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Human hair greying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath
Abstract
Although hair greying is a very common phenomenon characterized by loss of pigment in the hair shaft, the events that cause and control natural hair whitening with age in humans are still unclear.
To decipher the origin of natural hair whitening.
Human hair melanocytes were immunohistochemically characterized at different stages of whitening.
Loss of hair shaft melanin was found to be associated with a decrease in both bulb melanin content and bulb melanocyte population. Although few melanocytes were present in the bulbs of grey hair, they still expressed tyrosinase and tyrosinase-related protein-1, synthesized and transferred melanins to cortical keratinocytes as seen by the presence of melanin granules. In white hair bulbs, no melanocytes could be detected either with pMel-17 or vimentin labelling. Pigmented hair follicles are known to contain inactive melanocytes in the outer root sheath (ORS), and grey and white hairs were also found to contain some of these quiescent melanocytes. However, their population was decreased compared with pigmented hair follicles, ranging from small to nil. This depletion of melanocytes in the different areas of white hairs was detected throughout the hair cycle, namely at telogen and early anagen stages. In contrast, the infundibulum and sebaceous gland of both pigmented and white hairs showed a similar distribution of melanocytes. Furthermore, other distinct cell populations located in the ORS, namely putative stem cells, Merkel cells and Langerhans cells were equivalently identified in pigmented and white hairs.
Thus, hair greying appears to be a consequence of an overall and specific depletion of bulb and ORS melanocytes of human hair.
... Subsequently, pigmentation is initiated during anagen III, and reaches its maximum in anagen VI HFs, both in mice and humans (Slominski, Paus & Costantino, 1991;Slominski & Fig 2. The cellular composition of the human hair follicle (HF) changes during greying. (A) Illustration summarizing the compositional differences between the melanocyte compartment of white, grey and pigmented human scalp HFs, based on Horikawa et al. (1996), Commo, Gaillard & Bernard (2004, Nishimura, Granter & Fisher (2005) and Tobin (2009). In fully pigmented follicles, the anagen hair bulb is rich in pigment-producing melanocytes, but also contains amelanotic melanocytes in its peripheral epithelium. ...
... The gradual nature of greying is evident upon histological investigation. Grey HFs contain a reduced number of differentiated, i.e. melanogenically active, bulbar melanocytes (Commo, Gaillard & Bernard, 2004;Nishimura, Granter & Fisher, 2005;Tobin, 2009) (Fig. 2). Grey HF-resident melanocytes show vacuolization and incomplete melanization of melanosomes at the ultrastructural level (Orfanos, Ruska & Mahrle, 1970), and contain aberrantly distributed melanosomes (Nordlund et al., 2008). ...
... However, it is important to emphasize that even optically white scalp HFs may still contain a few isolated hair bulb melanocytes, some of which may engage in residual melanogenesis despite a lack of both dendritic morphology and transfer of melanin to the hair shaft (Arck et al., 2006) (Fig. 2). Amelanotic melanocytes present in the bulge, outer root sheath (ORS) and proximal matrix (Horikawa et al., 1996;Ito et al., 2004b;Commo, Gaillard & Bernard, 2004;Slominski et al., 2005b;Nishimura, Granter & Fisher, 2005) persist beyond the loss of the bulbar melanocytes, but are gradually lost over time. For instance, the number of gp100+ cells drops progressively in the ORS from grey and white HFs, and in some cases gp100+ cells of white HFs are completely absent (Horikawa et al., 1996;Commo, Gaillard & Bernard, 2004). ...
Hair greying (canities) is one of the earliest, most visible ageing-associated phenomena, whose modulation by genetic, psychoemotional, oxidative, senescence-associated, metabolic and nutritional factors has long attracted skin biologists, dermatologists, and industry. Greying is of profound psychological and commercial relevance in increasingly ageing populations. In addition, the onset and perpetuation of defective melanin production in the human anagen hair follicle pigmentary unit (HFPU) provides a superb model for interrogating the molecular mechanisms of ageing in a complex human mini-organ, and greying-associated defects in bulge melanocyte stem cells (MSCs) represent an intriguing system of neural crest-derived stem cell senescence. Here, we emphasize that human greying invariably begins with the gradual decline in melanogenesis, including reduced tyrosinase activity, defective melanosome transfer and apoptosis of HFPU melanocytes, and is thus a primary event of the anagen hair bulb, not the bulge. Eventually, the bulge MSC pool becomes depleted as well, at which stage greying becomes largely irreversible. There is still no universally accepted model of human hair greying, and the extent of genetic contributions to greying remains unclear. However, oxidative damage likely is a crucial driver of greying via its disruption of HFPU melanocyte survival, MSC maintenance, and of the enzymatic apparatus of melanogenesis itself. While neuroendocrine factors [e.g. alpha melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH), ß-endorphin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH)], and micropthalmia-associated transcription factor (MITF) are well-known regulators of human hair follicle melanocytes and melanogenesis, how exactly these and other factors [e.g. thyroid hormones, hepatocyte growth factor (HGF), P-cadherin, peripheral clock activity] modulate greying requires more detailed study. Other important open questions include how HFPU melanocytes age intrinsically, how psychoemotional stress impacts this process, and how current insights into the gerontobiology of the human HFPU can best be translated into retardation or reversal of greying.
... [6][7][8][9][10][11][12] Here, we focus on the depletion of MelSCs, which has been identified in the context of hair graying in multiple mouse models and in human aging. 2,5,[13][14][15] MelSC depletion in mice has been attributed to several factors, including, genotoxic stressors, 11,16 and other acute stressors (psychological or physical nociceptive stressors). 17 The prevalent mechanism of MelSC depletion was seen to involve premature differentiation of the stem cells within the niche. ...
... However, other mechanisms could in principle also contribute to melanocyte depletion, and they have not been specifically examined in the current study. 6,13,[34][35] For example, it will be interesting to examine the question of whether gender may contribute differentially to the behavior of hair follicles using this assay. ...
Hair graying depends on the altered presence and functionality of hair follicle melanocytes. Melanocyte stem cells (MelSCs) reside in the bulge of hair follicles and give rise to migrating and differentiating progeny during the anagen phase. Aging, genotoxic stress, redox stress, and multiple behavior‐associated acute stressors have been seen to induce hair graying by depleting the MelSC pool, a phenomenon which is accompanied by ectopic pigmentation of these cells, followed by their depletion from the stem cell niche. This aberrant differentiation produces a state from which a return to stem cell‐like quiescence appears to be lost. The cellular features of stress‐induced hair graying have been extensively studied in murine models. Here we describe a method to assess and quantify human hair follicle MelSC differentiation by measuring ectopically pigmented MelSCs in isolated human hair follicles exposed to specific stress signal mediators. Ionizing radiation, hydrogen peroxide, and noradrenaline have been shown to cause hair graying in mice. We demonstrate here that isolated, ex vivo cultured human hair follicles exposed to these treatments display similar ectopic pigmentation within the bulge area which is accompanied by induction of differentiated melanocytic markers. This study suggests that as in murine models, stress signaling induces closely matching phenotypic changes in human hair follicles which can be monitored and studied as a surrogate model for early steps in human hair graying.
... The process of hair pigmentation begins in the hair follicle's melanocytes, where several genetic and biochemical pathways regulate melanin production. 3,4 One key regulatory pathway is the melanogenesis pathway, which involves the enzyme tyrosinase. Tyrosinase catalyzes the conversion of tyrosine to dopaquinone, the initial step in melanin synthesis. ...
Premature hair graying (PHG) is the early loss of natural hair color, influenced by genetic, biological, and environmental factors. This review discusses the significant psychological impacts of PHG and explores its underlying mechanisms, related health conditions, and available treatments. The review examines the roles of genetics, oxidative stress, and lifestyle factors such as smoking and diet in premature graying. It also considers associated medical conditions and current and emerging treatment options. This overview aims to improve understanding of PHG and its broader implications.
... In fact, the biological mechanism behind gray hair seems to be linked with the gradual decline of pigment-producing cells [3]. While hair graying, or canities, is a typical part of the aging process, a portion of individuals undergo premature graying due to familial inheritance or pathological factors [4]. ...
Background
Graying is an inherent and unavoidable consequence of the aging process, impacting individuals of all genders. There are limited studies in Saudi Arabia that have examined the prevalence and predictors of premature graying of hair (PGH).
Objectives
This study aims to explore the prevalence and predictors of PGH before the age of 30 among the population of Saudi Arabia.
Methods
This is a cross‐sectional online survey that was conducted between July 2023 and February 2024 in Saudi Arabia. Binary logistic regression analysis was used to identify risk factors of having gray hair before the age of 30.
Results
A total of 1193 participants were involved in this study. A significant portion of respondents reported having gray hair before the age of 30 (55.9%). The younger population (younger than 44 years), smokers, and those who have comorbidities, have anxiety, have depression, have a family history of gray hair before the age of 30 years, have a dry scalp, suffer from vitamin or mineral deficiencies, have hair loss due to immune diseases (such as alopecia), and use minoxidil or rosemary for hair loss were more likely to have gray hair before the age of 30 years (p < 0.05).
Conclusion
This study highlighted the high prevalence rate and associated predictors of PGH in Saudi Arabia. Identified predictors include genetic, health, and lifestyle factors. Healthcare professionals and decision makers are advised to promote the awareness of the general public on its risk factors to enhance the prevention of PGH. Public health initiatives include campaigns on smoking cessation, healthy nutrition, and mental health.
... In humans, gray hairs consistently retain a moderate number of melanocytes and McSCs, whereas white hairs are reported to have either small numbers of melanocytes and McSCs or are completely devoid of both. 20,[74][75][76][77] Dramatic repigmentation of gray-haired patients after PD-1 or PD-L1 immunotherapy suggests that gray hairs may harbor inactive McSCs and demonstrates the capacity of these McSCs for reactivation in humans. 78,79 Based on the findings presented here, we predict that it is the PD-L1-expressing qMcSCs that are retained in non-pigmented and gray hairs, these cells are the target of anti-PD-L1 immunotherapy, and their presence is essential for the reversal of gray hair (Figure 7). ...
Cellular quiescence is a reversible and tightly regulated stem cell function essential for healthy aging. However, the elements that control quiescence during aging remain poorly defined. Using melanocyte stem cells (McSCs), we find that stem cell quiescence is neither passive nor static. For example, gene expression profiling of the transition from proliferating melanoblasts to quiescent melanocyte stem cells reveals tissue-specific regulation of the immune checkpoint protein PD-L1. In vitro, quiescence assays demonstrate that PD-L1 expression is a physiological attribute of quiescence in this cell lineage and reinforces this cell state. In vivo, a subset of quiescent McSCs is marked by PD-L1. While the overall number of McSCs decreases with age, PD-L1+ McSCs appear resistant to depletion. This phenomenon coincides with an aged McSC pool that exhibits a deeper transcriptomic quiescence. We predict that quiescent PD-L1+ stem cells retained with age may serve as cellular targets for reactivation.
