Constraints on the deformation of the vibrissa within the follicle.

Nearly all mammals have a vibrissal system specialized for tactile sensation, composed of whiskers growing from sensor-rich follicles in the skin. When a whisker deflects against an object, it deforms within the follicle and exerts forces on the mechanoreceptors inside. In addition, during active whisking behavior, muscle contractions around the follicle and increases in blood pressure in the ring sinus will affect the whisker deformation profile. To date, however, it is not yet possible to experimentally measure how the whisker deforms in an intact follicle or its effects on different groups of mechanoreceptors. The present study develops a novel model to predict vibrissal deformation within the follicle sinus complex. The model is based on experimental results from a previous ex vivo study on whisker deformation within the follicle, and on a new histological analysis of follicle tissue. It is then used to simulate whisker deformation within the follicle during passive touch and active whisking. Results suggest that the most likely whisker deformation profile is "S-shaped," crossing the midline of the follicle right below the ring sinus. Simulations of active whisking indicate that an increase in overall muscle stiffness, an increase in the ratio between deep and superficial intrinsic muscle stiffness, and an increase in sinus blood pressure will all enhance tactile sensitivity. Finally, we discuss how the deformation profiles might map to the responses of primary afferents of each mechanoreceptor type. The mechanical model presented in this study is an important first step in simulating mechanical interactions within whisker follicles.

Shedding light on cashmere goat hair follicle biology: from morphology analyses to transcriptomic landascape.

BACKGROUND: Cashmere goat is known for its precious undercoat. Being photoperiod-dictated, cashmere growth has been studied focusing mainly on hair follicle cycle phases (anagen, catagen and telogen). An accurate molecular knowledge of the goat hair follicle cycle, disentangling gene expression changes during phases and recognizing timing boundaries, could be useful to improve cashmere goat management and ultimately cashmere production. RESULTS: To better describe goat's hair follicle transcriptome we applied RNA-sequencing to isolated hair follicles from five Italian cashmere goats, during the anagen and catagen phase, identifying total of 214 differentially expressed genes (DEGs): 97 were up-regulated while 117 were down-regulated in catagen with respect to anagen. Gene Ontology and pathway analysis were performed. We detected 144 significant pathways spanning from estrogen, pluripotency of stem cells, thermogenesis and fatty acid metabolism that were strongly expressed during the hair follicle phases analysed. Finally, we validated promising DEGs by RT-qPCR in the same set of samples as well as in hair follicles and entire skin biopsies of another cashmere goats cohort accounting for early anagen, anagen, early catagen, and catagen phases. CONCLUSIONS: As in the isolated hair follicles, some target genes were homogenously modulated during the four hair follicle phases. Ceruloplasmin (CP) and Keratin 4 (K4), confirmed their clear cut expression between growing and resting phase. In fact, K4 was almost absent in catagen phases while CP was barely expressed in anagen phases. In particular, the strong expression of K4 in early anagen makes it an eligible marker to track the beginning of a new hair cycle, and therefore defining the optimum time for cashmere harvesting.

Getting under the skin of hair aging: the impact of the hair follicle environment.

Like the skin, our hair shows striking changes with age, producing hairs with altered diameter, lustre and texture. The biology of hair aging has focused predominately on various aspects of the hair cycle, follicle size and the fibre produced, but surprisingly the impact of the aging scalp dermal environment on the hair follicle and fibre has been generally overlooked. Hair loss affects both sexes with incidence increasing with age. In men, male pattern-balding (androgenetic alopecia) is driven by androgens and follows a specific pattern of frontotemporal and vertex regression. Women also experience female pattern hair loss (FPHL), presenting as more general, diffuse hair thinning. Hair thinning in women is commonly associated with the menopause, corresponding with other age-related changes in skin. The rapidly growing hair follicle undergoes continued renewal throughout the life span of an individual, where it is exposed to a substantial number of extrinsic and intrinsic stressors. As the hair follicle sits deep within the dermis with its bulb residing in the hypodermis, detrimental age-related changes in the surrounding scalp skin may likely disrupt the hair follicle machinery. The impacts of these changes are unknown, but evidence suggests that scalp skin aging and hair follicle aging go hand-in-hand. Herein, we summarize the evidence that the age-related changes observed in sun-exposed human skin also occur in scalp skin and that these changes are likely to play a contributing role in the aging hair phenotype.

