Hair Follicle Epithelium Research Articles

Prominent hair follicle epithelial mucinosis in a cat with eosinophilic plaque

AbstractThe feline eosinophilic granuloma complex is a well‐known dermatological problem that affects domestic cats. It has three characteristic components: eosinophilic plaque, eosinophilic granuloma and indolent ulcer. In this case report, we report a 5‐year‐old, mixed‐breed cat with pruritic plaque formation, which was typical for eosinophilic plaque by dermatological examination. The diagnosis was established by histopathological and clinical findings. As previous literature showed, hair follicle epithelium mucinosis as a histopathological finding could potentially give us fundamental clues about the microscopic diagnosis of this complex. We discuss the presentation, histopathology and treatment response in detail. This case highlights how intricate feline eosinophilic granuloma complex can be, and underscores the significance of hair follicle epithelium mucinosis as a diagnostic tool in histopathology.

Paris polyphylla Sm. characterized extract infused ointment accelerates diabetic wound healing in In-vivo model

Ethnopharmacological relevanceThe dried rhizome of Paris polyphylla Sm. is extensively used by traditional healers in India, China, and Vietnam to treat skin inflammation, cut wounds, uterine and traumatic bleeding, and cancer. Aim of the studyThe traditional use of P. polyphylla rhizomes for treating wounds and bleeding has been reported previously. However, the potential of P. polyphylla in the treatment of diabetic wounds has not yet been explored. Our present study focused on the investigation of the wound-healing activity of P. polyphylla infused ointment in streptozotocin (STZ)-induced diabetic rats to validate the traditional claim. Materials and methodsHydroalcoholic extract of the dried rhizomes of P. polyphylla were quantified by validated and optimized HPTLC (High-performance thin layer chromatography) method for Paris saponin VII, Dioscin and Polyphyllin V. The extract was used to prepare P. polyphylla ointments (5 and 10%). P. polyphylla ointment was subjected to physiochemical analysis and skin irritation test. Thirty STZ-induced diabetic adult male Wistar albino rats were divided into five groups (n = 6) and a circular excision wound was created. P. polyphylla ointment, ointment base (OB), and standard (STD) (Povidone Iodine 10%) were administered topically. The wound area of all groups were recorded every six days and compared with that of control. The epithelization period of each group was recorded. On day 18, the histopathological study of skin tissues of all groups was performed using hematoxylin and eosin (H&E) and Mallory's trichrome (MT). ResultsMarker analysis and quantification of phytomolecules in hydroalcoholic extract ofP. Polyphylla were found to be of paris saponin VII (3.28 ± 0.08% w/w), dioscin (1.94 ± 0.12% w/w), and polyphyllin V (1.87 ± 0.84% w/w). A physiochemical study of P. polyphylla ointment showed that the prepared ointment was within an acceptable range and was not irritable to the skin. Daily topical administration of 10% P. polyphylla ointment (PP10) for 18 days completely healed the STZ-induced diabetic wounds. On day 18, the 5% P. polyphylla ointment (PP5) showed 99.1 ± 2.9% wound closure, while that of the standard and control was 78.4 ± 7.3% and 18.5 ± 5.9%, respectively. The epithelialization period of PP10 was 18 days, whereas that of the control was 28 days. Histopathological analysis of the progression of PP10 and PP5 wounds showed a decrease in inflammatory cells, regenerated epithelial layer, keratosis layer, hair follicles, fibroblasts, and collagen. Upon collagen intensity quantification of MT stained sections, an increase in collagen density of PP10 and PP5 treated groups was observed, showing accelerated wound healing potential of P. polyphylla extract in diabetic wounds compared to the standard ointment. ConclusionThis study suggested the potential of P. polyphylla rhizomes derived formulation to treat diabetic wounds, although the plant is traditionally used to treat normal wounds. The results indicate the validation of traditional claim, which has been explored commercially in industrial aspect.

Activation of the integrated stress response in human hair follicles.