... Hair pigmentation can be affected by defects or depletion of MSCs, immature precursor cells, and mature melanocytes residing in the hair follicle bulge or bulb [44][45][46]. Loss of MSCs within the bulge niche preceded the loss of differentiated melanocytes in the hair matrix [47,48]. B-cell lymphoma 2 (BCL-2) deficiency caused selective apoptosis of MSCs, but not differentiated melanocytes, while MITF mutation accelerated pigmentation, differentiation, and senescence of MSCs [47]. ...
This review aims to gain insight into the major causes of hair graying (canities) and how plant-derived extracts and phytochemicals could alleviate this symptom. Research articles on human hair graying were searched and selected using the PubMed, Web of Science, and Google Scholar databases. We first examined the intrinsic and extrinsic factors associated with hair graying, such as the reduced capacity of melanin synthesis and transfer, exhaustion of melanocyte stem cells (MSCs) and melanocytes, genetics and epigenetics, race, gender, family history, aging, oxidative stress, stress hormones, systematic disorders, nutrition, smoking, alcohol consumption, lifestyle, medications, and environmental factors. We also examined various plants and phytochemicals that have shown a potential to interfere with the onset or progression of human hair graying at different levels from in vitro studies to clinical studies: the extract of Polygonum multiflorum and its major components, 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside and emodin; the extract of Eriodictyon angustifolium and its major flavonoid compounds, hydroxygenkwanin, sterubin, and luteolin; the extracts of Adzuki beans (Vigna angularis), Fuzhuan brick tea (Camellia sinensis), and Gynostemma pentaphyllum; bixin, a carotenoid compound found in Bixa orellana; and rhynchophylline, an alkaloid compound found in certain Uncaria species. Experimental evidence supports the notion that certain plant extracts and phytochemicals could alleviate hair graying by enhancing MSC maintenance or melanocyte function, reducing oxidative stress due to physiological and environmental influences, and managing the secretion and action of stress hormones to an appropriate level. It is suggested that hair graying may be reversible through the following tactical approaches: selective targeting of the p38 mitogen-activated protein kinase (MAPK)–microphthalmia-associated transcription factor (MITF) axis, nuclear factor erythroid 2-related factor 2 (NRF2), or the norepinephrine–β2 adrenergic receptor (β2AR)–protein kinase A (PKA) signaling pathway.
... The most significant change in hair greying is the loss of melanocytes with decreased melanin production in hair bulb, as observed by a diminished dihydroxyphenylalanine (dopa) reaction in grey hair vs. negative reaction in white hair (Commo et al., 2004). Melanin is still present in the pre-cortical keratinocytes of hair follicles in grey hair but absent in white hair. ...
... Melanocytes are situated in the bulb of the follicle, where they transfer melanin to cortical keratinocytes of the hair shaft, thus defining the hair pigmentation unit. 2 The large variety of hair colour results from variable amounts and mixing of different melanin, specifically eumelanin and phaeomelanin, in the hair cortex. Eumelanin is responsible for the black and brown colour of skin, eyes and hair. ...
Hair is a valuable anatomical structure of the body, having cosmetological and sociological importance in drafting the beauty and personality of an individual. Greying of hair represents the sign of ageing known as Palitya in Ayurveda. But when hair starts greying before the usual age of onset, known as premature greying of hair. Premature hair greying is called Akalaja Palitya, which occurs due to various factors resulting in the vitiation of Pitta dosha. Due to mankind’s hectic, sedentary and busy schedule, the current scenario is witnessing several challenges, and premature greying of hair is one among them. Premature hair greying has multifactorial aetiology, including oxidative stress, nutritional deficiency, smoking, and dysfunctional thyroid hormones, but the exact aetiology is still unknown. Acharyas have mentioned various rasayana for preventing and treating premature hair greying, i.e., Akalaja Palitya. Rasayana therapy aims primarily to promote the strength and vitality of the body. It also helps maintain the integrity of sapta dhatus (fundamental structural component) by improving digestive power resulting in the sound production of successive dhatus and their malas. Dhatryadi rasayana is a polyherbal formulation consisting of three ingredients, i.e., Dhatri (Emblica officinalis Gaertn.), Bhringraj (Eclipta alba Hassk.) and Tila (Sesamum indicum Linn.). All three plants have the keshya property. Emblica officinalis Gaertn. and Sesamum indicum Linn. both act as a 5α-reductase inhibitor. Eclipta alba Hassk. stimulates the proliferation of follicular keratinocytes by downregulating the TGF-β1 (Transforming Growth Factor Beta 1) expression. Furthermore, all ingredients of Dhatryadi rasayana have antioxidant properties and contribute to essential nutritional supplements required for proper hair development and growth.
... At its simplest, the pigment loss in greying hair follicles is due to a marked reduction in melanogenically active melanocytes in the hair bulb. Although it has not yet been completely understood why melanocytes are lost with aging, some mechanisms have been proposed (Figure 9) [468][469][470]. 023, 12, x FOR PEER REVIEW 31 of 57 The traditional view proposes that the depletion of hair follicle bulbar melanocytes correlates with oxidative stress. ...
Simple Summary
The frequency of use of permanent hair dyes to change natural colour are associated with fibre damage and with an increased risk of serious health problems. The future of hair dyeing could be the topical modulation of the pigment production that occurs in special cells, called melanocytes, localized in the hair roots. The success of such approaches is dependent on expanding and deepening our knowledge on hair pigmentation biology. In this context, the paper aims to critically review the vast bibliography on mammalian pigmentation having in view the topical modulation of hair follicle biology to produce a desired change in the hair fibre colour.
Abstract
The natural colour of hair shafts is formed at the bulb of hair follicles, and it is coupled to the hair growth cycle. Three critical processes must happen for efficient pigmentation: (1) melanosome biogenesis in neural crest-derived melanocytes, (2) the biochemical synthesis of melanins (melanogenesis) inside melanosomes, and (3) the transfer of melanin granules to surrounding pre-cortical keratinocytes for their incorporation into nascent hair fibres. All these steps are under complex genetic control. The array of natural hair colour shades are ascribed to polymorphisms in several pigmentary genes. A myriad of factors acting via autocrine, paracrine, and endocrine mechanisms also contributes for hair colour diversity. Given the enormous social and cosmetic importance attributed to hair colour, hair dyeing is today a common practice. Nonetheless, the adverse effects of the long-term usage of such cosmetic procedures demand the development of new methods for colour change. In this context, case reports of hair lightening, darkening and repigmentation as a side-effect of the therapeutic usage of many drugs substantiate the possibility to tune hair colour by interfering with the biology of follicular pigmentary units. By scrutinizing mammalian pigmentation, this review pinpoints key targetable processes for the development of innovative cosmetics that can safely change the hair colour from the inside out.
... This is because melanin, being the source of hair color, is no longer generated. There have been many studies on the cause of graying hair [11,12]. Before graying, the color of pigmented hair may change with age. ...
In a previous study, we observed that the hair color of Japanese females darkens with age and that the causes of this are the increase in melanosome size, the amount of melanin, and the mol% of 5,6-dihydroxyindole (DHI) which has a high absorbance. In this study, we extended the same analyses to male hair to examine the sex differences in hair color, melanin composition, and melanosome morphology. Male hair also tended to darken with age, but it was darker than female hair in those of younger ages. Although there was no age dependence of DHI mol% in male hair, as with female hair, the melanosomes’ sizes enlarged with age, the total melanin amount increased, and these findings were correlated with hair color. The analyses, considering age dependence, revealed that there were significant sex differences in the ratio of absorbance of dissolved melanin at the wavelength of 650 nm to 500 nm, in pheomelanin mol%, and in melanosome morphology parameters such as the minor axis. This may be the cause of the sex differences in hair color. Furthermore, the factors related to hair color were analyzed using all the data of the male and female hairs. The results suggested that total melanin amount, pheomelanin mol%, and DHI mol% correlated with hair color.
... Unlike skin, hair colour tends to fade with sun or ultraviolet (UV) exposures via oxidative processes. [31][32][33] Aging leads to a progressive loss of melanocytes of the hair follicle, 34,35 ultimately leading to hairs fully deprived of pigments, perceived as white hairs, a dreaded signature of aging. Of note, on a worldwide aspect, it comes clear that brown to dark hairs largely predominate, even in non-Hispanic European and Euro-American population who present the widest palette of hair colours, red hairs included. ...
Objective
To determine the aesthetical accordance between a given skin tone and the 11 possible colours of head hairs, covered by a marketed hair colouration product.
Material and methods
The photographs of professional top models, representing several ancestries (non‐Hispanic European and Euro–American, East Asian, Hispanic Euro–American, and African–American ancestries), were used to virtually modify skin tones (from light, medium to dark) and hair colour by an artificial intelligence (AI)‐based algorithm. Hence, 117 modified photographs were then assessed by five local panels of about 60 women each (one in China, one in France and three in US). The same questionnaire was given to the panels, written in their own language, asking which and how both skin tones and hair colours fit preferentially (or not appreciated), asking in addition the reasons of their choices, using fixed wordings.
Results
Answers from the five panels differed according to origin or cultural aspects, although some agreements were found among both non‐Hispanic European and Euro‐American groups. The Hispanic American panel in US globally much appreciated darker hair tones (HTs). Two panels (East Asian in China and African American in US) and part of non‐Hispanic European panel in France declared appreciating all HTs, almost irrespective with the skin tone (light, medium and dark). This surprising result is very likely caused by gradings (in %) that differ by too low values, making the establishment of a decisive or significant assessment. By nature highly subjective (culturally and/or fashion driven), the assessments should be more viewed as trends, an unavoidable limit of the present virtual approach. The latter offers nevertheless a full respect of ethical rules as such objective could hardly be conducted in vivo: applying 10 or 11 hair colourations on the same individual is an unthinkable option.
Conclusion
The virtual approach developed in the present study that mixes two major facial coloured phenotypes seems at the crossroad of both genetic backgrounds and the secular desire of a modified appearance. Nonetheless, this methodology could afford, at the individual level in total confidentiality, a great help to subjects exposed to some facial skin disorders or afflictions.
... By the age of 60, approximately 50 % of the population has half gray hair on the body and a higher percentage of gray/white hair on the head. The change of the color to gray is explained by a gradual decrease in the number and function of melanocytes located both in the area of hair follicles and external root sheath [23]. ...
The review analyzes current experimental and clinical data on skin aging. One of skin aging phenomena is the aging of its cells. Senescent cells produce a broad spectrum of cytokines that alter the microenvironment of tissues. The results of recent studies show that the microenvironment affects the functional activity of stem cells, which is accompanied by impairment in skin regeneration and recovery.
... It has been established that the loss of hair shaft melanin is related to reduction of the bulb melanin content, as well as of the bulb melanocyte population. Hair graying is presumably an aftermath of the entire and specific emptying of the bulb and in the outer root sheath melanocytes of human hair 49 . When the reservoir of stem cells is depleted, the production of pigment ceases and the hairs turn gray. ...
Aging interventions will be ineffective if we do not understand the basic principles of aging. Currently, there is no consensus on the issue whether aging is programmed or not. The hypothesis presented in this article indicates that aging (at least graying of male hairs) is programmed. This hypothesis is supported by the symmetry of the graying of male beard hairs. According to stochastic theories of aging, aging is a passive non-programmed process where random dispersion of graying hairs should result. On the contrary, programmed theories of aging would predict that there should be symmetry on the left and right parts of the face showing the same proportion, pattern and time of appearance of graying hairs.