Analyses of histological and transcriptome differences in the skin of short-hair and long-hair rabbits.

BACKGROUND: Hair fibre length is an important economic trait of rabbits in fur production. However, molecular mechanisms regulating rabbit hair growth have remained elusive. RESULTS: Here we aimed to characterise the skin traits and gene expression profiles of short-hair and long-hair rabbits by histological and transcriptome analyses. Haematoxylin-eosin staining was performed to observe the histological structure of the skin of short-hair and long-hair rabbits. Compared to that in short-hair rabbits, a significantly longer anagen phase was observed in long-hair rabbits. In addition, by RNA sequencing, we identified 951 genes that were expressed at significantly different levels in the skin of short-hair and long-hair rabbits. Nine significantly differentially expressed genes were validated by quantitative real-time polymerase chain reaction. A gene ontology analysis revealed that epidermis development, hair follicle development, and lipid metabolic process were significantly enriched. Further, we identified potential functional genes regulating follicle development, lipid metabolic, and apoptosis as well as important pathways including extracellular matrix-receptor interaction and basal cell carcinoma pathway. CONCLUSIONS: The present study provides transcriptome evidence for the differences in hair growth between short-hair and long-hair rabbits and reveals that lipid metabolism and apoptosis might constitute major factors contributing to hair length.

Ultrasound Characteristics of the Hair Follicles and Tracts, Sebaceous Glands, Montgomery Glands, Apocrine Glands, and Arrector Pili Muscles.

OBJECTIVES: To explore the capability of very high-frequency ultrasound (US; 50-71 MHz) to detect the normal morphologic characteristics of the hair follicles and tracts, sebaceous glands, Montgomery glands, apocrine glands, and arrector pili muscles. METHODS: A retrospective study, approved by the Institutional Review Board, evaluated the normal US morphologic characteristics of the hair and adnexal structures in a database of very high-frequency US images extracted from the perilesional or contralateral healthy skin of 1117 consecutive patients who underwent US examinations for localized lesions of the skin and 10 healthy individuals from December 2017 to June 2018. These images were matched with their counterparts from the database of normal histologic images according to the corporal region. The Cohen concordance test and regional mean diameters of the hair follicles and adnexal structures were analyzed. RESULTS: The normal hair follicles and tracts, sebaceous glands, Montgomery glands, apocrine glands, and arrector pili muscles were observed on US images and matched their histological counterparts in all the corporal regions. There was significant US concordance (κ = 0.82; P = .0001) among observers. Regional mean diameters (millimeters) of the hair follicles, sebaceous glands, and apocrine glands are provided. CONCLUSIONS: The hair follicles and tracts, sebaceous glands, Montgomery glands, apocrine glands, and arrector pili muscles are detectable with very high-frequency US, including some regional and anatomic variants. Knowledge of their normal US appearances is a requisite for detecting subclinical changes, understanding the physiopathologic characteristics, and supporting the early diagnosis and management of common dermatologic diseases.

An efficient method for eccrine gland isolation from human scalp.

We describe a simple and efficient method to isolate eccrine sweat glands from the human scalp. This method is inspired by the hair graft harvesting method used in hair transplantation. Based on the recently described anatomical relationship between the scalp hair follicle and the eccrine gland, we have found that scalp follicular unit grafts are an excellent eccrine gland isolation source, especially for the coiled component. In order to make the gland visible for stereoscopic microdissection, the follicular units need to be previously stained with a vital dye like methylene blue or neutral red. The simplicity and efficiency of this isolation method should encourage further research into human eccrine sweat gland function which has always been hindered by the difficulty of gland isolation.

Functional anatomy of the hair follicle: The Secondary Hair Germ.