Unravelling how energy metabolism and stress responses are regulated in human scalp hair follicles could reveal novel insights into the controls of hair growth and provide new targets to manage hair loss disorders. The Mitochondrial Pyruvate Carrier (MPC) imports pyruvate, produced via glycolysis, into the mitochondria, fuelling the TCA cycle. Previous work has shown that MPC inhibition promotes lactate generation, which activates murine epithelial hair follicle stem cells (eHFSCs). However, by pharmacologically targeting the MPC in short-term human hair follicle ex vivo organ culture experiments using UK-5099, we induced metabolic stress-responsive proliferative arrest throughout the human hair follicle epithelium, including within Keratin 15+ eHFSCs. Through transcriptomics, MPC inhibition was shown to promote a gene expression signature indicative of disrupted FGF, IGF, TGFβ and WNT signalling, mitochondrial dysfunction, and activation of the integrated stress response (ISR), which can arrest cell cycle progression. The ISR, mediated by the transcription factor ATF4, is activated by stressors including amino acid deprivation and ER stress, consistent with MPC inhibition within our model. Using RNAScope, we confirmed the upregulation of both ATF4 and the highly upregulated ATF4-target gene ADM2 on human hair follicle tissue sections in situ. Moreover, treatment with the ISR inhibitor ISRIB attenuated both the upregulation of ADM2 and the proliferative block imposed via MPC inhibition. Together, this work reveals how the human hair follicle, as a complex and metabolically active human tissue system, can dynamically adapt to metabolic stress.

Efficacy of Janus kinase inhibitors in adult patients with alopecia areata

Alopecia areata (AA) is a chronic, immune-mediated disorder resulting in localized hair loss due to targeting hair follicle epithelium. The authors aimed to summarize the existing literature on patients with AA who underwent treatment with Janus kinase inhibitors (JAKis) and discuss the current evidence regarding their efficacy and safety. An extensive scientific literature search was conducted between January 1, 2017, and April 16, 2023, using a recognized medical and scientific database. The extracted data were synthesized and analyzed, focusing on the effect of JAKis in reducing hair loss in adult patients with AA. The evidence suggests that oral JAKis such as tofacitinib, ruxolitinib, and Baricitinib show promise in treating AA regarding both efficacy and safety. The group of drugs JAKis are a good treatment option even in severe clinical conditions of AA, further investigation should be taken to consideration including dosage and treatment duration.

MOF-mediated histone H4 Lysine 16 acetylation governs mitochondrial and ciliary functions by controlling gene promoters

Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase MOF, orchestrates gene expression regulation and chromatin interaction. However, the roles of MOF and H4K16ac in controlling cellular function and regulating mammalian tissue development remain unclear. Here we show that conditional deletion of Mof in the skin, but not Kansl1, causes severe defects in the self-renewal of basal epithelial progenitors, epidermal differentiation, and hair follicle growth, resulting in barrier defects and perinatal lethality. MOF-regulated genes are highly enriched for essential functions in the mitochondria and cilia. Genetic deletion of Uqcrq, an essential subunit for the electron transport chain (ETC) Complex III, in the skin, recapitulates the defects in epidermal differentiation and hair follicle growth observed in MOF knockout mouse. Together, this study reveals the requirement of MOF-mediated epigenetic mechanism for regulating mitochondrial and ciliary gene expression and underscores the important function of the MOF/ETC axis for mammalian skin development.

Proliferative necrotizing otitis externa in two young cats

In this paper, proliferative necrotizing otitis externa is described in two young cats. The lesions were characterized by proliferative, erosive to ulcerative dermatitis with necrosis affecting the medial aspect of the pinna, the entrance of the ear canal and the periaural skin of both ears. The lesions developed rapidly and were covered by adherent crusts. Histopathology of the lesions was characterized by severe epidermal hyperplasia, with parakeratotic hyperkeratosis, scattered apoptotic keratinocytes in the epidermis and superficial hair follicle epithelium, and serocellular crusts. In both cases, regression of the lesions appeared after systemic and topical immunomodulatory therapy.

