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Prevention of hair graying by factors that promote the growth and differentiation of melanocytes
Abstract
Epidermal melanocyte precursors migrate into developing hair follicles to form the melanocyte stem cell system required to supply pigmented melanocytes necessary for hair pigmentation in repetitive hair cycles. Hair graying is caused by irreversible defects in the self-renewal and/or development of follicular melanocyte stem cells in the hair follicles. To investigate the mechanism(s) of hair graying during the normal aging process, we established a hair graying model in mice by repeatedly plucking or shaving trunk hairs. We repeatedly plucked or shaved trunk hairs to induce and accelerate the hair graying and counted the gray hairs. By using this functional model of hair graying in mice, we assessed the effects of genes known to affect melanocyte development, such as Kitl, hepatocyte growth factor (HGF) and endotheline 3 (ET3). After increasing the total numbers of cumulative hair cycles by plucking or shaving, we observed a significant increase in the gray hair of C57BL/6 mice. Kitl expression in the skin was the most effective for preventing hair graying and a significant effect was also confirmed for HGF and ET3 expression. The repeated hair plucking or shaving led to hair graying without any genetic lesion. Kitl is a more effective factor for prevention of hair graying than HGF or ET3. Our simple model of hair graying may provide a basic tool for screening the molecules or reagents preventing the progression of hair graying.
... One-time hair plucking induces melanogenesis in the regenerating hair bulb. The consequent hair hyperpigmentation and repeated hair plucking but not shaving cause inflammation in the hair follicles and injure the McSCs, leading to hair graying (Endou et al., 2014;Li and Hou, 2018;Iida et al., 2020). After five hair cycles (approximately five times of hair plucking), hair graying was observed in C57BL/6 mice (Endou et al., 2014); this repeated hair pluckinginduced mouse model is the closest to age-related human hair graying. ...
... The consequent hair hyperpigmentation and repeated hair plucking but not shaving cause inflammation in the hair follicles and injure the McSCs, leading to hair graying (Endou et al., 2014;Li and Hou, 2018;Iida et al., 2020). After five hair cycles (approximately five times of hair plucking), hair graying was observed in C57BL/6 mice (Endou et al., 2014); this repeated hair pluckinginduced mouse model is the closest to age-related human hair graying. ...
... Its functions manifest as white spotting or hair graying in Kit and Kitl mutant mice (Tosaki et al., 2006). Heterozygous loss-of-function mutants (Kit W/þ and Kit V620A tg1/þ ) have white spots in their coats and are more susceptible to hair graying through X-ray irradiation or repeated hair plucking than the wild type (WT) (Aoki et al., 2011;Endou et al., 2014). In contrast, exogenous expression of Kitl in the skin prevented X-ray-induced hair graying (Aoki et al., 2011). ...
Hair graying in mice is caused by various injuries such as X-ray radiation and repeated plucking that ultimately damage melanocytes and their stem cells (McSCs). In X-ray-induced hair graying, injuries first manifest as a loss-of-niche function of hair follicular keratinocyte stem cells (HFKSCs) to maintain McSCs. Thus, we hypothesized that HFKSCs could be a practical target to prevent hair graying. Here, we investigated the in vivo effect of the flavonoid hydroxygenkwanin (HGK), which has been shown to exert the best protection on human epidermal keratinocytes against in vitro X-ray-induced cytological effects, using X-ray-induced and repeated hair plucking-induced hair graying mice models. We found that HGK exerted a remarkable effect in preventing hair graying; however, when receptor tyrosine kinase Kit-mutant mice were used, no prevention effect was observed. Therefore, we propose that Kit signaling might be involved in the HGK-induced protective effect against hair graying.
... However, in this patients treated with this kind of therapy, hair repigmentation was considered as a good response marker. Endou et al., 2014 Effects of genes indicated to affect melanocyte development is shown in a functional model of mouse' hair graying; Kitl, hepatocyte growth factor (HGF) and endotheline 3 (ET3) are examples of the genes among them Kitl is considered as a more efficient factor in preventing canities, compared to HGF or ET3. ...
... In this review, we found that biologic-immunotherapy anti-melanoma/anti-cancer agents [15][16][17][18][19][20] , chemotherapy agents [21][22][23][24][25][26][27][28][29][30][31] , biologic anti-psoriatic agents33-38, retinoids [32][33][34][35][36][37] , and other drugs like clofazimine [38] , interferon and ribavirin [39] , indinavir [40] , latanoprost48, systemic steroid49, and thyroid hormone therapy50 have been reported being in association with hair repigmentation. ...
