransplanted onto SCID/beige mice sufficed to rapidly induce characteristic AA lesions. This provides the first evidence that ILC1lc, which are positive for the ILC1 phenotype and negative for the classical NK markers, suffice to induce AA in previously healthy human HFs ex vivo and in vivo, and further questions the conventional wisdom that AA is always an autoantigen-dependent, CD8 +T cell-driven autoimmune disease.