Application of Topical Sandalore® Increases Epidermal Dermcidin Synthesis in Organ-Cultured Human Skin ex vivo

Introduction: Several olfactory receptors (ORs) are expressed in human skin, where they regulate skin pigmentation, barrier function, wound healing, and hair growth. Previously, we found that the selective activation of OR family 2 subfamily AT member 4 (OR2AT4) by the synthetic, sandalwood-like odorant Sandalore® differentially stimulates the expression of antimicrobial peptides (AMPs) in human scalp hair follicle epithelium ex vivo. As OR2AT4 is also expressed by epidermal keratinocytes, we hypothesized that it may modulate intraepidermal AMP synthesis, thereby contributing to skin microbiome management. Methods: We investigated this hypothesis in organ-cultured human skin in the presence of Sandalore® and antibiotics and evaluated epidermal production of two AMPs, LL37 (cathelicidin) and dermcidin (DCD), as well as OR2AT4, by quantitative immunohistomorphometry. Moreover, we quantified DCD secretion into the culture medium by ELISA and studied the effect of culture medium on selected bacterial and fungal strains. Results: Topical application of Sandalore®to organ-cultured human skin increased OR2AT4 protein expression, the number of DCD-positive intraepidermal cells, and DCD secretion into culture media, without significantly affecting epidermal LL37 expression. In line with the significantly increased secretion of DCD into the culture medium, we demonstrated, in a spectrophotometric assay, that application of conditioned media from Sandalore®-treated skin promotes Staphylococcus epidermidis, Malassezia restricta, and, minimally, Cutibacterium acnes and inhibits Staphylococcus aureus growth. Conclusion: In addition to demonstrating for the first time that DCD can be expressed by epidermal keratinocytes, our pilot study suggests that topical treatment of human skin with a cosmetic odorant (Sandalore®) has the potential to alter the composition of the human skin microbiome through the selective upregulation of DCD. If confirmed, Sandalore® could become an attractive adjuvant, nondrug treatment for dermatoses characterized by dysbiosis due to overgrowth of S. aureus and Malassezia, such as atopic dermatitis and seborrheic dermatitis.

A Clinico-Mycological and Histopathological Study of Recurrent Dermatophytosis

Background: A few recent studies have shown fungal elements within the hair follicle epithelium, which may act as a reservoir and responsible for recurrent dermatophytosis. Objectives: To assess the clinical patterns, mycological profile, and histopathology of recurrent dermatophytosis and to determine the prevalence of fungal hyphae in the hair follicle epithelium and other appendages. Materials and Methods: One hundred and fifty clinically diagnosed cases of recurrent dermatophytic infection were included. Skin samples were taken for direct microscopy, fungal culture, and histopathological analysis. Haematoxylin and eosin and special staining with periodic acid Schiff (PAS) and Gomori's methenamine silver (GMS) were performed to detect the fungal hyphae in the skin and hair follicle epithelium. Results: The most common clinical pattern observed was tinea corporis et cruris in 64 patients (42.66%). On direct microscopy and fungal culture, positive results were obtained in 116 cases (77.33%) and 78 (52%) cases, respectively. Presence of fungal hyphae in the stratum corneum, hair follicle, and acrosyringium was seen in 107 patients (71.33%), 47 patients (31.33%), and five patients (3.33%), respectively. Out of the 52 cases with hair follicle and eccrine gland involvement, history of fixed drug combinations (FDC) cream use was present in 42 cases (80.76%) and absent in ten cases (19.24%) (P = 0.000062). Limitations: Skin samples were taken only from a single skin lesion. Higher incidence of follicular invasion may have been detected if multiple biopsy samples were taken. Conclusion: Hair follicle/eccrine sweat gland involvement was observed in nearly one-third of the patients, which may act as a reservoir and may be responsible for recurrence and chronicity. Histopathology should be considered as an important adjuvant tool in recurrent dermatophytosis to establish the extent of the infection, which guides the further management.