... Stem cell factors, hepatocyte growth factors, and endothelin-3 can be potentially triggered by inhibition of PD1 and, consequently, recruit inactive melanocyte stem cells to produce pigments in the hair follicles. [14,16,39] . ...
Background and Objective: Hair whitening is among important cosmetic problems in both genders but more annoying between women which necessitates more research about hair repigmenting methods or probable therapeutic drugs. The objective of this research was to review the mechanisms of hair pigmentation as well as the drug-related hair repigmentation. Methods: In this review article, we searched PubMed, Medline and Google scholar databases and reviewed all related articles in this area (hair repigmentation) since the reversal of canities has been an important cosmetic concern many years ago. Results: No reports of changes of hair color have been identified with lamivudine in the present research. Herein can be reported as the first case of hair repigmentation following the use of lamivudine. Conclusion: We reported a case of hair pigmentation with lamivudine for the first time that could be a desirable drug-induced side effect, also review all related articles about hair repigmention or reversal of canities. By research on probable mechanisms of drug-induced hair repigmentation, we may achieve a therapeutic strategy of hair graying as an important and highly prevalent cosmetic concern. Keywords: Lamivudine; hair repigmentation; reversal canities; drug-induced, review
... Therefore, model animals that progressively develop hair graying with aging, which was defined as age-related hair graying in this study, are useful tools for analyzing the mechanisms of hair graying. To our knowledge, more than 10 kinds of genetically modified mice with hair graying have been reported (Kurita et al., 2005;Moriyama et al., 2006;Tanimura et al., 2011), while wild-type mice with hair graying are very limited (Endou et al., 2014;Inoue-Narita et al., 2008;Nishimura et al., 2005). However, analysis of age-related hair graying is difficult even in the model mice because many of the animals are models for premature hair graying with a limited life span rather than age-related hair graying. ...
... Senescence markers including p16 ink4a and senescence-associated beta-galactosidase (SA-ßgal) have been established in previous studies (Baker et al., 2011;Ressler et al., 2006). Correspondingly, hair graying is also promoted through depilation (Endou et al., 2014;Inoue-Narita et al., 2008). ...
... Recent studies on hair graying in mice have shown that a microenvironment of MSCs, known as a niche of MSCs, is formed by KSCs and plays a crucial role in survival of MSCs. Notch (Moriyama et al., 2006), stem cell factor (SCF) (Endou et al., 2014), and transforming growth factor beta (TGF-ß) signals (Nishimura et al., 2010) from follicular KSCs have been reported to be essential for the development and maintenance of follicular MSCs. Interaction between endothelins (ETs) in follicular KSCs and endothelin receptor B (Ednrb) in follicular MSCs has also been reported to promote proliferation, expansion, and differentiation of MSCs in young mice stably expressing ß-catenin in keratin 15-positive keratinocytes (Rabbani et al., 2011;Takeo et al., 2016). ...
Hair graying is a representative sign of aging in animals and humans. However, the mechanism for hair graying with aging remains largely unknown. In this study, we found that the microscopic appearance of hair follicles without melanocyte stem cells (MSCs) and descendant melanocytes as well as macroscopic appearances of hair graying in RET‐transgenic mice carrying RET oncogene (RET‐mice) are in accordance with previously reported results for hair graying in humans. Therefore, RET‐mice could be a novel model mouse line for age‐related hair graying. We further showed hair graying with aging in RET‐mice associated with RET‐mediated acceleration of hair cycles, increase of senescent follicular keratinocyte stem cells (KSCs), and decreased expression levels of endothelin‐1 (ET‐1) in bulges, decreased endothelin receptor B (Ednrb) expression in MSCs, resulting in a decreased number of follicular MSCs. We then showed that hair graying in RET‐mice was accelerated by congenitally decreased Ednrb expression in MSCs in heterozygously Ednrb‐deleted RET‐mice [Ednrb(+/−);RET‐mice]. We finally partially confirmed common mechanisms of hair graying with aging in mice and humans. Taken together, our results suggest that age‐related dysfunction between ET‐1 in follicular KSCs and endothelin receptor B (Ednrb) in follicular MSCs via cumulative hair cycles is correlated with hair graying with aging.