... The color in pigmented HSs is provided by melanin granules, a mature form of melanosomes continuously supplied to the trichocytes of the growing hair shaft by melanocytes of the hair follicle pigmentary unit (HFPU) (Tobin, 2011). Age-related greying is thought to involve bulb and outer root sheath melanocyte stem cell (MSC) exhaustion (Commo et al., 2004;Nishimura et al., 2005), neuroendocrine alterations (Paus, 2011), and other factors, with oxidative damage to the HFPU likely being the dominant, initial driver (Arck et al., 2006;Paus, 2011;Trueb and Tobin, 2010). While loss of pigmentation is the most visible change among greying hairs, depigmented hairs also differ in other ways from their pigmented counterparts (Tobin, 2015), including in their growth rates (Nagl, 1995), HF cycle, and other biophysical properties (Van Neste and Tobin, 2004). ...
Background: Hair greying is a hallmark of aging generally believed to be irreversible and linked to psychological stress.
Methods: Here, we develop an approach to profile hair pigmentation patterns (HPPs) along individual human hair shafts, producing quantifiable physical timescales of rapid greying transitions.
Results: Using this method, we show white/grey hairs that naturally regain pigmentation across sex, ethnicities, ages, and body regions, thereby quantitatively defining the reversibility of greying in humans. Molecularly, grey hairs upregulate proteins related to energy metabolism, mitochondria, and antioxidant defenses. Combining HPP profiling and proteomics on single hairs, we also report hair greying and reversal that can occur in parallel with psychological stressors. To generalize these observations, we develop a computational simulation, which suggests a threshold-based mechanism for the temporary reversibility of greying.
Conclusions: Overall, this new method to quantitatively map recent life history in HPPs provides an opportunity to longitudinally examine the influence of recent life exposures on human biology.
Funding: This work was supported by the Wharton Fund and NIH grants GM119793, MH119336, and AG066828 (MP).
... Among the known genes for coat colour, the function of genes in the category related to 'the component of melanosome and their precursor' and 'Eumelanin and pheomelanin' are melanin synthesis and the switch between eumelanin and pheomelanin in the skin or hair [134,135]. The association between less melanin with lighter phenotype was observed in humans [136], alpacas [137], llamas [138], and horses [139]. This demonstrates that the AP1 family of TFs, especially the JUN family, plays an important role in melanin synthesis and expression of melanogenesis-associated genes. ...
The transcriptional regulation of gene expression in higher organisms is essential for different cellular and biological processes. These processes are controlled by transcription factors and their combinatorial interplay, which are crucial for complex genetic programs and transcriptional machinery. The regulation of sex-biased gene expression plays a major role in phenotypic sexual dimorphism in many species, causing dimorphic gene expression patterns between two different sexes. The role of transcription factor (TF) in gene regulatory mechanisms so far has not been studied for sex determination and sex-associated colour patterning in zebrafish with respect to phenotypic sexual dimorphism. To address this open biological issue, we applied bioinformatics approaches for identifying the predicted TF pairs based on their binding sites for sex and colour genes in zebrafish. In this study, we identified 25 (e.g., STAT6-GATA4; JUN-GATA4; SOX9-JUN) and 14 (e.g., IRF-STAT6; SOX9-JUN; STAT6-GATA4) potentially cooperating TFs based on their binding patterns in promoter regions for sex determination and colour pattern genes in zebrafish, respectively. The comparison between identified TFs for sex and colour genes revealed several predicted TF pairs (e.g., STAT6-GATA4; JUN-SOX9) are common for both phenotypes, which may play a pivotal role in phenotypic sexual dimorphism in zebrafish.
... The progressive loss of hair pigmentation with age is called canities or senile "hair greying" and results in the emergence of grey hair fibres from the epidermis surface [7]. The "hair greying" is a consequence of melanogenesis reduction during the anagen phase of the hair cycle and seems to be universal. ...
One of the most visible signs of hair ageing is greying of the hair, also known as canities. This hair disorder is mainly caused by oxidative stress. In preliminary work, we designed various models mimicking the impact of oxidative stress on hair pigmentation, showing an accumulation of reactive oxygen species (ROS) production and a decrease in the presence of melanocytes and melanoblasts, resulting in a decrease in hair pigmentation. A proteomic study on skin scalp explants was performed to identify the dysregulated biological pathways related to canities. We developed a smart active ingredient which has been tested on these biological pathways. We demonstrated that these negative effects were rectified in the presence of the ingredient, showing a reduction of ROS, protection of melanocyte reservoirs and reactivation of hair pigmentation. Finally, a clinical study was carried out on a panel of 44 male volunteers with grey hair. After 4 months, we evidenced a reduction in the proportion of grey hair and in the number of grey hairs/cm² relative to Day 0. In conclusion, we clearly evidenced that oxidative stress is a key factor in triggering a cascade of events leading to a loss of hair pigmentation. We developed this active ingredient which is capable of restoring all the disrupted mechanisms and of providing hair repigmentation within only 4 months.
... Depletion of follicular melanocyte stem cells (MSC) causes persistent loss of functional melanocytes from the hair matrix, [1][2][3] without hair graying recovery. Age-related hair graying correlates with a decrease in the number of MSC per follicle. ...
Hair follicular keratinocyte stem cells (HFKSC) which provide a functional niche for melanocyte stem cells (MSC) are the primary target of hair graying. However, little research has been done on anti-hair graying medicines targeting HFKSC. We focused on Eriodictyon angustifolium (Ea), which reduces human hair graying when applied topically. To investigate the protective effect of dietary Ea tea (EaT) on hair pigmentation, we used an acute mouse model of hair graying that mimics X-ray-induced DNA damage associated with age-related hair graying. Our results suggest that dietary EaT maintained the niche HFKSC function against X-ray-induced DNA damage and hair graying. These results indicate that dietary EaT may prevent age-related hair graying and serve as an anti-hair graying herbal medicine.
Graphical Abstract Fullsize Image
... Grey hair (canities) is often age-related, with one study suggesting 50% of people had at least 50% grey hair by age 50 18 , but it can also be premature. It can cause psychological distress at any age and result in the use of harsh products which can cause additional problems. ...
Background: The appearance of grey hair can be unwelcome at any age and have far reaching implications. Canities can impact self-esteem, and result in the application of harmful products. In Unani medicine Coffea Arabica is said to stain hair dark brown and mask all grey, but no research investigating these claims was found.
Objective: A preliminary exploration to test the efficacy of coffee to stain hair dark brown, and mask all grey, and to evaluate its feasibility and acceptability.
Materials and methods: A concentrated solution of instant coffee (100% Arabica) was applied externally to hair up to once a day over seven months. This autobiographical pre-pilot study (n = 2; Ages 54 and 57) was evaluated using the Feasibility, Reach-out, Acceptability, Maintenance, Efficacy, Implementation, Tailorability (FRAME-IT) framework.
Results: A coffee colour tone was apparent, but coverage was only partial. Individual hairs ranged from dark brown to light brown to grey. The overall effect was darker. Coffee solution, applied to hair as a wash and spray, was feasible, acceptable, and effective in visually reducing greyness for a nuanced and natural look. Additional benefits to hair, and also to scalp and skin conditions were observed.
Conclusion: Coffee did not uniformly stain hair dark brown; its effect on grey was nuanced. Participants found it to be a low-risk, inexpensive, convenient alternative, and appreciated the nuanced look. A pilot-study and testing in wider populations, with different levels of greyness is recommended, as is the identification of a low-risk mordant to address colour permanency.
... In contrast, depletion of follicular MSCs causes persistent loss of functional melanocytes from the hair matrix [15][16][17], with no recovery from hair greying expected under these circumstances. The percentage of grey hair-containing follicles, and depletion of MSCs, is reported to be increased as a result of cumulative progression of the hair cycle with advancing age [16,17]. ...
Objective
Yerba Santa (Eriodictyon angustifolium and Eriodictyon californicum) has been used for many years in traditional medicine. However, the effect of Yerba Santa on melanogenesis has not yet been investigated. We aimed to assess the biological effects of Yerba Santa on hair pigmentation.
Methods
Yerba Santa extracts were assessed for their cytological effects following X‐ray irradiation treatment, and then tested directly for the prevention of human hair graying. Ultra‐performance liquid chromatography (UPLC) was utilized to identify the individual extract components.
Results
E. angustifolium extract significantly increased melanin synthesis in the melanoma cell line through activation of the WNT/MITF/tyrosinase‐signaling pathway. In contrast, E. californicum had no effect on melanin synthesis. E. angustifolium extract also demonstrated a protective effect against the damage induced by X‐ray irradiation in human keratinocytes. Application of the extracts to subjects who had gray beards demonstrated a reduced number of gray beard hair per year specifically with the E. angustifolium extract. A significant decrease in gray head hair was also observed after application of E. angustifolium extract. Upregulation of gene expression related to melanin production and WNT signaling was observed after the application of E. angustifolium extract. Sterubin was the most abundant flavonoid detected by UPLC in E. angustifolium extract. In addition, sterubin showed the highest difference in terms of quantity, between E. angustifolium and E. californicum extract.
Conclusion
E. angustifolium extract, which is abundant in sterubin, may be suitable as a potential cosmetic and medical agent for the prevention and improvement of hair graying.
... 5 A person having premature hair graying or baldness/hair loss have severe complications and effects on the physical appearance, self-esteem, and socio-cultural acceptance of the affected person. 6,7 As people mostly view it as a sign of old age and malnourishment, influenced people are frequently subjected to social disgrace, separation, and troubles in marriage. 8 Very limited data is available regarding association of smoking or tobacco use with premature graying of hair. ...
Background and Objectives: Smoking is a global health problem responsible for significant diseases that may lead to morbidity as well as mortality. Smoking has also been associated with gray hair and baldness in recent studies. Very limited data is available regarding association of smoking or tobacco use with premature graying of hair in our community, therefore, this study was designed to see any potential effect of smoking on graying of hair and baldness. Methods: This analytical cross sectional study was conducted on 398 male subjects keeping prevalence of premature gray hair as 50.2% and 5% error. Non-Probability convenient sampling was used to collect data. The volunteer subjects were briefed about the purpose of research and questionnaire. After collection of data, it was entered and analyzed in SPSS version 20. Mean and Standard deviation were used to mention age, whereas, frequency and percentages were reported for qualitative variables. Chi Square test was used to see association between graying of hair and baldness, with smoking and other potential risk factors. Results: The mean age of males was 36.50 ± 12.11 years with minimum and maximum ages of 17.00 and 72.00 years respectively. Out of total 398 subjects, 317 (79.6%) had gray hair among whom 172 (54.3%) reported that the onset of gray hair was at less than 30 years of age. There were 209 (52.5%) males who reported baldness and among them the onset of baldness in 99 (52.0%) subjects was at less than 30 years of age. A statistically significant association was found between baldness and smoking (p-value < 0.001). Also, a significant association was found of baldness with family history of gray hair (p-value = 0.007), with family history of baldness (p-value < 0.001), thyroid disease (p-value = 0.043), and vitiligo (p-value = 0.041). However, gray hairs were not associated with any of these risk factors. Conclusion: Our study concludes that premature hair graying and baldness has become quite common in our population. Though smoking has significant contribution in baldness, some other factors such as family history of gray hair and baldness, thyroid disease and vitiligo cannot be ignored as they also have significant association with baldness but not with gray hair.