Treatment of Frontal Fibrosing Alopecia

Introduction. Frontal fibrosing alopecia (FFA) is known as a lymphocytic primary cicatricial alopecia. The main characteristic of FFA is progressive frontotemporal hairline recession. The pathogenesis of FFA is not completely understood. Destructing the stem cells of the epithelial hair follicles causes permanent hair loss and seems to be the main cause of FFA. Studies have reported significantly decreased quality of life in patients with hair loss. On the other hand, late diagnosis and treatment of FFA can decrease the success rate of the treatment. In this regard, different topical and systemic therapies have been developed to resolve the symptoms; however, only a partial response to treatment is usually achieved. We conducted a systematic review of the literature to identify the effectiveness of the available treatment modalities used for FFA patients and the related outcomes. Methods. On April 2022, we made a wide systematic computer‐assisted search of PubMed and Google Scholar databases, using “frontal fibrosing alopecia” and “treatment” keywords. We scanned 1,514 articles. All the studies concerning a therapeutic regimen for FFA were included. After removing duplicate studies, 50 studies containing the therapeutic regimen of 1,478 FFA patients were included in this review. Results. The 5‐alpha‐reductase inhibitors (oral finasteride/dutasteride) were the most used medications (usually prescribed as a combination therapy with other medications). Topical corticosteroids were the second commonly used medication for the treatment of FFA. Systemic corticosteroids seem to be ineffective in improving FFA progression. Oral isotretinoin (or alitretinoin) had the most promising effect on improving facial papules of FFA patients with a 92% rate of facial papule improvement. Conclusion. In our review, intralesional corticosteroid injection and 5‐alpha‐reductase inhibitors (finasteride/dutasteride) were reported as the most effective treatment modalities. Oral isotretinoin (or alitretinoin) is considered as the most promising treatment for improving facial papules in the context of FFA. However, it had minimal effects on hair regrowth or stabilization of hairline recession in FFA patients.

Therapeutic Angiogenesis Using Autologous CD34-Positive Cells for Vascular Diseases.

CD34 is a cell surface marker, which is expressed in various somatic stem/progenitor cells such as bone marrow (BM)-derived hematopoietic stem cells and endothelial progenitor cells (EPCs), skeletal muscle satellite cells, epithelial hair follicle stem cells, and adipose tissue mesenchymal stem cells. CD34+ cells in BM and peripheral blood are known as a rich source of EPCs. Thus, vascular regeneration therapy using granulocyte colony stimulating factor (G-CSF) mobilized- or BM CD34+ cells has been carried out in patients with various vascular diseases such as chronic severe lower limb ischemia, acute myocardial infarction, refractory angina, ischemic cardiomyopathy, and dilated cardiomyopathy as well as ischemic stroke. Pilot and randomized clinical trials demonstrated the safety, feasibility, and effectiveness of the CD34+ cell therapy in peripheral arterial, cardiovascular, and cerebrovascular diseases. This review provides an overview of the preclinical and clinical reports of CD34+ cell therapy for vascular regeneration.

382 Environmental pathobiology of frontal fibrosing alopecia (FFA): Does linalool promote FFA development and progression by inducing epithelial hair follicle stem cell damage and MICA expression in the bulge?

Frontal fibrosing alopecia (FFA) is the most common cicatricial alopecia, whose prevalence has greatly increased, mainly in post-menopausal women, results from irreversible epithelial hair follicle (HF) stem cell (eHFSC) damage. Exposure to ingredients commonly found in personal care products might trigger FFA-related immune responses. In fact, 76.2% of patients with FFA and/or LPP show type IV sensitization to allergens found in these products. Since the terpene fragrant, linalool, is one of the most common allergens identified in FFA patients, we have probed the hypothesis that linalool may promote bulge HF immune privilege (IP) collapse and/or eHFSC damage, i.e.

571 Human Hair Follicles can “Taste”: Stimulation of the Bitter Taste Receptor TAS2R4 Inhibits Hair Growth Ex Vivo by Up-Regulating TGF-β2

Besides taste buds, several other tissues express taste receptors (TR), where these exert various non-gustatory functions, e.g. in immunity, metabolism, endocrinology and/or reproduction. Human skin expresses the bitter TR, TAS2R4, whose functions in skin biology remain unknown. Since we show here that the epithelium of human scalp hair follicles (HFs) prominently and hair cycle-dependently expresses functional TAS2R4, we have explored these human chemosensory (mini-)organs as accessible model systems to dissect non-classical TR functions in human tissue physiology.

Transcriptional regulation of the thymus master regulator Foxn1.

FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle cell (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses of the evolutionary conservation and chromatin status of the Foxn1 locus in different tissues and states and identified several putative cis-regulatory regions unique to TECs versus HFCs. Furthermore, experiments using genetically modified mice with specific deletions in the Foxn1 locus and additional bioinformatic analyses helped us identify key regions and transcription factors involved in either positive or negative regulation of Foxn1 in both TECs and HFCs. Specifically, we identified SIX1 and FOXN1 itself as key factors inducing Foxn1 expression in embryonic and neonatal TECs. Together, our data provide important mechanistic insights into the transcriptional regulation of the Foxn1 gene in TEC versus HFC and highlight the role of FOXN1 in its autoregulation.

TREM2 macrophages induced by human lipids drive inflammation in acne lesions.

Acne affects 1 in 10 people globally, often resulting in disfigurement. The disease involves excess production of lipids, particularly squalene, increased growth of Cutibacterium acnes, and a host inflammatory response with foamy macrophages. By combining single-cell and spatial RNA sequencing as well as ultrahigh-resolution Seq-Scope analyses of early acne lesions on back skin, we identified TREM2 macrophages expressing lipid metabolism and proinflammatory gene programs in proximity to hair follicle epithelium expressing squalene epoxidase. We established that the addition of squalene induced differentiation of TREM2 macrophages in vitro, which were unable to kill C. acnes. The addition of squalene to macrophages inhibited induction of oxidative enzymes and scavenged oxygen free radicals, providing an explanation for the efficacy of topical benzoyl peroxide in the clinical treatment of acne. The present work has elucidated the mechanisms by which TREM2 macrophages and unsaturated lipids, similar to their involvement in atherosclerosis, may contribute to the pathogenesis of acne.

Frontal fibrosing alopecia: A review of disease pathogenesis.

Frontal fibrosing alopecia (FFA) is a primary patterned cicatricial alopecia that mostly affects postmenopausal women and causes frontotemporal hairline regression and eyebrow loss. Although the incidence of FFA has increased worldwide over the last decade, its etiology and pathology are still unclear. We cover the latest findings on its pathophysiology, including immunomodulation, neurogenic inflammation, and genetic regulation, to provide more alternatives for current clinical treatment. A persistent inflammatory response and immune privilege (IP) collapse develop and lead to epithelial hair follicle stem cells (eHFSCs) destruction and epithelial-mesenchymal transition (EMT) in the bulge area, which is the key process in FFA pathogenesis. Eventually, fibrous tissue replaces normal epithelial tissue and fills the entire hair follicle (HF). In addition, some familial reports and genome-wide association studies suggest a genetic susceptibility or epigenetic mechanism for the onset of FFA. The incidence of FFA increases sharply in postmenopausal women, and many FFA patients also suffer from female pattern hair loss in clinical observation, which suggests a potential association between FFA and steroid hormones. Sun exposure and topical allergens may also be triggers of FFA, but this conjecture has not been proven. More evidence and cohort studies are needed to help us understand the pathogenesis of this disease.

709 Stem cell niche architecture dictates hair progenitor distribution and differentiation

Stem cells and their nearby niche cells generate an organ architecture essential to its function. For hair production, the hair follicle remodels its epithelial architecture through stem cell behaviors under the instruction of a juxtaposed fibroblast niche -- dermal papilla. Although dermal papilla’s signaling crosstalk with hair follicle epithelium is well-characterized, little is known about how dermal papilla’s physical architecture is organized to support epithelial stem cells. Here, we leveraged live mice imaging, 3D reconstruction, and genetic manipulations to understand how dermal papilla fibroblasts remodel its niche architecture in orchestration with the stem cell progeny -- hair progenitors.