... 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]. ...
... 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]. Furthermore, at least in the case of radiation-induced hair greying, the primary effect involves follicular keratinocytes rather than loss of MSC proliferation [18]. ...
... Because the human head hair cycle repeats approximately every seven years, the hair starts to grey after undergoing around five complete hair cycles [27,34]. Grey hair has also been observed in normal C57BL/6 mice after five hair cycles, whereas this hair cycledependent hair greying is prevented in transgenic mice expressing the melanocyte stimulatory factors Kitl, EDN3 and HGF in the basal layer of the skin [17]. It is therefore possible that the topical application of Ea extract may activate these signalling factors. ...
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.
... Rather, it induces the formation of more melanosomes in the regenerating hair bulb and consequently hair hyperpigmentation. However, repeated hair plucking leads to loss of McSCs and hair graying (Endou et al., 2014). The differences between single and repeated hair plucking may be Collectively, all of these injuries regulate proliferation, differentiation, and migration of McSCs in hair follicles. ...
... suggest that KIT signaling exerts a radioprotective effect on McSCs. Similarly, robust expression of Kitl from the same promoter can preserve McSCs and rescue hair graying caused by wound healing or repeated plucking (Endou et al., 2014;Yuriguchi et al., 2016 Conditional knockout of both B-Raf and C-Raf in mice does not affect early melanocyte lineage development but leads to absence of McSCs in the hair bulge and to hair graying (Valluet et al., 2012). ...
... dermis hyperpigmentation in neonatal mice (Aoki et al., 2009). In hair follicles, forced expression of Edn3 shows a slight effect on preserving McSCs and rescuing hair graying in response to wound injury or repeated plucking (Endou et al., 2014;Yuriguchi et al., 2016). ...
Somatic stem cells are regulated by their niches to maintain tissue homeostasis and repair throughout the lifetime of an organism. An excellent example to study stem cell/niche interactions is provided by the regeneration of melanocytes during the hair cycle and in response to various types of injury. These processes are regulated by neighboring stem cells and multiple signaling pathways, including WNT/β‐catenin, KITL/KIT, EDNs/EDNRB, TGFβ/TGFβR, α‐MSH/MC1R, and Notch signaling. In this review, we highlight recent studies that have advanced our understanding of the molecular crosstalk between melanocyte stem cells and their neighboring cells, which collectively form the niche microenvironment, and we focus on the question of how McSCs/niche interactions shape the responses to genotoxic damages and mechanical injury.
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... Genetic studies in horses (Marklund et al. 1999;Grilz-Seger et al. 2020;Voß et al. 2020), cattle (Charlier et al. 1996;Seitz et al. 1999), pigs Lim et al. 2011;Fontanesi and Russo 2013), and goats (Talenti et al. 2018) have shown a shared association between roan and the candidate genes KIT proto-oncogene, receptor tyrosine kinase (KIT) or KIT ligand (KITLG). The biological cause of roan is predicted to be the premature depletion of melanocyte stem-cells (melanoblasts) within hair follicles, leading to gradual and permanent depigmentation of individual fibres (Hachiya et al. 2009;Endou et al. 2014;Bian et al. 2019;Qiu et al. 2019). KIT and KITLG are essential signalling proteins involved in migration, differentiation, maturation, and survival of melanoblasts (Besmer et al. 1993;Wehrle-Haller 2003). ...
... pigment intensity, with a higher copy number correlating to higher intensity (Weich et al. 2020). Since the early depletion of hair follicle melanoblasts, thus causing gradual and permanent depigmentation, is the probable cause of roan (Hachiya et al. 2009;Endou et al. 2014;Bian et al. 2019;Qiu et al. 2019), it is plausible that a related mechanism may also contribute to pigment intensity. Although we did not account for variation in pigment intensity in this work, the observed A copy-version counts were higher among the Australian (unrelated) roans than the US roans (related). ...