... Hair colour depends on melanin content in the hair bulb. With age, melanocytes produce less melanin and hair loses its natural color [41]. Research has shown that people using hair dye products look a lot younger [42], but there is no accurate repeatable scientific data on how exactly gray hair affects the perceived age, yet we know that the difference is significant [43] In addition, colouring damages the hair follicles. ...
The purpose of this paper is to discuss the most important factors affecting perceived age. Aging is an unavoidable and irreversible process, but perceived age is a modifiable psychosocial factor. Our exterior has become one of the determinants of our social position, the key to success in our professional and personal lives. Today, we see people through their appearance, we judge after the first impression. With the help of aesthetic medicine, we can change the perceived age, but we cannot stop aging. This article discusses factors affecting the perceived age, such as hair color, skin color, general appearance and environmental factors. Many cannot be avoided, but we can make changes in life to look younger and more well-groomed. Indeed, we can change our habits for the benefit of the whole body, not only for the skin.
... Hair shaft pigmentation, also called follicular melanogenesis, in both mice and humans is tightly linked to the growth phase (anagen) of the hair cycle [6][7][8], which is followed by a regression phase (catagen) and a resting phase (telogen) [9]. During early anagen, melanoblasts are recruited from the hair follicle bulge region in the outer root sheath and migrate to the hair follicle bulb where they start establishing the pigmentary-unit [9][10][11]. Melanocytes mature during high anagen and are then fully functional with respect to melanogenesis. ...
The human hair follicle is a neuroendocrine mini-organ that can be used to study aging processes in vitro. Neurotrophins maintain homeostasis in hair biology via the Trk-family of receptors. TrkA, the high affinity receptor for nerve growth factor (NGF), is expressed in hair follicle melanocytes and keratinocytes, where it regulates proliferation, differentiation and apoptosis and may thereby play a role in hair pigmentation and growth. We investigated TrkA expression during the human hair cycle and the effects of a selective high affinity TrkA agonist, Gambogic Amide, on hair pigmentation and hair growth in human hair follicles in vitro. In human scalp skin, TrkA expression was strongest in proliferating melanocytes re-establishing the pigmentary unit in the hair bulb during the early hair growth phase, anagen. During high anagen and in the de-composing pigmentary-unit of the regression phase, catagen, bulb-melanocytes lost TrkA expression and only undifferentiated outer root sheath melanocytes maintained it. In cultured human anagen hair follicles, Gambogic Amide was able to prevent gradual pigment loss, while it stimulated hair shaft elongation. This was achieved by increased melanocyte activation, migration and dendricity, highlighted by distinct c-KIT-expression in melanocyte sub-populations. Our results suggest that Gambogic Amide can maintain hair follicle pigmentation by acting on undifferentiated melanocytes residing in the outer root sheath and making them migrate to establish the pigmentary-unit. This suggests that the selective TrkA agonist Gambogic Amide acts as an anti-hair greying and hair growth promoting molecule in vitro.
Graying of hair, also known as greying, canities, or achromotrichia, is the progressive loss of hair pigmentation, leading to grey or white hair. The process typically occurs naturally with aging.
This research explores the phenomenon of gray hair and its consequences for human health. Additionally, Biblical references to gray hair are analyzed from a contemporary perspective to provide further insights.
Various factors are involved in the graying of hair. While the pattern of graying varies among different studied populations.
In the Bible, gray hair symbolizes wisdom, dignity, experience, respect for the elderly, and the blessing of a long life. Therefore, we should embrace the Biblical perspective on gray hair, recognizing it as a sign of honor and wisdom.
Hair graying is a common and visible sign of aging resulting from decreased or absence of melanogenesis. Although it has been established that gray hair greatly impacts people's mental health and social life, there is no effective countermeasure other than hair dyes. It has long been thought that reversal of gray hair on a large scale is rare. However, a recent study reported that individual gray hair darkening is a common phenomenon, suggesting the possibility of large-scale reversal of gray hair. In this article, we summarize the regulation mechanism of melanogenesis and review existing cases of hair repigmentation caused by several factors, including monoclonal antibodies drugs, tyrosine kinase inhibitors (TKIs), immunomodulators, other drugs, micro-injury, and tumors, and speculate on the mechanisms behind them. This review offers some insights for further research into the modulation of melanogenesis and presents a novel perspective on the development of clinical therapies, with emphasis on topical treatments.
Aging is a complex natural process that leads to a decline in physiological functions, which is visible in signs such as hair graying, thinning, and loss. Although hair graying is characterized by a loss of pigment in the hair shaft, the underlying mechanism of age-associated hair graying is not fully understood. Hair graying and loss can have a significant impact on an individual's self-esteem and self-confidence, potentially leading to mental health problems such as depression and anxiety. Omics technologies, which have applications beyond clinical medicine, have led to the discovery of candidate hair biomarkers and may provide insight into the complex biology of hair aging and identify targets for effective therapies. This review provides an up-to-date overview of recent omics discoveries, including age-associated alterations of proteins and metabolites in the hair shaft and follicle, and highlights the significance of hair aging and graying biomarker discoveries. The decline in hair follicle stem cell activity with aging decreased the regeneration capacity of hair follicles. Cellular senescence, oxidative damage and altered extracellular matrix of hair follicle constituents characterized hair follicle and hair shaft aging and graying. The review attempts to correlate the impact of endogenous and exogenous factors on hair aging. We close by discussing the main challenges and limitations of the field, defining major open questions and offering an outook for future research.
Hair graying is an early and obvious phenotypic and physiological trait with age in humans. Several recent advances in molecular biology and genetics have increased our understanding of the mechanisms of hair graying, which elucidate genes related to the synthesis, transport, and distribution of melanin in hair follicles, as well as genes regulating these processes above. Therefore, we review these advances and examine the trends in the genetic aspects of hair graying from enrichment theory, Genome-Wide association studies, whole exome sequencing, gene expression studies, and animal models for hair graying with age, aiming to overview the changes in hair graying at the genetic level and establish the foundation for future research. Meanwhile, by summarizing the genetics, it's of great value to explore the possible mechanism, treatment, or even prevention of hair graying with age.
The authors present the reader with alopecia lesions sparing white hair, colocalization of vitiligo and alopecia areata, melanogenesis impairment heralding alopecia areata, regrowth of white hair in alopecia areata, regrowth of red hair in black-haired alopecia areata boy, perinevoid alopecia, congenital red hair heterochromia of the scalp, acquired transient heterochromia of the scalp hair, segmented heterochromia in a single scalp hair, depigmented macules developed following hair graying at the age of 40, canities subita, permanent poliosis following repetitive plucking, premature canities sparing hair margin, and premature hair graying initially affecting the pubic hair.
Hair thinning occurs during normal chronological aging in women and in men leading to an increased level of thinner hair shafts alongside original thicker shafts. However, the characteristics of age-associated thin hairs remain largely unknown. Here we analyzed these characteristics by comparing at multiscale thin and thick hairs originated from Caucasian women older than 50 years. We observed that the cortex of thick hair contains many K35(+)/K38(-) keratinocytes that decrease in number with decreasing hair diameter. Accordingly, X-ray diffraction revealed differences supporting that thin and thick hairs are different with regards to the nature of the intermediate filaments making up their cortices. In addition, we observed a direct correlation between hair ellipticity and diameter with thin hairs having an unexpected round shape compared to the elliptic shape of thick hairs. We also observed fewer cuticle layers and a reduced frequency of a medullae in thin hairs. Regarding mechanical properties, thin hairs exhibited a surprising increased rigidity, a decrease of the viscosity and a decrease of the water diffusion coefficient. Hence, aged-associated thin hairs exhibit numerous modifications likely due to changes of hair differentiation program as evidenced by the modulations in the expression of hair keratins and keratin-associated proteins and by the X-ray diffraction specters. Hence, hair thinning with age does not consist simply of the production of a smaller hair. It is rather a more profound process likely relying on the implementation of an "aged hair program" that takes place within the hair follicle.
As one of the earliest and most visible phenomenon of aging, gray hair makes it a unique model system for investigating the mechanism of aging. Ionizing radiation successfully induces gray hair in mice, and also provides a venue to establish an organ-cultured human gray hair model. To establish a suitable organ-cultured human gray HF model by IR, which imitates gray hair in the elderly, and to explore the mechanisms behind the model. By detecting growth parameters, melanotic and senescence markers of the model, we found that the model of 5 Gy accords best with features of elderly gray hair. Then, we investigated the formation mechanisms of the model by RNA-sequencing. We demonstrated that the model of organ-cultured gray HFs after 5 Gy irradiation is closest to the older gray HFs. Moreover, the 5 Gy inhibited the expression of TRP-1, Tyr, Pmel17, and MITF in hair bulbs/ORS of HFs. The 5 Gy also significantly induced ectopically pigmented melanocytes and increased the expression of DNA damage and senescence in HFs. Finally, RNA-seq analysis of the model suggested that IR resulted in cell DNA damage, and the accumulation of oxidative stress in the keratinocytes. Oxidative stress and DNA damage caused cell dysfunction and decreased melanin synthesis in the gray HFs. We found that HFs irradiated at 5 Gy successfully constructed an appropriate aging HF model. This may provide a useful model for cost-effective and predictable treatment strategies to human hair graying and the process of aging.
Stable isotope analysis is a powerful tool for reconstructing the diet and health of ancient individuals. The carbon and nitrogen stable isotope compositions of human tissues reflect those of the foodstuffs consumed and can be altered by physio-pathological stressors. The δ¹³C and δ¹⁵N values can be measured in the protein as a whole or in the amino acids constituting the protein by using a bulk or compound-specific isotope technique, respectively.
Human scalp hair is considered an ideal tissue in stable isotope studies because it is resistant to degradation, is predominantly composed of proteins (keratins), grows fast and at a ‘known’ rate (circa 1 cm/month when in anagen phase), and it does not remodel after deposition. The isotope signal is recorded sequentially as the tissue grows and remains unaltered through time, with the most recent information found at the hair root. The sampling procedure is minimally invasive and therefore comparative studies on living individuals can be performed.
Stable isotope analysis of sequential segments of scalp hair is a means of achieving a highly detailed and temporally resolved reconstruction of an individual’s life. Dietary intake and health status of individuals can be reconstructed on a fortnightly basis when 0.5-cm-long hair segments are incrementally analysed.
As humans grow older, signs of aging become evident in all the organs of the human body. The first visible signs of aging appear on the skin. The aging skin changes due to a combination of endogenous factors (gene mutations, cellular metabolism, hormonal environment) and exogenous ones (chemicals, toxins, pollutants, UV radiation, smoking, diet, lifestyle). Sun-exposed skin areas will be mostly affected by exogenous factors, presenting as “extrinsic aging”. In contrast, typical changes resulting from endogenous factors are most visible in sun-protected areas and are primarily attributed to individual genetic and epigenetic mechanisms with interindividual variation. This process is coined “intrinsic aging”.