The secondary hair germ (SHG)-a transitory structure in the lower portion of the mouse telogen hair follicle (HF)-is directly involved in anagen induction and eventual HF regrowth. Some crucial aspects of SHG functioning and ontogenetic relations with other HF parts, however, remain undefined. According to recent evidence (in contrast to previous bulge-centric views), the SHG is the primary target of anagen-inducing signalling and a source of both the outer root sheath (ORS) and ascending HF layers during the initial (morphogenetic) anagen subphase. The SHG is comprised of two functionally distinct cell populations. Its lower portion (originating from lower HF cells that survived catagen) forms all ascending HF layers, while the upper SHG (formed by bulge-derived cells) builds up the ORS. The predetermination of SHG cells to a specific morphogenetic fate contradicts their attribution to the "stem cell" category and supports SHG designation as a "germinative" or a "founder" cell population. The mechanisms of this predetermination driving transition of the SHG from "refractory" to the "competent" state during the telogen remain unknown. Functionally, the SHG serves as a barrier, protecting the quiescent bulge stem cell niche from the extensive follicular papilla/SHG signalling milieu. The formation of the SHG is a prerequisite for efficient "precommitment" of these cells and provides for easier sensing and a faster response to anagen-inducing signals. In general, the formation of the SHG is an evolutionary adaptation, which allowed the ancestors of modern Muridae to acquire a specific, highly synchronized pattern of hair cycling.

Eccrine sweat glands associate with the human hair follicle within a defined compartment of dermal white adipose tissue.

BACKGROUND: Eccrine sweat glands (ESGs) are critical for thermoregulation and are involved in wound healing. ESGs have traditionally been considered as separate skin appendages without connection to the pilosebaceous unit (PSU). However, recent preliminary evidence has encouraged the hypothesis that the PSU and ESG are more interconnected than previously thought. OBJECTIVES: To re-evaluate the morphology of human skin adnexa with an integrated three-dimensional (3D) perspective in order to explore the possible interconnections that the PSU and the ESG may form. METHODS: A systematic 3D reconstruction method of skin sections, direct visualization of human scalp follicular unit transplant grafts and a scalp strip ex vivo were used to validate and further explore the hypothesis. RESULTS: We demonstrate that the coiled portion of most ESGs is morphologically integrated into the PSU of human scalp skin and forms a structural unit that is embedded into a specific, hair follicle-associated region of dermal white adipose tissue (dWAT). This newly recognized unit is easily accessible and experimentally tractable by organ culture of follicular units and can be visualized intravitally. CONCLUSIONS: We propose a model of functional human skin anatomy in which ESGs are closely associated with the PSU and the dWAT to form a common homeostatic tissue environment, which may best be encapsulated in the term 'adnexal skin unit'. The challenge now is to dissect how each component of this superstructure of human skin functionally cooperates with and influences the other under physiological conditions, during regeneration and repair and in selected skin diseases.

Study on Hair Distribution in Healthy Males for Hair Restoration Design.

BACKGROUND: The incidence of hair loss among Chinese male has increased to 21.3 per hundred. Hair restoration has been an effective technique. Detailed hair distribution has a tremendous impact on the surgery design. OBJECTIVE: To investigate the pattern of hair distribution in Chinese young adult males. METHODS: A total of 1000 males without hair disease were enrolled. We evaluated the locations of the main anatomical marks at different sites on the scalp and analyzed the hair density and follicular unit structure using the standard photographs and trichoscope. RESULTS: The hairline shapes were classified as: linear (48.7%), linear with central protrusion (27.9%), round (9.8%), round with central protrusion (13.7%). The average height of the median line was 6.78 ±â€Š0.75 cm, the ratio of the median line and the forehead height was 0.333. The average distance from the parietal whorl to the vertical bimeatal line was 7.05 ±â€Š3.32 cm, and most of the PWs were on the right (51.4%) and had a clockwise pattern (73.3%). The hair density was 171.12 ±â€Š18.32 hairs/cm in the vertex. 1-hair follicular units were (75.90% and 56.39%) in anterior hairline and temporal area. CONCLUSION: Our study clearly assisted understanding of scalp anatomy and hair distribution in Chinese young adult males.