Context The alpaca roan pattern is characterised by white and coloured fibre interspersed together, with a distinctive lighter body and darker extremities, and commonly is believed to be inherited in an autosomal dominant manner. It is of interest to the alpaca fibre industry as it causes ‘contamination’ of coloured fibre with white fibres, but cannot be detected in white or light fawn animals. Other livestock species, such as horses, cattle, goats, and pigs, exhibit comparable phenotypes, which are associated with candidate variant(s) in either KIT or KITLG. Aims To identify a region or regions of the genome that is/are causative of the roan pattern in alpacas. Methods We conducted a genome-wide association study (GWAS) by using 13 roan and 14 non-roan alpacas sampled from the USA, Australia, and New Zealand. Regions of genome-wide significance were examined for variants that correlated with the roan phenotype. Key results A novel candidate single-nucleotype polymorphism (SNP; Super-Scaffold_15:39 742 851T > A), located 272 kb upstream of KITLG, was identified in 1 of 12 regions with genome-wide significant association (P ≤ 5 × 10−8). We identified the candidate SNP-containing region (Super-Scaffold_15:39 742 096–39 887 419) to be a 145 kb copy number variant (CNV) that is likely to be a tandem duplication. All 13 roan alpacas had one or two copies of the roan-associated T allele and all except three non-roans had zero copies. Furthermore, we determined the Mendelian inheritance of copy number haplotypes and their allelic composition in a roan and a non-roan family. Conclusions Our data support the hypothesised autosomal incomplete dominant mode of inheritance of the roan pattern in alpacas and suggests that the effect of the T allele CNV version is likely to be suppressed when in cis with the A allele CNV version. However, additional verification is required to validate the finding and determine the functional effect. Implications Identification of the cause, or a marker for roan pattern will allow alpaca breeders to select for or against the roan pattern, even when the phenotype is hidden, and therefore increase production output and profitability.
... 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. ...
... Age-related hair graying correlates with a decrease in the number of MSC per follicle. 2,3) It has been demonstrated that the cause of mouse hair graying due to X-ray radiation was not a direct effect on MSC, but a loss of their niche function from hair follicular keratinocyte stem cells (HFKSC). 4) Therefore, HFKSC comprising the niche for MSC 4,5) may constitute an additional cause of hair graying. ...
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
... MITF is colocalized with pMel17 in amelanotic melanocytes in the outer root sheath and hair matrix. These factors are absent in most hair follicles of human between age 80 and 90 131 HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation 133,134 . SCF, HGF, and End3 are effective factors for preventing hair graying. ...
... SCF, HGF, and End3 are effective factors for preventing hair graying. Among these factors, SCF seems to function more effectively in preventing hair graying 134 . Indeed, inhibition of SCF/c-kit signaling by c-Kit antibody induces gray hairs formation through reducing the number of hair follicle melanocytes 135 . ...
Skin evolves essential appendages and indispensable types of cells that synergistically insulate the body from environmental insults. Residing in the specific regions in the skin such as epidermis, dermis and hair follicle, melanocytes perform an array of vital functions including defending the ultraviolet radiation and diversifying animal appearance. As one of the adult stem cells, melanocyte stem cells in the hair follicle bulge niche can proliferate, differentiate, and keep quiescence to control and coordinate tissue homeostasis, repair, and regeneration. In synchrony with hair follicle stem cells, melanocyte stem cells in the hair follicles undergo cyclic activation, degeneration, and resting phases, to pigment the hairs and to preserve the stem cells. Disorder of melanocytes results in severe skin problems such as canities, vitiligo, and even melanoma. Here, we compare and summarize recent discoveries about melanocyte in the skin, particularly in the hair follicle. A better understanding of the physiological and pathological regulation of melanocyte and melanocyte stem cell behaviors will help to guide the clinical applications in regenerative medicine.
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... Depletion of follicular MSCs causes persistent loss of functional melanocytes from the hair matrix [5,6], leading to graying, with no recovery expected. Gray hair-containing follicles that are depleted of MSCs increase along with the cumulative progression of the hair cycle with age [6]. ...
... Depletion of follicular MSCs causes persistent loss of functional melanocytes from the hair matrix [5,6], leading to graying, with no recovery expected. Gray hair-containing follicles that are depleted of MSCs increase along with the cumulative progression of the hair cycle with age [6]. Loss of proliferative ability of follicular keratinocytes, rather than MSCs, has also been reported in radiation-induced hair graying [7], suggesting the involvement of keratinocytes in hair graying and their potential as a practical target for its prevention. ...
... It is also worth emphasizing the role of growth factors as key regulators of hair follicle homeostasis and melanogenesis [27][28][29][30][31][32]. Indeed, it has been shown that Stem Cell Factor (SCF) expression positively correlates with the rise of tyrosinase activity. ...