Altern ist ein grundlegender biologischer Vorgang, der für alle Organe charakteristisch abläuft. Der Alterungsprozess führt zur Abnahme der Maximalfunktion und Reservekapazität aller Organsysteme, einschließlich der Haut und ihrer Anhangsgebilde. Vom frühen bis ins späte Erwachsenenalter belaufen sich diese Verluste auf 50 % und machen das Individuum zunehmend anfälliger für Verletzung und Krankheit (Yaar/Gilchrest 2001).
Background:
Studies on mice and aging human hair follicles provide compelling evidence that graying of hair results from premature differentiation of Melanocyte stem cells (MeSC) in the niche/bulge.
Objective:
To analyze whether differentiation of melanocyte stem cells is responsible for premature graying of hair (PGH).
Methods:
Twenty- five patients of PGH (n=25) attending dermatology department were recruited. Five unpigmented and five pigmented hairs were obtained per patient by separating individual follicles by 1 mm punch biopsies. The hairs were dissected at a distance of 2 mm from the bulb to separate the stem cells (upper segment) (US) from the melanocytes (lower segment) (LS). RNA was extracted from hair follicle segments US and LS, and expression of GP100, Tyrosinase (TYR) and Tyrosinase related protein-1 (TYRP1) genes was quantified using Qiagen one-step RT-PCR kit.
Results:
We found melanogenesis gene expression in both temporary (US) and permanent (LS) segments of unpigmented and pigmented hair follicles. When compared between the US and LS of white hair, the expression of TYR and GP100 was much higher in US than LS, suggestive of melanogenesis in the bulge. Similarly, when compared between white and black US, the expression of all three genes was higher in white US than black US, although not statistically significant.
Limitations:
Low samples size and lack of data pertaining to the expression of genes at protein level are the limitations of current study.
Conclusion:
Even though this pilot study data yielded key information about the expression of GP100, TYR and TYRP-1 at mRNA level, further studies quantifying the expression of these genes at protein level are needed to provide additional clues to further address the results in detail.
Aging is associated with widespread physiological changes, including skeletal muscle weakening, neuron system degeneration, hair loss, and skin wrinkling. Previous studies have identified numerous molecular biomarkers involved in these changes, but their regulatory mechanisms and functional repercussions remain elusive. In this study, we conducted next-generation sequencing of DNA methylation and RNA sequencing of blood samples from 51 healthy adults between 20 and 74 years of age and identified aging-related epigenetic and transcriptomic biomarkers. We also identified candidate molecular targets that can reversely regulate the transcriptomic biomarkers of aging by reconstructing a gene regulatory network model and performing signal flow analysis. For validation, we screened public experimental data including gene expression profiles in response to thousands of chemical perturbagens. Despite insufficient data on the binding targets of perturbagens and their modes of action, curcumin, which reversely regulated the biomarkers in the experimental dataset, was found to bind and inhibit JUN, which was identified as a candidate target via signal flow analysis. Collectively, our results demonstrate the utility of a network model for integrative analysis of omics data, which can help elucidate inter-omics regulatory mechanisms and develop therapeutic strategies against aging.
Objective
Hair greying (i.e canitie) is a physiological process occurring with the loss of melanin production and deposition within the hair shafts. Many studies reported the oxidation as the main biological process underlying this defect of pigmentation. Even though the overall appearance and biomechanical properties of hairs are reported to be altered with greying, there is a lack of information about molecular modifications occurring in grey hair shafts.
The aim of this study was thus to investigate the molecular signature and associated changes occurring in greying hair shafts by confocal Raman microspectroscopy.
Methods
This study was conducted on pigmented, intermediate (i.e. grey) and unpigmented hairs taken from 29 volunteers. Confocal Raman microspectroscopy measurements were acquired directly on hair shafts.
Results
Automatic classification of Raman spectra revealed 5 groups displaying significant differences. Hence, the analysis of the molecular signature highlighted the existence of 3 sub‐groups within grey hair: light, medium and dark intermediate. Among molecular markers altered in the course of greying, this study identified for the first time a gradual modification of lipid conformation (trans/gauche ratio) and protein secondary structure (α‐helix/β‐sheet ratio), referring respectively to an alteration of barrier function and biomechanical properties of greying hair.
Conclusion
This study thus reports for the first time a highly specific molecular signature as well as molecular modifications within grey hair shaft.
Melanin plays an important role in determining skin colour. Apoptosis of melanocytes and defect in melanin production cause vitiligo. Various studies have been conducted to treat the disease, but its treatment is still difficult. Therefore, this study aimed to investigate the effect of spermidine, which is known as an inhibitor of ageing‐related oxidized proteins, on melanogenesis. Even though spermidine above 50 μM had no effect on antioxidant activity and DOPA oxidation, it displayed tyrosinase activity. However, spermidine at 2000 μM was cytotoxic in B16F1 cells using MTT assay. Spermidine above 125 μM decreased the amount of intracellular hydrogen peroxide in a concentration‐dependent manner in DCFH‐DA analysis. It was also found that spermidine above 2000 μM increased melanin synthesis in living cells. However, spermidine above 1000 μM increased melanin synthesis in a concentration‐dependent manner in H2O2‐treated B16F1 cells. Furthermore, spermidine enhanced the expression of tyrosine hydroxylase via MITF transcription factor involved in melanogenesis in H2O2‐treated B16F1 cells. Therefore, these results suggest that spermidine could be applied as a potential stimulator of melanin synthesis for the prevention of hair greying.
Efforts have been conducted to evaluate hair features empirically, for example, color; however, a review of current literature showed few studies investigating cortical texture analysis. The development of high‐resolution digital microscopes allows researchers to obtain more accurate measurements of hair features. In this study, digital microscopy was used to explore variance within the cortical texture, color, and density characteristics throughout hair strands. In this study, 20–25 naturally shed hairs from 12 individuals of different ancestries were collected. Measurements of three different features were collected: entropy texture measurements, that is, measurement of the randomness of pigment granules and cortical fusi; color distributions of the hairs via a red–green–blue (RGB) color model; and the calculation of the pigment density ratio using hue–saturation–value color model. Analysis of variance was performed on data collected from each analysis type to assess inter‐ and intra‐person variability. The F‐ratios obtained, which compares inter‐person to intra‐person variability, ranged from 9.29 to 69.24. Cortical texture and color measurements showed promising results in differentiating between inter‐person samples. Although density ratios showed the least potential for discrimination, it provided another level for differentiating inter‐person hair samples. The location that provided the best differentiation of strands from different donors could be made at a 20.0 mm distance from the strand's proximal end for all three features measured. The methods proposed in this study show the potential to quantify hair features that exhibit better differentiation of hair from different individuals.
The quantity and quality of hair are closely related to the nutritional state of an individual. In instances of protein and calorie malnutrition, deficiency of essential amino acids, of trace elements, and of vitamins, hair growth and pigmentation may be perturbed. The effects of nutrition on hair growth and pigmentation have been recognized from observations in rare inborn errors of metabolism of copper (Menkes kinky hair syndrome), zinc (acrodermatitis enteropathica), biotin (biotinidase and holocarboxylase synthetase deficiency), and amino acids (homocystinuria, Hartnup disease, phenylketonuria, and methionine malabsorption syndrome), in specific acquired deficiency disorders, and from the respective supplementation studies. All vitamins were identified by 1948, ushering in a half century of discovery focused on single-nutrient-deficiency diseases. The first half of the twentieth century witnessed the identification and synthesis of many of the known essential vitamins and minerals and their use to prevent and treat nutritional deficiency-related diseases, specifically protein-calorie malnutrition, deficiencies of biotin, vitamin C, vitamin B12, niacin, essential fatty acids, iron, zinc, copper, selenium, and vitamin D. Accelerating economic development and modernization of agricultural, food processing, and food formulation techniques continued to reduce single-nutrient-deficiency diseases globally. In response, nutrition science shifted to the research on the role of nutrition in more complex conditions, such as gluten sensitivity, obesity, bariatric surgery, anorexia and bulimia, alcoholism, aging, and the oncologic patient. Additional complexity may arise in nutritional recommendations for general well-being versus treatment of specific conditions. Recognition of complexity is a key lesson of the past. Initial observations lead to reasonable, simplified theories that achieve certain practical benefits, which are then inevitably advanced by new knowledge and recognition of ever-increasing complexity.
Care of the aging man is not complete without expert dermatologic care. Skin problems, ranging from skin cancers to dermatoses, are extremely common with age, and some common problems, such as photoaging, are more prominent in men. Men are increasingly seeking cosmetic treatments, mostly procedures with fast recovery times.
Hair is a defining feature of mammals. In other species hair confers important functions that affect survival. Most have been lost or are irrelevant in humans but the role of hair in social and sexual signalling in women and in men survives and thrives. Departures from cultural norms, either physiological or due to pathology, can therefore cause much concern and anxiety. Following an introduction to hair biology, this chapter considers the approach to the diagnosis and management of the patient with hair loss before discussing specific hair disorders. These include the various forms of hair loss due to hair follicle pathology, disturbances in hair cycling and hair shaft dystrophies, and disorders associated with excessive hair growth. The chapter concludes with a discussion of acquired alterations in hair pigmentation.
Background:
The etiology of premature hair graying (PHG) remains incompletely understood with limited treatment options, although has profound impacts on patient's quality of life.
Aims:
To assess demographic and clinical profiles of Egyptian PHG patients and explore association of various epidemiological risk factors and serum vitamin D and ferritin levels with PHG.
Materials and methods:
300 PHG patients and equal number of controls, aged ‹30 years were included. Assessment of epidemiological and clinical characteristics, biometric data and stress perception using perceived stress scale (PSS- 10) was done, with measurement of serum vitamin D and ferritin levels for all subjects. PHG was graded into mild, moderate and severe if ‹10, 10-100 and › 100 gray hairs respectively. Statistical significance for various compared parameters was done employing suitable tests, with p-value≤ 0.05 considered significant.
Results:
Results reported significant positive relation of PHG with family history, sedentary life style and stress (p= 0.001, 0.029 & 0.001 respectively), while no significant relation with smoking, body mass index or frequent hair dyes use (›3 per year) (p= 0.425, 0.5 and 0.65 respectively). No significant difference was found in mean vitamin D between patients and controls (23.79± 13.01 ng/ml vs. 24.85± 13.19 ng/ml, p= 0.701), while low serum ferritin (‹20 ng/ml) was significantly associated with PHG (14.7 % patients vs. 2.7% controls, p= 0.017).
Conclusions:
PHG in Egyptian population is significantly associated with positive family history, stress, sedentary life style and low serum ferritin level, while role of vitamin D deficiency should be further evaluated.
This chapter focuses on the microscopical examination of hair in the forensic domain. It discusses the relevant biological aspects of hair to provide the necessary background information upon which forensic hair examinations are based. The chapter introduces the methodologies and techniques used by forensic hair examiners. It describes the basic chemistry and basic histology of hairs. Each individual hair progresses through a regular and predictable cycle. This cycle is classically described as having three major phases: anagen, catagen, and telogen. While a variety of methods can be used, forceps and tape lifts are the two most commonly employed techniques for collecting hairs. Most forensic hair cases involve the examination of human hair. Historically, the emphasis has been placed on human hair comparisons. The chapter provides general guidelines for the comparison of hairs. Finally, the interpretation and significance of the results obtained through a microscopical hair examination are considered.