Retrospective Assessment of Follicular Unit Density in Asian Men With Androgenetic Alopecia.

BACKGROUND: Hair density, together with hair diameter has a tremendous impact on the cosmetic outcome of hair transplantation surgery. OBJECTIVE: This retrospective study aims to assess the average number of follicular unit (FU) grafts in the donor area of Asian men with androgenetic alopecia. METHODS: Seventy patients (ages 24-65 years old) with virgin scalp who had their first hair transplantation were included. During the harvesting procedure, a 2- to 3-cm-wide area of the donor site was shaved from ear to ear with 5 specific areas assigned as reference points for the study namely the central occipital area, left and right parietal and temporal areas. A video microscope was used to capture the field of each reference point. Follicular units in each area were counted and the number of 1-hair, 2-hair, and 3-hair follicular groupings was recorded. RESULTS: East and Southeast Asians had an average of 61.1 FU/cm (111.2 hairs/cm); West Asians had an average density of 63.6 FU/cm (126.8 hairs/cm); South Asians were noted to have an average density of 63.5 FU/cm (126.8 hairs/cm). CONCLUSION: Asian hair density has slight variations in the number of FU grafts in each donor area.

Is the eccrine gland an integral, functionally important component of the human scalp pilosebaceous unit?

The pilosebaceous unit (PSU) and the eccrine sweat gland (ESG) are classically described as completely independent skin appendages. However, careful inspection of scalp follicular units reveals that the secretory segment of the ESG spatially approximates the hair follicle in a position below the sebaceous gland and the insertion of the arrector pili muscle. Therefore, we propose here that, contrary to conventional wisdom, the PSU and the ESG should not be viewed in isolation, and may form instead, along with the arrector pili muscle and the apocrine gland (where present),one functional unit. For this, we suggest the more inclusive term of 'Hair Cluster' (HC). If confirmed, e.g. by 3D imaging techniques, the novel concept of a functional HC, whose individual components may communicate via secreted molecules and may share selected progenitor cell populations for HC repair/regeneration, has major physiological and pathological implications, which are briefly discussed.

Biology of the eyelash hair follicle: an enigma in plain sight.

Because of their crucial impact on our perception of beauty, eyelashes constitute a prime target for the cosmetic industry. However, when compared with other hair shafts and the mini-organs that produce them [eyelash hair follicles (ELHFs)], knowledge on the biology underlying growth and pigmentation of eyelashes is still rudimentary. This is due in part to the extremely restricted availability of human ELHFs for experimental study, underappreciation of their important sensory and protective functions and insufficient interest in understanding why they are distinct from scalp hair follicles (HFs) (e.g. ELHFs produce shorter hair shafts, do not possess an arrector pili muscle, have a shorter hair cycle and undergo greying significantly later than scalp HFs). Here we synthesize the limited current knowledge on the biology of ELHFs, in humans and other species, their role in health and disease, the known similarities with and differences from other HF populations, and their intrinsic interethnic variations. We define major open questions in the biology of these intriguing mini-organs and conclude by proposing future research directions. These include dissecting the molecular and cellular mechanisms that underlie trichomegaly and the development of in vitro models in order to interrogate the distinct molecular controls of ELHF growth, cycling and pigmentation and to probe novel strategies for the therapeutic and cosmetic manipulation of ELHFs beyond prostaglandin receptor stimulation.

The Hair Follicle: A Comparative Review of Canine Hair Follicle Anatomy and Physiology.

The hair follicle (HF) has a wide range of functions including thermoregulation, physical and immunological protection against external insults, sensory perception, social interactions, and camouflage. One of the most characteristic features of HFs is that they self-renew during hair cycle (HC) throughout the entire life of an individual to continuously produce new hair. HC disturbances are common in humans and comparable to some alopecic disorders in dogs. A normal HC is maintained by follicular stem cells (SCs), which are predominately found in an area known as the bulge. Due to similar morphological characteristics of the human and canine bulge area, the particularity of compound HFs in humans and dogs as well as similarities in follicular biomarker expression, the dog might be a promising model to study human HC and SC disorders. In this review, we give an overview of normal follicular anatomy, the HC, and follicular SCs and discuss the possible pathogenetic mechanisms of noninflammatory alopecia.