... Moreover, SCF is crucial for melanocyte survival during development, and its gene mutation results in unpigmented hairs [27]. Hepatocyte Growth Factor (HGF) is known to promote in vivo survival, proliferation and differentiation of melanocyte precursors [28] and its expression prevents hair greying [29]. It was also reported that Platelet Derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF) both activate melanocyte stem cells, and are efficient for reversal of hair greying [30,31]. ...
Objective
Hair greying (i.e., canities) is a component of chronological aging and occurs regardless of gender or ethnicity. Canities is directly linked to the loss of melanin and increase in oxidative stress in the hair follicle and shaft. To promote hair pigmentation and reduce the hair greying process, an agonist of α‐melanocyte‐stimulating hormone (α‐MSH), a biomimetic peptide (palmitoyl tetrapeptide‐20; PTP20) was developed. The aim of this study was to describe the effects of the designed peptide on hair greying.
Methods
Effect of the PTP20 on the enzymatic activity of catalase and the production of H2O2 by Human Follicle Dermal Papilla Cells (HFDPC) was evaluated. Influence of PTP20 on the expression of melanocortin receptor‐1 (MC1‐R) and the production of melanin were investigated. Enzymatic activity of sirtuin 1 (SIRT1) after treatment with PTP20 was also determined. Ex vivo studies using human micro‐dissected hairs allowed to visualise the effect of PTP20 on the expression in hair follicle of catalase, TRP‐1, TRP‐2, Melan‐A, ASIP and MC1‐R. These investigations were completed by a clinical study on 15 human male volunteers suffering from premature canities.
Results
The in vitro and ex vivo studies revealed the capacity of the examined PTP20 peptide to enhance the expression of catalase and to decrease (30%) the intracellular level of H2O2. Moreover, PTP20 was shown to activate in vitro and ex vivo the melanogenesis process. In fact, an increase in the production of melanin was shown to be correlated with elevated expression of MC1‐R, TRP‐1 and Melan‐A, and with the reduction in ASIP expression. A modulation on TRP‐2 was also observed. The pivotal role of MC1‐R was confirmed on protein expression analyzed on volunteer's plucked hairs after 3 months of the daily application of lotion containing 10 ppm of PTP20 peptide.
Conclusion
The current findings demonstrate the ability of the biomimetic PTP20 peptide to preserve the function of follicular melanocytes. The present results suggest potential cosmetic application of this newly designed agonist of α‐MSH to promote hair pigmentation and thus, reduce the hair greying process.
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... EDN3 is well known for its effects on stimulating the growth and differentiation of melanocyte precursors 1,25,26 . Recently, transgenic overexpression of EDN3 has been reported to prevent hair graying caused by repeatedly epilation 27 , suggesting that EDN3 also affects McSCs. To investigate the effect of EDN3 on McSCs, we isolated DCT+ cells from E16.5 wildtype epidermis and stimulated them with EDN3 or BQ788 (an EDNRB inhibitor). ...
... Indeed, genetic and pharmacological disruption of Ednrb blocks epilation-induced regeneration of epidermal melanocytes, decreases melanocyte proliferation in hair bulbs and reduces skin pigmentation and hair hyperpigmentation. In contrast, transgenic overexpression of EDN3 can prevent hair graying caused by repeated epilation 27 . This role of EDN3/EDNRB signaling can also be observed in epidermal pigmentation following skin wounding. ...
In response to various types of injury, melanocyte stem cells (McSCs) located in the bulge of hair follicles can regenerate mature melanocytes for hair and skin pigmentation. How McSCs respond to injury, however, remains largely unknown. Here we show that after epilation of mice, McSCs regenerate follicular and epidermal melanocytes, resulting in skin and hair hyperpigmentation. We further show that epilation leads to endogenous EDN3 upregulation in the dermal papilla, the secondary hair germ cells, and the epidermis. Genetic and pharmacological disruption of the EDN3 receptor EDNRB in vivo significantly blocks the effect of epilation on follicular and epidermal melanocyte regeneration as well as skin and hair hyperpigmentation. Taken together, these results indicate that epilation induces McSCs activation through EDN3/EDNRB signaling and in turn leads to skin and hair hyperpigmentation. The findings suggest that EDN/EDNRB signaling may serve as a potential therapeutic target to promote repigmentation in hypopigmentation disorders.