Here we describe the isolation of epidermal melanocytes and hair follicle melanocytes from human skin tissue. Epidermal and hair follicle melanocytes are two distinct populations of melanocytes which are contained within the skin and the hair follicle, with differing yet overlapping roles. Epidermal melanocytes are normally isolated from the epidermis of vellus-haired skin tissue (e.g., face, breast, abdomen), while hair follicle melanocytes are derived from the outer root sheath (ORS) of the middle/lower terminal anagen hair follicles of the scalp. These methods utilize ethically sourced human skin tissue obtained from donors undergoing plastic surgery.
To increase the current understanding of the gene-expression profiles in different skin regions associated with different coat colors and identify key genes for the regulation of color patterns in goats, we used the Illumina RNA-Seq method to compare the skin transcriptomes of the black- and white-coated regions containing hair follicles from the Boer and Macheng Black crossbred goat, which has a black head and a white body. Six cDNA libraries derived from skin samples of the white-coated region (n = 3) and black-coated region (n = 3) were constructed from three full-sib goats. On average, we obtained approximately 76.5 and 73.5 million reads for skin samples from black- and white-coated regions, respectively, of which 75.39% and 76.05% were covered in the genome database. A total of 165 differentially expressed genes (DEGs) were detected between these two color regions, among which 110 were upregulated and 55 were downregulated in the skin samples of white- vs. black-coated regions. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that some of these DEGs may play an important role in controlling the pigmentation of skin or hair follicles. We identified three key DEGs, i.e., Agouti, DCT, and TYRP1, in the pathway related to melanogenesis in the different skin regions of the crossbred goat. DCT and TYRP1 were downregulated and Agouti was upregulated in the skin of the white-coated region, suggesting a lack of mature melanocytes in this region and that Agouti might play a key developmental role in color-pattern formation. All data sets (Gene Expression Omnibus) are available via public repositories. In addition, MC1R was genotyped in 200 crossbred goats with a black head and neck. Loss-of-function mutations in MC1R as well as homozygosity for the mutant alleles were widely found in this population. The MC1R gene did not seem to play a major role in determining the black head and neck in our crossbred goats. Our study provides insights into the transcriptional regulation of two distinct coat colors, which might serve as a key resource for understanding coat color pigmentation in goats. The region-specific expression of Agouti may be associated with the distribution of pigments across the body in Boer and Macheng Black crossbred goats.
The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.
The adult mammalian forebrain subependyma contains neural stem cells and their progeny, the constitutively proliferating progenitor cells. Using bromodeoxyuridine labeling to detect mitotically active cells, we demonstrate that the endogenous expression of transforming growth factor-alpha (TGFalpha) is necessary for the full proliferation of progenitor cells localized to the dorsolateral corner of the subependyma and the full production of the neuronal progenitors that migrate to the olfactory bulbs. Proliferation of these progenitor cells also is diminished with age (in 23- to 25-months-old compared with 2- to 4-months-old mice), likely because of a lengthening of the cell cycle. Senescence or the absence of endogenous TGFalpha does not affect the numbers of neural stem cells isolated in vitro in the presence of epidermal growth factor. These results suggest that endogenous TGFalpha and the effects of senescence may regulate the proliferation of progenitor cells in the adult subependyma, but that the number of neural stem cells is maintained throughout life.
Ageing is associated with a progressive deterioration in the functions of many organs within the body. In tissue with high cell turnover, the maintenance of the stem cells is of particular importance. Any accumulation of damage in stem cells may affect their function and hence threaten the homeostasis and regenerative capacity of the tissue. The small intestine represents a good model for the study of stem cells because of its spatial and hierarchical organisation. We have examined the effect of age on stem cell regenerative capacity after irradiation, using the microcolony assay. Crypt survival levels, the growth rate of surviving crypts, and the number of cells able to repopulate a crypt have been investigated by irradiating groups of 6-7 month old and 28-30 month old ICRFa male mice. After high doses of irradiation, the surviving crypts in old mice were both smaller and fewer in number than in young mice. The growth rate of surviving crypts was determined by measuring the crypt area and the number of cells/crypt at various times after 14 Gy irradiation. There was a growth delay of between about one half and one day in the older mice. Surprisingly, the number of clonogenic cells per crypt was estimated to be greater in the older mice. These studies indicate important age-related alterations in the capacity to regenerate the crypts after radiation damage.
Hair graying, an age-associated process of unknown etiology, is characterized by a reduced number and activity of hair follicle (HF) melanocytes. Stem cell factor (SCF) and its receptor c-kit are important for melanocyte survival during development, and mutations in these genes result in unpigmented hairs. Here we show that during cyclic HF regeneration in C57BL/6 mice, proliferating, differentiating, and melanin-producing melanocytes express c-kit, whereas presumptive melanocyte precursors do not. SCF overexpression in HF epithelium significantly increases the number and proliferative activity of melanocytes. During the induced hair cycle in C57BL/6 mice, administration of anti-c-kit antibody dose-dependently decreases hair pigmentation and leads to partially depigmented (gray) or fully depigmented (white) hairs, associated with significant decreases in melanocyte proliferation and differentiation, as determined by immunostaining and confocal microscopy. However, in the next hair cycle, the previously treated animals grow fully pigmented hairs with the normal number and distribution of melanocytes. This suggests that melanocyte stem cells are not dependent on SCF/c-kit and when appropriately stimulated can generate melanogenically active melanocytes. Therefore, the blockade of c-kit signaling offers a fully reversible model for hair depigmentation, which might be used for the studies of hair pigmentation disorders.
Recent genetic and molecular studies of hair follicle (HF) biology have provided substantial insight; however, the molecular data, including expression patterns, cannot be properly appreciated without an understanding of the basic cellular rearrangements and interactions that underpin HF cyclic transformations. We present a novel interpretation of the major cellular processes that take place during HF cycling--the hypothesis of hair follicle predetermination. This hypothesis is an extension of previous models of HF cellular kinetics but has two critical modifications: the dual origin of the cycling portion of the HF, and the timing of the recruitment of stem cells. A compilation of evidence suggests that the ascending portion of the HF (hair shaft and inner root sheath) arises not from bulge-located HF stem cells that contribute to the formation of only the outer root sheath (ORS), but instead from the germinative cells localized in the secondary hair germ. In middle anagen, upon completion of the downward growth of the HF, cells derived from the bulge region migrate downward along the ORS to reside at the periphery of the HF bulb as a distinct, inactive cell population that has specific patterns of gene expression - 'the lateral disc'. These cells survive catagen-associated apoptosis and, under the direct influence of the follicular papilla (FP), transform into the hair germ and acquire the ability to respond to FP signaling and produce a new hair. Thus, we propose that the specific sensitivity of germ cells to FP signaling and their commitment to produce the ascending HF layers are predetermined by the previous hair cycle during the process of transformation of bulge-derived lateral disc cells into the secondary hair germ.
Stem cells which have the capacity to self-renew and generate differentiated progeny are thought to be maintained in a specific environment known as a niche. The localization of the niche, however, remains largely obscure for most stem-cell systems. Melanocytes (pigment cells) in hair follicles proliferate and differentiate closely coupled to the hair regeneration cycle. Here we report that stem cells of the melanocyte lineage can be identified, using Dct-lacZ transgenic mice, in the lower permanent portion of mouse hair follicles throughout the hair cycle. It is only the population in this region that fulfils the criteria for stem cells, being immature, slow cycling, self-maintaining and fully competent in regenerating progeny on activation at early anagen (the growing phase of hair follicles). Induction of the re-pigmentation process in K14-steel factor transgenic mice demonstrates that a portion of amplifying stem-cell progeny can migrate out from the niche and retain sufficient self-renewing capability to function as stem cells after repopulation into vacant niches. Our data indicate that the niche has a dominant role in the fate determination of melanocyte stem-cell progeny.
We consider some of the problems involved in current discussions on stem cells in adult mammalian tissues. The present concepts involve a number of pitfalls, weaknesses and logical, semantic and classification problems. This indicates the necessity for new and well-defined concepts that are amenable to experimental analysis. One of the major difficulties in considering stem cells is that they are defined in terms of their functional capabilities which can only be assessed by testing the abilities of the cells, which itself may alter their characteristics during the assay procedure: a situation similar to the uncertainty principle in physics. The terms that describe stem cell functions are often not well defined and are used loosely, which can lead to confusion. If such context-dependent interactions exist between the manipulation and measurement process and the challenged stem cells, the question of, for example, the number of stem cells, in a tissue has to be posed in a new way. Rather than obtaining a single number one might end up with various different numbers under different circumstances, all being complementary. This might suggest that stemness is not a property but a spectrum of capabilities from which to choose. This concept might facilitate a reconciliation between the different and sometimes opposing experimental results. Given certain experimental evidence, we have attempted to provide a novel concept to describe structured cell populations in tissues involving stem cells, transit cells and mature cells. It is based on the primary assumption that the proliferation and differentiation/maturation processes are in principle independent entities in the sense that each may proceed without necessarily affecting the other. Stem cells may divide without maturation while cells approaching functional competence may mature but do not divide. In contrast, transit cells divide and mature showing intermediate properties between stem cells and mature functional cells. The need to describe this transition process and the variable coupling between proliferation and maturation leads us to formulate a spiral model of cell and tissue organisation. This concept is illustrated for the intestinal epithelium. It is concluded that the small intestinal crypts contain 4–16 actual stem cells in steady state but up to 30–40 potential stem cells (clonogenic cells) which may take over stem cell properties following perturbations. This implies that transit cells can under certain circumstances behave like actual stem cells while they undergo maturation under other conditions. There is also evidence that the proliferation and differentiation/maturation processes are subject to controls that ultimately lead to a change in the spiral trajectories.(ABSTRACT TRUNCATED AT 400 WORDS)
The publisher regrets that an error appeared in the Abstract of the above article. The corrected ®rst paragraph of the Abstract is given below: The visual appearance of humans derives predominantly from their skin and hair color. The phylogenetically ancient biochemical pathway underlying this phenomenon is called melanogenesis and results in the production of melanin pigments in neural crest-derived melanocytes, followed by its transfer to epithelial cells. While melanin from epidermal melanocytes clearly protects human skin by screening harmful ultraviolet radiation, the biologic value of hair pigmentation is less clear. In addition to important roles in social/ sexual communication, one potential bene®t of pigmented scalp hair in humans may be the rapid excretion of heavy metals, chemicals, toxins from the body by their selective binding to melanin. The hair follicle and epidermal melanogenic systems are broadly distinct, though open. The primary distinguishing feature of follicular melanogenesis, compared to the continuous melanogenesis in the epidermis, is the tight coupling of hair follicle melanogenesis to the hair growth cycle. This cycle appears to involve periods of melanocyte proliferation (during early anagen), maturation (mid to late anagen) and melanocyte death via apoptosis (during early catagen). Thus, each hair cycle is associated with the reconstruction of an intact hair follicle pigmentary unit¼ at least for the ®rst 10 cycles or so. Thereafter, gray and white hairs appear, suggesting an age-related, genetically regulated exhaustion of the pigmentary potential of each individual hair follicle. Melanocyte aging may be associated with reactive oxygen species-mediated damage to nuclear and mitochondrial DNA with resultant accumulation of mutations with age, in addition to dysregulation of anti-oxidant mechanisms or pro/anti-apoptotic factors within the cells.