732 Treatment with cyclohexyl salicylate, an olfactory receptor 2A4/7 agonist, promotes human hair follicle growth and bulge stem cell progeny expansion

Topically applicable non-drugs that enhance the efficacy of available FDA-licensed drugs would be a welcome therapeutic addition in hair loss management. Since the olfactory receptor (OR) agonist, Sandalore, promotes human hair growth and reduces telogen effluvium, we have explored here whether other cosmetic OR ligands can unfold similar properties. We focused on OR2A4/7, since its stimulation promotes epidermal keratinocyte proliferation and differentiation. In situ hybridization showed that OR2A4/7 mRNA is widely expressed in the hair follicle (HF) epithelium, namely the outer root sheath (ORS) and hair matrix (HM). Yet, in freshly embedded human scalp skin, OR2A4/7 protein was mainly restricted to the infundibulum. However, OR2A4/7 protein became widely expressed in the ORS and HM during HF organ culture (OC), suggesting up-regulation of intrafollicular OR2A4/7 expression under tissue stress conditions. In scalp HF OC, the cosmetic OR2A4/7 agonist, cyclohexyl salicylate (CHS), delayed catagen development and tendentially increased HM proliferation. While CHS did not seem to impact on K15+ bulge stem cells, the % of CD34+ cells, i.e. their immediate progeny, was significantly increased in the suprabulbar ORS, as was the % of CD71+ transit amplifying cells (thought to derive from CD34+ cells) in the HM and suprabulbar ORS. Thus, stimulating OR2A4/7 via the non-drug CHS promotes hair growth and expands the progeny of K15+ stem cells, inviting the use of CHS as a novel cosmetic adjuvant treatment for hair loss disorders characterized by premature catagen development and a reduced capacity of K15+ stem cells to generate progeny, such as androgenetic alopecia.

829 Cytotoxic T lymphocytes target henle’s layer in alopecia areata

Autoimmune disease occurs when a specific adaptive immune response is mounted against self-antigen(s) and immune-mediated tissue damage is sustained until the self-antigen is eliminated. We recently identified immunogenic cell death via necroptosis in the hair follicle (HF) epithelium as the primary initiating mechanism in alopecia areata (AA). Here, we aimed to identify the major target cells of T cell-mediated cytotoxicity in AA, after the autoimmune response was initiated. Using the C3H/HeJ mouse model of AA, we first established a spatiotemporal map of caspase-8-driven immune-mediated apoptosis in HF epithelial cells during premature HF regression in AA.

Erythroderma in a neonate

Erythroderma in a neonate

Peroxisome proliferator-activated receptor-γ signalling protects hair follicle stem cells from chemotherapy-induced apoptosis and epithelial-mesenchymal transition.

Permanent chemotherapy-induced alopecia (pCIA), for which preventive interventions remain limited, can manifest with scarring. While the underlying pathomechanisms of pCIA are unclear, depletion of epithelial hair follicle (HF) stem cells (eHFSCs) is likely to play a role. To explore the hypothesis that, besides apoptosis, eHFSCs undergo pathological epithelial-mesenchymal transition (EMT) in pCIA, thus explaining the scarring phenotype. Furthermore, we tested whether a peroxisome proliferator-activated receptor (PPAR)-γ modulator could prevent pCIA-associated pathomechanisms. Organ-cultured human scalp HFs were treated with the cyclophosphamide metabolite 4-hydroperoxycyclophosphamide (4-HC). Additionally, HFs were pretreated with the agonistic PPAR-γ modulator N-acetyl-GED-0507-34-Levo (NAGED), which has previously been shown to promote K15 expression and antagonize EMT in eHFSCs. In accordance with anticipated hair bulb cytotoxicity, dystrophy and catagen induction, 4-HC promoted apoptosis along with increased p53 expression, DNA damage and pathological EMT in keratin 15+ (K15) eHFSCs, as evidenced by decreased E-cadherin expression and the appearance of fibronectin+ and vimentin+ cells in the hair bulge. Pretreatment with NAGED protected against 4-HC-induced hair bulb cytotoxicity/dystrophy, and apoptosis, p53 upregulation and EMT in the bulge, thereby significantly preventing depletion of K15+ human eHFSCs ex vivo. Since a key cyclophosphamide metabolite alone suffices to damage and deplete human scalp eHFSCs by promoting apoptosis, DNA damage and EMT ex vivo, strategies to prevent pCIA need to target these pathomechanisms. Given the ability of NAGED to prevent chemotherapy-induced eHFSCs damage exvivo, our study introduces the stimulation of PPAR-γ signalling as a novel intervention strategy for the prevention of pCIA.