... Previous studies established that part of the hair graying process is due to the reduction in melanogenic-active melanocytes in the hair bulb of anagen hair follicles and the increase in oxidative stress in the bulb [1][2][3]. While follicular melanocyte stem cells can self-renew during hair cycles, the eventual loss of melanocyte stem cells is thought to cause hair graying [5,6]. ...
... Intact male and female C57BL6 mice did not show any visibly obvious signs of hair greying over their lifetime, probably because their lifespan was too short for depigmentation to begin in the hair shaft. Based on a previous report demonstrating that repetitive shaving or plucking accelerates hair greying, 9 we applied this method to increase the susceptibility of hair shafts to greying in response to experimental intervention. As expected, neither a single shaving nor waxing session to pluck hair shafts from the back was sufficient to induce hair greying (shaving, 16-week-old males (n = 12) and females (n = 12); plucking, 16-week-old males (n = 52) and females (n = 12)). ...
Depigmentation of hair shafts is a hallmark of human aging. However, it remains unclear how aging causes human hair to grey. Here, we found that a single session of hair plucking via waxing causes hair to grey in castrated mice. Moreover, this hair greying continued for several hair cycles. Given that androgen secretion decreases with age in both male and female humans, the present result suggests that this decrease may contribute to age-related hair greying. In addition, our experimental procedure may represent an effective way to generate a new mouse model of hair greying without the need for genetic engineering.
... The number of pigmented feathers in Almond pigeons also increases with each successive molt, and this effect is more pronounced in males [29,30]. Notably, this phenomenon is the opposite of what is typically observed with pigmentation traits that change throughout the lifespan of an individual, such as vitiligo and graying, which result in a decrease in pigment over time [31][32][33][34][35]. In addition to Almond, at least six other alleles at St lead to varying degrees of depigmentation in pigeons, suggesting that the St locus might be a mutational hotspot [28,36]. ...
Rock pigeons (Columba livia) display an extraordinary array of pigment pattern variation. One such pattern, Almond, is characterized by a variegated patchwork of plumage colors that are distributed in an apparently random manner. Almond is a sex-linked, semi-dominant trait controlled by the classical Stipper (St) locus. Heterozygous males (ZStZ⁺ sex chromosomes) and hemizygous Almond females (ZStW) are favored by breeders for their attractive plumage. In contrast, homozygous Almond males (ZStZSt) develop severe eye defects and often lack plumage pigmentation, suggesting that higher dosage of the mutant allele is deleterious. To determine the molecular basis of Almond, we compared the genomes of Almond pigeons to non-Almond pigeons and identified a candidate St locus on the Z chromosome. We found a copy number variant (CNV) within the differentiated region that captures complete or partial coding sequences of four genes, including the melanosome maturation gene Mlana. We did not find fixed coding changes in genes within the CNV, but all genes are misexpressed in regenerating feather bud collar cells of Almond birds. Notably, six other alleles at the St locus are associated with depigmentation phenotypes, and all exhibit expansion of the same CNV. Structural variation at St is linked to diversity in plumage pigmentation and gene expression, and thus provides a potential mode of rapid phenotypic evolution in pigeons.
... The maintenance and regeneration of the melanocyte population is dependent on MSCs that are located in the bulge and the sub-bulge areas of HF [2,10]. Premature differentiation of bulge MSCs is also observed during physiological hair graying in mice and in humans [11]. Amelanotic MCs (AMMCs) from HFs, which may be MSCs and/or their immediate progenies, were first successfully cultured by Tobin et al. [12] and have been confirmed by other research teams [13,14]. ...
... Following the onset of PHG the graying tends to be progressive and permanent but spontaneous re-pigmentation in the early stages of canities can occur due to melanogenesis in the deactivated bulbar melanocytes [2]. The process leading to normal hair graying may include irreversible defects in the self renewal and/ or development of follicular melanocyte stem cells gradual decrease of melanin production in the affected hair follicle over time and a drop in the catalase enzyme which stops hydrogen peroxide from breaking down melanin [4]. Some studies have linked cases of PHG with a variety of metabolic and degenerative conditions such as myocardial infarction, cancer, osteopenia, stroke, cirrhosis of the liver and gut problems. ...