Der Ursprung der Melanozyten, die in der Haarwurzel whrend jedes Haarzyklus erscheinen, ist bisher unbekannt gewesen. Helle dendritische Zellen im ruhenden Haarkeim, welche an der Haarpapilla liegen, die sich whrend der frhen Anagen teilen und whrend Anagen III–IV Farbkrperchen hervorbringen, sind augenscheinlich die Vorlufer der Haarmelanozyten.
The presence, densities, and patterns of distribution of melanocytes in the epidermis of human embryos and fetuses, ranging in age from 40 d to 140 d estimated gestational age (EGA), were studied using the HMB-45 monoclonal antibody that recognizes an antigen in melanoma cells and fetal melanocytes. Immunostained sections of skin and epidermal sheets revealed dendritic melanocytes within the basal or intermediate layers of 50 d EGA and older skin. Melanocytes could not be identified by immunostaining or electron microscopy in younger (40–50 d EGA) epidermis or in cultured epidermal cells from these specimens. However, skin from a 45 d EGA embryo grown in organ culture for 11 d stained positively with HMB-45, suggesting that melanocytes are present at that age either in the epidermis or dermis of the explant. Double-labeling experiments using ATPase and HMB-45 confirmed the specificity of HMB-45 for melanocytes and demonstrated that melanocytes and Langerhans cells are nonoverlapping populations. Melanocytes were present in the embryonic epidermis in relatively high numbers (mean value of 1050 cells/mm2); they increased in density to 2300 cells/mm2 during the late first trimester and early second trimester, then declined during later stages of development to a density of 800 cells/mm2, within the range of values for the newborn child and young adult. Equivalent numbers of melanocytes were recognized by silver staining and with the HMB-45 antibody in an 87 d EGA test sample, indicating that HMB-45 reacted with the total melanocytic population. Melanocytes appeared to be distributed in epidermal sheets in a regular pattern. Statistical tests used to evaluate the randomness of a population revealed a tendency toward a non-random distribution in specimens younger than 80 d EGA, just prior to appendage formation and epidermal stratification into multiple layers, however there was variability in the degree of randomness for any given age. The results of this study have closed the gap in timing between the conclusion of neural crest formation and migration (around 6 weeks) and the appearance of melanocytes in the skin between 40–50 d EGA.
Besides decreasing the number of secretory melanocytes in the hair follicle, X-irradiation can cause change in the length of dendrites, decrease in the secretion of pigment granules, change in the color of melanin granules, and alteration in the distribution of melanin in the hair.Graying or lightening of hair color is often caused by a shortening of the dendrites, which alters the balance of pigment in the hair. Decreased dendrite length reduces the quantity of pigment in the hair cortex, but does not greatly alter the quantity of pigment in the medulla. This type of graying can be induced by X-irradiation and by genetic change. It also occurs cyclically during the growth of normally pigmented hairs.Melanocytes in the dermal papilla of the dilute-black rabbit follicle give off granules of melanin to the connective tissue ground substance and to the dermal papilla cells. This is a rare example of melanin granule secretion, and possibly cytocrine activity, taking place in the absence of the usual melanocyte-epithelial relationship.In the rabbit hair follicle the secretion of pigment was studied in melanocytes that completely lack dendrites. In these cells, the cytocrine transfer of melanin involves the budding of granules from the smooth surface of the melanocyte, with the simultaneous engulfing of the granules by adjacent epithelial cells. This suggests that the dendrite is not an essential device for carrying out the transfer of melanin. In hair follicles of the rabbit, dendrites appear to have three important functions: they greatly increase the surface area of the secretory membrane and thus facilitate pigment granule transfer, they control hair color intensity by regulating the distribution of pigment in the developing hair, and they may help to anchor the melanocyte to the dermal papilla or “basement membrane.”By tracing the flow of pigment granules secreted by single melanocytes, the relative movements of hair cells and melanocytes can be demonstrated in the growing follicle of the rabbit. This type of study indicates that secretory melanocytes are not positioned in or held by the bulb epithelium, as has previously been believed. Instead, they adhere to the dermal papilla, to the “basement membrane” of the hair follicle bulb, or to both. Actually, there is no stable region of epithelium that can hold or anchor the secretory melanocytes. All the epithelial cells bordering the upper part of the dermal papilla migrate around the melanocytes, pick up granules of pigment, and then differentiate into the medulla of the hair. These observations do not disprove the idea that pigment cells migrate back and forth between the hair follicle bulb and dermal papilla during the growth cycle, but they do indicate that it is unnecessary to postulate such movements.Large changes occur in the morphology and physiology of the melanocytes and epithelial cells of the ahir follicle during the period of hair growth (anagen VI or metagen). When the hair begins to form, a minimum number of melanocytes appears at the bulb-papilla interface, and long dendrites from these cells deliver pigment to both the medulla and cortex of the hair. As the hair increases in width the dermal papilla and hair follicle bulb enlarge, and many new melanocytes start to synthesize the additional melanin needed to maintain the color of the hair. When the narrow basal part of the hair begins to grow, the dermal papilla and hair follicle bulb shrink to a minimal size once more, and many of the melanocytes disappear. The dendrites of the remaining melanocytes shorten, and a minimum amount of pigment is delivered to only the medulla or central part of the hair.
Both aging and sun exposure have well-documented effects on the human melanocyte system. Paired biopsies of habitually exposed and nonexposed skin from adjacent anatomic sites were obtained from 8 donors aged 28 to 80 yr in order to study the combined effect of chronic actinic irradiation and chronologic aging. Density of dopa-positive melanocytes was roughly twofold higher in the exposed than in the nonexposed skin at all ages, suggesting an irreversible effect of sun exposure. Melanocyte density declined approximately 6 to 8% of the surviving population per decade in both sites. Dopa-positivity of individual melanocytes was consistently greater in the chronically exposed skin than in the nonexposed skin of the same subject and did not vary with age. These data strengthen and expand earlier observations of age-related melanocyte changes, and explain the apparent paradox of a generalized increase in pigmentation and simultaneous decrease in melanocyte density which frequently accompany advancing age. In addition, the present study suggests that the principal effect of chronic sun exposure on the human pigmentary system is not premature "aging" as currently recognized histologically, but rather activation and/or proliferation of the exposed melanocytes.
In order to determine whether amelanotic melanocytes are present in senile white hair, we attempted to detect tyrosinase mRNA and its protein using in situ hybridization and immunohistochemical staining. Specifically stained cells containing tyrosinase mRNA or its protein were detected by each technique in 7/23 (30.4%) or 4/14 (28.6%) senile white hairs, respectively. These cells were located in the outer root sheath between the hair-bulb and the infundibulum. Silver staining was used to determine whether melanin was present within the outer root sheath of the senile white hair. Because none of the 21 white hairs tested showed specific staining within the outer root sheath, the absence of melanin was confirmed. Thus our results suggest the presence of amelanotic melanocytes within the outer root sheath of senile white hair.
We consider some of the problems involved in current discussions on stem cells in adult mammalian tissues. The present concepts involve a number of pitfalls, weaknesses and logical, semantic and classification problems. This indicates the necessity for new and well-defined concepts that are amenable to experimental analysis. One of the major difficulties in considering stem cells is that they are defined in terms of their functional capabilities which can only be assessed by testing the abilities of the cells, which itself may alter their characteristics during the assay procedure: a situation similar to the uncertainty principle in physics. The terms that describe stem cell functions are often not well defined and are used loosely, which can lead to confusion. If such context-dependent interactions exist between the manipulation and measurement process and the challenged stem cells, the question of, for example, the number of stem cells, in a tissue has to be posed in a new way. Rather than obtaining a single number one might end up with various different numbers under different circumstances, all being complementary. This might suggest that stemness is not a property but a spectrum of capabilities from which to choose. This concept might facilitate a reconciliation between the different and sometimes opposing experimental results. Given certain experimental evidence, we have attempted to provide a novel concept to describe structured cell populations in tissues involving stem cells, transit cells and mature cells. It is based on the primary assumption that the proliferation and differentiation/maturation processes are in principle independent entities in the sense that each may proceed without necessarily affecting the other. Stem cells may divide without maturation while cells approaching functional competence may mature but do not divide. In contrast, transit cells divide and mature showing intermediate properties between stem cells and mature functional cells. The need to describe this transition process and the variable coupling between proliferation and maturation leads us to formulate a spiral model of cell and tissue organisation. This concept is illustrated for the intestinal epithelium. It is concluded that the small intestinal crypts contain 4-16 actual stem cells in steady state but up to 30-40 potential stem cells (clonogenic cells) which may take over stem cell properties following perturbations. This implies that transit cells can under certain circumstances behave like actual stem cells while they undergo maturation under other conditions. There is also evidence that the proliferation and differentiation/maturation processes are subject to controls that ultimately lead to a change in the spiral trajectories.(ABSTRACT TRUNCATED AT 400 WORDS)
Inconsistent with the view that hair follicle stem cells reside in the matrix area of the hair bulb, we found that label-retaining cells exist exclusively in the bulge area of the mouse hair follicle. The bulge consists of a subpopulation of outer root sheath cells located in the midportion of the follicle at the arrector pili muscle attachment site. Keratinocytes in the bulge area are relatively undifferentiated ultrastructurally. They are normally slow cycling, but can be stimulated to proliferate transiently by TPA. Located in a well-protected and nourished environment, these cells mark the lower end of the "permanent" portion of the follicle. Our findings, plus a reevaluation of the literature, suggest that follicular stem cells reside in the bulge region, instead of the lower bulb. This new view provides insights into hair cycle control and the possible involvement of hair follicle stem cells in skin carcinogenesis.
We studied tyrosinase activity from human hairbulbs from 51 subjects, aged 5-72 years. We used anagen hairbulbs and grouped the subjects according to hair colour. We did not observe an age-dependent fall in hairbulb tyrosinase activity. We observed considerable inter-individual variation in activity, with a range of 8-342 pmol DOPA formed/three hairbulbs/30 min. The mean tyrosinase activity from red hairbulbs was significantly higher than the mean for the other hair colours. White hairbulbs did not express tyrosinase activity, and specific antibodies to tyrosinase were used to establish that tyrosinase antigen was absent from white hairbulbs.
GREYING of hair is probably the most obvious sign of ageing in man. To
determine whether or not its onset and progress are influenced by hair
colour we have examined a sample of Australians.