Human epithelial hair follicle stem cells and their progeny: current state of knowledge, the widening gap in translational research and future challenges.

Epithelial hair follicle stem cells (eHFSCs) are required to generate, maintain and renew the continuously cycling hair follicle (HF), supply cells that produce the keratinized hair shaft and aid in the reepithelialization of injured skin. Therefore, their study is biologically and clinically important, from alopecia to carcinogenesis and regenerative medicine. However, human eHFSCs remain ill defined compared to their murine counterparts, and it is unclear which murine eHFSC markers really apply to the human HF. We address this by reviewing current concepts on human eHFSC biology, their immediate progeny and their molecular markers, focusing on Keratin 15 and 19, CD200, CD34, PHLDA1, and EpCAM/Ber-EP4. After delineating how human eHFSCs may be selectively targeted experimentally, we close by defining as yet unmet key challenges in human eHFSC research. The ultimate goal is to transfer emerging concepts from murine epithelial stem cell biology to human HF physiology and pathology.

Deflection of a vibrissa leads to a gradient of strain across mechanoreceptors in a mystacial follicle.

Rodents use their vibrissae to detect and discriminate tactile features during active exploration. The site of mechanical transduction in the vibrissa sensorimotor system is the follicle sinus complex and its associated vibrissa. We study the mechanics within the ring sinus (RS) of the follicle in an ex vivo preparation of the mouse mystacial pad. The sinus region has a relatively dense representation of Merkel mechanoreceptors and longitudinal lanceolate endings. Two-photon laser-scanning microscopy was used to visualize labeled cell nuclei in an ∼ 100-nl vol before and after passive deflection of a vibrissa, which results in localized displacements of the mechanoreceptor cells, primarily in the radial and polar directions about the vibrissa. These displacements are used to compute the strain field across the follicle in response to the deflection. We observe compression in the lower region of the RS, whereas dilation, with lower magnitude, occurs in the upper region, with volumetric strain ΔV/V ∼ 0.01 for a 10° deflection. The extrapolated strain for a 0.1° deflection, the minimum angle that is reported to initiate a spike by primary neurons, corresponds to the minimum strain that activates Piezo2 mechanoreceptor channels.

Human hair follicle organ culture: theory, application and perspectives.

For almost a quarter of a century, ex vivo studies of human scalp hair follicles (HFs) have permitted major advances in hair research, spanning diverse fields such as chronobiology, endocrinology, immunology, metabolism, mitochondrial biology, neurobiology, pharmacology, pigmentation and stem cell biology. Despite this, a comprehensive methodological guide to serum-free human HF organ culture (HFOC) that facilitates the selection and analysis of standard HF biological parameters and points out both research opportunities and pitfalls to newcomers to the field is still lacking. The current methods review aims to close an important gap in the literature and attempts to promote standardisation of human HFOC. We provide basic information outlining the establishment of HFOC through to detailed descriptions of the analysis of standard read-out parameters alongside practical examples. The guide closes by pointing out how serum-free HFOC can be utilised optimally to obtain previously inaccessible insights into human HF biology and pathology that are of interest to experimental dermatologists, geneticists, developmental biologists and (neuro-) endocrinologists alike and by highlighting novel applications of the model, including gene silencing and gene expression profiling of defined, laser capture-microdissected HF compartments.

The effect of parathyroid hormones on hair follicle physiology: implications for treatment of chemotherapy-induced alopecia.

Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) influence hair follicles through paracrine and intracrine routes. There is significant evidence that PTH and PTHrP influence the proliferation and differentiation of hair follicle cells. The PTH/PTHrP receptor signalling plays an important role in the hair follicle cycle and may induce premature catagen-telogen transition. Transgenic mice with an overexpression or blockade (PTH/PTHrP receptor knockout mice) of PTHrP activity revealed impaired or increased hair growth, respectively. Some findings also suggest that PTHrP may additionally influence the hair cycle by inhibiting angiogenesis. Antagonists of the PTH/PTHrP receptor have been shown to stimulate proliferation of hair follicle cells and hair growth. A hair-stimulating effect of a PTH/PTHrP receptor antagonist applied topically to the skin has been observed in hairless mice, as well as in mice treated with cyclophosphamide. These data indicate that the PTH/PTHrP receptor may serve as a potential target for new (topical) hair growth-stimulating drugs, especially for chemotherapy-induced alopecia.

High follicle density does not decrease sweat gland density in Huacaya alpacas.

When exposed to high ambient temperatures, mammals lose heat evaporatively by either sweating from glands in the skin or by respiratory panting. Like other camelids, alpacas are thought to evaporate more water by sweating than panting, despite a thick fleece, unlike sheep which mostly pant in response to heat stress. Alpacas were brought to Australia to develop an alternative fibre industry to sheep wool. In Australia, alpacas can be exposed to ambient temperatures higher than in their native South America. As a young industry there is a great deal of variation in the quality and quantity of the fleece produced in the national flock. There is selection pressure towards animals with finer and denser fleeces. Because the fibre from secondary follicles is finer than that from primary follicles, selecting for finer fibres might alter the ratio of primary and secondary follicles. In turn the selection might alter sweat gland density because the sweat glands are associated with the primary follicle. Skin biopsy and fibre samples were obtained from the mid-section of 33 Huacaya alpacas and the skin sections were processed into horizontal sections at the sebaceous gland level. Total, primary, and secondary follicles and the number of sweat gland ducts were quantified. Fibre samples from each alpaca were further analysed for mean fibre diameter. The finer-fibred animals had a higher total follicle density (P<0.001) and more sweat glands (P<0.001) than the thicker-fibred animals. The fibre diameter and total follicle density were negatively correlated (R(2)=0.56, P<0.001). Given that the finer-fibred animals had higher follicle density and more sweat glands than animals with thicker fibres, we conclude that alpacas with high follicle density should not be limited for potential sweating ability.

Dermoscopic evaluation of skin in healthy cats.

BACKGROUND: Dermoscopy is a diagnostic tool that can reveal morphological structures not visible upon clinical examination. HYPOTHESIS/OBJECTIVES: To assess the usefulness and applicability of dermoscopy for the examination of healthy cat skin. ANIMALS: Twenty-one domestic short-haired cats from a feline rescue association. METHODS: Four regions (head, dorsal neck, sacral and abdominal regions) were examined with both a contact hand-held nonpolarized light dermoscope at 10-fold magnification and a videodermoscope at 70-fold magnification. Findings were assessed using histological analysis of skin samples cut both longitudinally and transversely, set as the gold standard. RESULTS: With a hand-held dermoscope at 10-fold magnification, thick, straight primary hairs surrounded by multiple secondary hairs were observed. With a videodermoscope at 70-fold magnification, hair shaft thickness was measured and the follicular openings and arrangement of vessels were clearly observed. Correspondence was observed between dermoscopic and histological results. CONCLUSIONS AND CLINICAL IMPORTANCE: Dermoscopy represents a valid noninvasive and reproducible technique that could be helpful in clinical examination.

Hair type-specific function of canonical Wnt activity in adult mouse skin.

Wnt/ß-catenin signalling is a key regulator of hair follicle (HF) morphogenesis and life-long HF regeneration. In a recently published issue of Experimental Dermatology, Lei et al. report that sustained WNT10B supply and pathway activation in regenerating mouse HF increased the width of hair bulbs, hair shafts and the dermal papilla (DP), and enlarged the CD34(+) HF bulge cell compartment. Notably, WNT10B affected primarily zigzag HFs, while size and morphology of other HF types remained largely unaffected. Thus, these findings raise a number of questions regarding a HF type-specific function of Wnt/ß-catenin and on the role of the WNT-stimulated DP in this process.