... While progress is being made on the control of hair graying (Correa-Selm & Grichnik, 2017), the factors required to drive repigmentation in these patients remains a mystery. Repigmentation in these patients may be driven by local changes in the inflammatory response, changes in the cellular milieu, or simply changes in cytokines, such as stem cell factor, hepatocyte growth factor, and endothelin 3, which could potentially be triggered by PD1 inhibition and consequently recruiting inactive melanocyte stem cells to produce pigment in the hair follicle (Endou, Aoki, Kobayashi, & Kunisada, 2014) There is more work to be done but there are increasing clues that it may be pharmacologically possible to restore natural pigmentation to graying hair. ...
... Hair follicular melanogenesis involves, sequentially, the melanogenic activity of follicular melanocytes, the transfer of melanin granules into cortical and medulla keratinocytes, and the formation of pigmented hair shafts [7]. The common aging process of graying hair is caused by defects in or the frailty of melanocytes [8]. There are also several associated diseases, such as vitiligo, that occur when melanin synthesis is impaired because the melanocytes are either absent or no longer function [9]. ...
This study evaluated frequency-dependent effects of extremely low frequency electromagnetic fields (ELF-EMFs) on melanogenesis by melanocytes in vitro. Melanocytes were exposed to 2 mT EMFs at 30-75 Hz for 3 days before melanogenesis was examined. Exposure to ELF-EMFs at 50 and 60 Hz induced melanogenic maturation without cell damage, without changing cell proliferation and mitochondrial activity. Melanin content and tyrosinase activity of cells exposed to 50 Hz were higher than in controls, and mRNA expression of tyrosinase-related protein-2 was elevated relative to controls at 50 Hz. Phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) levels were higher than controls in cells exposed to ELF-EMFs at 50-75 Hz. Immunohistochemical staining showed that melanocyte-specific markers (HMB45, Melan-A) were strongly expressed in cells exposed to EMFs at 50 and 60 Hz compared to controls. Thus, exposure to ELF-EMFs at 50 Hz could stimulate melanogenesis in melanocytes, through activation of p-CREB and p-p38 and inhibition of phosphorylated extracellular signal-regulated protein kinase and phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase. The results may form the basis of an appropriate anti-gray hair treatment or be applied in a therapeutic device for inducing repigmentation in the skin of vitiligo patients.
... As such, the hair coats of aged and young mice are usually quite similar in appearance. However, when mice are forced by repeated depilation to undergo excessive hair cycling, their hair coat greys, suggesting a deleterious impact on melanocyte SCs that are activated along with Bu-HFSCs during regeneration (32). In this regard, it is interesting that the Foxc1-cKO hair coat also greyed as mice aged. ...
Significance
Stem cells (SCs) of the hair follicle (HF) undergo cyclical bouts of activity during which hair regeneration occurs. They reside in a specialized niche, the bulge, which confers upon them extended periods of quiescence. Here, we identify Forkhead box C1 (FOXC1) as a key transcriptional regulator of HFSC activity and bulge maintenance. Loss of FOXC1 reduces the threshold for HFSC activation, causing excessive HFSC usage and dramatically shortening periods between hair growth cycles. Additionally, signs of weakened cellular junctions are seen within the niche, resulting in mechanically induced, premature loss of established hairs along with some SCs. The consequences of these defects are dire for aging animals, which display diminished HFSC niches and a sparse hair coat.
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.
For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations¹, which leads to hair greying in most humans and mice2,3. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli4–8. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.
In mice, coat pigmentation requires a stem cell (SC) system in which the survival, proliferation, and differentiation of melanocytes (MCs) are regulated by microenvironments in hair follicles (HFs). In vitro systems are required to analyze the behavior of single melanocyte stem cells (MCSCs) and their potential to form SC systems in vivo. We describe here an experimental system for the isolation, self-renewal, and differentiation of MCSCs, as well as an in vivo reconstitution assay for assessing their potential. Using Dct(tm1(Cre)Bee)/CAG-CAT-GFP mice, we show that, in the presence of stem cell factor and basic fibroblast growth factor and the XB2 feeder cell line, purified MCSCs can undergo clonogenic proliferation, resulting in c-Kit(low) side scatter(low) cells. In culture, these cells maintain their capacity to differentiate and reconstitute an MCSC system in HFs. As these cells are present in the upper part of the HF near the bulge region, express only low levels of housekeeping genes, and are resistant to neonatal treatment with ACK2, it is likely that only MCSCs that are quiescent in vivo have clonogenic activity in vitro. We also found that MCSCs can be purified from wild-type mice by fluorescent cell sorting and can be characterized in vitro.