We examined keratins 19 and 8 in extracted human hair follicles using monoclonal antibodies Ks19.1 and CAM5.2, respectively. Ks19.1 reactivity was found in the bulge and infundibulum. Ks19.1(+) cells were dense in the bulge of vellus and intermediate hair follicles. The intact bulge of terminal hair could not be extracted, but the presence of Ks19.1(+) cells was confirmed in transverse sections. Infundibular Ks19.1(+) cells exhibited a dense network pattern of staining in terminal hair follicle, but only a few cells were labeled in vellus and intermediate hair follicles. CAM5.2(+) cells, i.e., Merkel cells, were found in the same locations as Ks19.1(+) cells but were less dense. These patterns of distribution and staining density were not influenced by different phases of hair cycle. Sequential staining of Ks19.1 and CAM5.2 in the same hair follicle demonstrated that the same cells could be reactive for both. However, considering the large number of Ks19.1(+) cells and rather small number of CAM5.2 in the same locations, it was assumed that only a subset of Ks19.1(+) cells are Merkel cells. It was postulated that the bulge area of human adult hair follicles houses embryonic pluripotential cells characterized by stem cells and post-stem cells and that the Merkel cells in the bulge area arise from these immature cells and may play a role in the maintenance and stimulation of this group of immature cells.
The distribution of Merkel cells in fetal and adult terminal hair follicles of human scalp was studied immunohistochemically using cytokeratin (CK) 20 as a specific Merkel cell marker. In hair follicles of adult scalp, abundant Merkel cells were found enriched in two belt-like clusters, one in the deep infundibulum and one in the isthmus region. No Merkel cells were found in the deep follicular portions including the bulb, or in the dermis. In early fetal hair follicles (bulbous peg stage), Merkel cells were only detected in the basal layer of the developing infundibulum but not in deeper follicular areas. In later stages, Merkel cells were also present in the isthmus and bulge. No Merkel cells were seen in the dermis around developing hair follicles. Nerve growth factor receptor was not only present in nerves but was found to be widely distributed within fetal skin. In adult skin, this receptor was localized to the basal cell layers of the outer root sheath of the bulb and the suprabulbar area, but was not detectable in the areas containing Merkel cells. The present study localizing Merkel cells within the permanent hair follicle structures close to their possible stem cells suggests that they have paracrine functions.
The phototrichogram is a non-invasive technique by which, on the same precise area of the scalp, each individual hair may be identified, and its current growth phase established. This technique was used to study the duration of hair cycles in 10 male subjects, balding and non-balding, by observations at monthly intervals over a period of 8-14 years. The accumulated data served to characterize the effects of ageing in these subjects: a reduction in the duration of hair growth and in the diameter of hair shafts, most evident in the thickest hairs, and a prolongation of the interval separating the loss of a hair in telogen and the emergence of a replacement hair in anagen. These various aspects of ageing of scalp hair contribute to its progressive overall impoverishment. They resemble those observed in the course of male-pattern balding, although their development is less marked.
It is believed that DOPA-negative melanocytes in the outer root sheath of the human hair follicle are activated, become identifiable by DOPA staining, and migrate into the epidermis during the repigmenting phase of vitiligo. These cells are difficult to identify, however, and otherwise have not been characterized. These cells are readily identified by immunofluorescence, immunohistochemistry, and immunoelectronmicroscopy using the antibodies NKI/beteb and A4F11, which recognize premelanosome-related antigens. The majority of the outer root sheath melanocytes were found in the mid to the upper portion of the hair follicle. Double staining revealed that these cells were distinct from HLA-DR-bearing dendritic cells. Further immunohistochemical investigation using alpha-PEP-7, alpha-PEP-1, or TMH-1 and alpha-PEP-8 antibodies revealed that outer root sheath melanocytes cannot be identified by antibodies to tyrosinase, TRP-1, or TRP-2, respectively. These cells also did not react with HMB45 antibody, which recognizes a melanosome-associated cytoplasmic antigen. We believe that the inactive outer root sheath melanocytes contain some of the early structural proteins but not any of the enzymatic proteins necessary for melanogenesis. Therefore, activation is the process whereby outer root sheath melanocytes acquire all of the structural and enzymatic proteins necessary for melanogenesis.
We have purified hematopoietic stem cells (HSCs) from the bone marrow of old mice and compared their properties to HSCs in young and middle-aged mice. Single, reconstituting HSCs (by limit dilution) from old and young mice exhibited indistinguishable progenitor activities in vivo. HSCs were five times as frequent in the bone marrow of old mice; however, HSCs from old mice were only one-quarter as efficient at homing to and engrafting the bone marrow of irradiated recipients. HSCs in young and middle-aged mice rarely were in the S/G2/M phases of the cell cycle, but HSCs in old mice were frequently in cycle. We speculate that the unexpected proliferation of HSCs in old mice might be related to the increased incidence of leukemia in old mice. HSCs change with age, but it is unknown whether these changes are determined intrinsically or caused by the aging of their environment.
The transition from the growth phase (anagen) to the involution phase (catagen) involves profound morphological changes in the human hair follicle. Club hair and epithelial column formation, for example, are key features of the catagen phase, which result in the disruption of physical interaction between the bulb and the dermal papilla. However, the dynamics and tissue remodelling that occur during this involution process remain largely unknown. Using monoclonal antibodies directed against K14 keratin, trichohyalin, transglutaminase I, desmoglein and Ki67 antigen, we followed the movements of each of the main hair follicle compartments during the onset of catagen. Our results indicate that the inner root sheath is an early target in this process, suggesting a key role for this compartment in the maintenance of hair follicle homeostasis.
Using immunohistochemical techniques, we mapped and quantified the distribution of Langerhans cells (LCs) within the follicular epithelium of normal human skin in serial horizontal sections. Ten skin biopsies from disparate, disease‐free sites from individuals of various skin types were stained with antibody to CD1a. LCs concentrated in the infundibular epithelium (x=16.16 cells), including the follicular bulge, and extended into the germinative sebaceous epithelium (x=8.84). In contrast, rare LCs (x=1.06) were observed in the follicular epithelium below the entry of sebaceous glands into the follicle. LCs were absent in bulbar epithelium.
This infundibulocentric distribution of LCs corresponds to the pattern of follicular inflammation in the scarring folliculitides of lupus erythematosus and lichen planopilaris, as well as allogeneic graft versus host reaction and infundibulofolliculitis of atopy. Follicular LCs may act as the trigger and/or target for these T cell‐mediated inflammatory processes.
Current knowledge on the regulation of mammalian pigmentation at the genetic and biochemical level, and constituents that participate in melanosomal organization, is summarized. Approximately 25% of the more than 80 genes known to regulate pigmentation in mammals have been cloned and characterized to date. Almost half of those encode proteins that localize, either specifically or nonspecifically, to melanosomes; mutations in those genes generally lead to phenotypic changes in pigmentation as well as in other pleiotropic changes. The expression and function of these proteins not only affects phenotypic appearance, but also the properties of melanins, especially their photoprotective characteristics. Because many of those melanosomal proteins also serve as melanoma-specific targets, regulation of their expression has dramatic implications for immune targeting of malignant melanoma.
The human hair cycle is characterized by successive phases of growth and involution that imply tissue regression and regeneration. As a consequence, the hair melanin unit has to be renewed in a cyclic manner. Actually, the behavior of human hair follicle melanocytes throughout the hair cycle has been poorly studied. Thus, the origin of melanocytes present in the bulb after human hair regeneration is still not clarified, and neither are the events that control the melanin biosynthesis activity in the human hair bulb. In this study, we showed at the cellular level that in human pigmented hair follicles, the expression of tyrosinase and tyrosinase-related protein-1 (TRP-1) was detectable during the anagen phases III/IV through VI, only in those melanocytes which were located in the bulb. During the catagen phase, the two evaluated melanogenic enzymes were detectable no more, although melanocytes were still present in the preceding bulbar area. The epithelial column of catagen follicles and the capsule of telogen follicles also contained inactive melanocytes as evidenced by pMel-17 labeling. At the induction of a new anagen hair follicle, some melanocytes were committed to cell division, but only when located in the nascent bulb close to the dermal papilla. Our results emphasize the close relationship between melanogenesis and the hair cycle and suggest that in humans, melanogenesis is restricted to anagen hair follicles not because of the regulation of tyrosinase activity, but because of melanogenic enzyme expression, e.g., tyrosinase and TRP-1. Furthermore, the fact that in the newly developing anagen hair follicles, cell-division commitment and tyrosinase and TRP-1 expression were observed in melanocytes only when located in the nascent bulb suggests a highly regio-specific melanocyte stimulation in early the anagen phase.
The location of follicular and epidermal stem cells in mammalian skin is a crucial issue in cutaneous biology. We demonstrate that hair follicular stem cells, located in the bulge region, can give rise to several cell types of the hair follicle as well as upper follicular cells. Moreover, we devised a double-label technique to show that upper follicular keratinocytes emigrate into the epidermis in normal newborn mouse skin, and in adult mouse skin in response to a penetrating wound. These findings indicate that the hair follicle represents a major repository of keratinocyte stem cells in mouse skin, and that follicular bulge stem cells are potentially bipotent as they can give rise to not only the hair follicle, but also the epidermis.
The visual appearance of humans derives predominantly from their skin and hair color. The phylogenetical pathway underling this phenomenon is called melanogenesis and results in the production of melanin pigments in neural crest-derived melanocytes, followed by its transfer to epithelial cells. While melanin from epidermal melanocytes clearly protects human skin by screening harmful ultraviolet radiation, the biologic value of hair pigmentation is less clear. In addition to important roles in social/sexual communication, one potential benefit of pigmented scalp hair in humans may be the rapid excretion of heavy metals, chemicals, toxins from the body by their selective binding to melanin.
The upper region of the outer root sheath of vibrissal follicles of adult mice contains multipotent stem cells that respond to morphogenetic signals to generate multiple hair follicles, sebaceous glands, and epidermis, i.e., all the lineages of the hairy skin. At the time when hair production ceases and when the lower region of the follicle undergoes major structural changes, the lower region contains a significant number of clonogenic keratinocytes, and can then respond to morphogenetic signals. This demonstrates that multipotent stem cells migrate to the root of the follicle to produce whisker growth. Moreover, our results indicate that the clonogenic keratinocytes are closely related, if not identical, to the multipotent stem cells, and that the regulation of whisker growth necessitates a precise control of stem cell trafficking.
Up to now, the localization of stem cells in human anagen hair follicle relied on three complementary approaches; namely, detection of slow cycling cells, detection of high colony forming cells, and differential immunohistochemical staining. These techniques, however, gave conflicting results since stem cells were localized either as long label retaining cells in the so-called bulge area or as high colony forming cells in the lower third of the follicle. In the present study we investigated the expression of cytokeratin 19, a marker for putative stem cell-containing epithelial compartments, in order to characterize stem cell distribution in the human hair follicle throughout the hair cycle. We found that anagen human hair follicles contain two distinct reservoirs for stem cells located in the upper and lower thirds of the follicle. These two reservoirs fuse during the catagentelogen transition phase and individualize again in the newly forming anagen hair follicle.
A current disturbing trend in stem cell biology is the abandonment of rigorous definitions of stem and progenitor cells in favor of more ambiguous, all-encompassing concepts. However, recent studies suggest that there are consistent, functional differences in the biology of these two cell types. Admittedly, it can be difficult to harmonize the in vivo and in vitro functional differences between stem and progenitor cells. Nonetheless, these distinctions between cell types should be emphasized rather than ignored, as they can be used to test specific hypotheses in neural stem cell biology.
The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.
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