Radiation-induced hair graying is caused by irreversible defects in the self-renewal and/or development of follicular melanocyte stem cells in the hair follicles. Kit signaling is an essential growth and differentiation signaling pathway for various cell lineages including melanocytes, and its radioprotective effects have been shown in hematopoietic cells. However, it is uncertain whether Kit signaling exerts a radioprotective effect for melanocytes. In this study, we found that various loss-of-function mutations of Kit facilitate radiation-induced hair graying. In contrast, transgenic mice expressing the ligand for Kit (Kitl) in the epidermis have significantly reduced levels of radiation-induced hair graying. The X-ray doses used did not show a systemic lethal effect, indicating that the in vivo radiosensitivity of Kit mutants is mainly caused by the damaged melanocyte stem cell population. X-ray-damaged melanocyte stem cells seemed to take the fate of ectopically pigmented melanocytes in the bulge regions of hair follicles in vivo. Endothelin 3, another growth and differentiation factor for melanocytes, showed a lesser radioprotective effect compared with Kitl. These results indicate the prevention of radiation-induced hair graying by Kit signaling.
Unlike the thoroughly investigated melanocyte population in the hair follicle of the epidermis, the growth and differentiation requirements of the melanocytes in the eye, harderian gland and inner ear - the so-called non-cutaneous melanocytes - remain unclear. In this study, we investigated the in vitro and in vivo effects of the factors that regulate melanocyte development on the stem cells or the precursors of these non-cutaneous melanocytes. In general, a reduction in KIT receptor tyrosine kinase signaling leads to disordered melanocyte development. However, melanocytes in the eye, ear and harderian gland were revealed to be less sensitive to KIT signaling than cutaneous melanocytes. Instead, melanocytes in the eye and harderian gland were stimulated more effectively by endothelin 3 (ET3) or hepatocyte growth factor (HGF) signals than by KIT signaling, and the precursors of these melanocytes expressed the lowest amount of KIT. The growth and differentiation of these non-cutaneous melanocytes were specifically inhibited by antagonists for ET3 and HGF. In transgenic mice induced to express ET3 or HGF in their skin and epithelial tissues from human cytokeratin 14 promoters, the survival and differentiation of non-cutaneous and dermal melanocytes, but not epidermal melanocytes, were enhanced, apparently irrespective of KIT signaling. These results provide a molecular basis for the clear discrimination between non-cutaneous or dermal melanocytes and epidermal melanocytes, a difference that might be important in the pathogenesis of melanocyte-related diseases and melanomas.
In order to clarify the time of onset of the differentiation of epidermal melanoblasts and melanocytes in C57BL/ 10J mice, pieces of skin were excised on various days after gestation and subjected to the dopa reaction and to the combined dopa- premelanin reaction. Cells positive to the combined dopa- premelanin reaction ( melanoblast -melanocyte population) were first identified on prenatal day 14 in the dorsal and ventral skin, and increased in number until day 17. The population remained constant (about 140 cells/0.1 mm2 for the dorsal skin and about 65 cells/0.1 mm2 for the ventral skin) until postnatal day 4, and then decreased. However, cells positive to the dopa reaction (melanocyte population) were first identified on prenatal day 16 in the dorsal and ventral skin, and increased until postnatal day 4 (about 95 cells/0.1 mm2 for the dorsal skin and about 25 cells/0.1 mm2 for the ventral skin), then gradually decreased and disappeared by day 30. These results indicate that mouse epidermal melanoblasts begin to differentiate on prenatal day 14, and 2 days later tyrosinase activity is induced within the cells.
Mutations at the murine dominant white spotting (KitW) and steel (MgfSl) loci, encoding c-Kit receptor kinase and its ligand respectively, exert developmental defects on hematopoietic cells, melanocytes, germ cells and interstitial cells of Cajal. The expression patterns of steel factor (SLF) observed in the skin and gonads suggest that SLF mediates a migratory or a chemotactic signal for c-Kit-expressing stem cells (melanocyte precursors and primordial germ cells). By targeting expression of SLF to epidermal keratinocytes in mice, we observed extended distribution of melanocytes in a number of sites including oral epithelium and footpads where neither melanocytes nor their precursors are normally detected. In addition, enlarged pigmented spots of KitW and other spotting mutant mice were observed in the presence of the SLF transgene. These results provide direct evidence that SLF stimulates migration of melanocytes in vivo. We also present data suggesting that SLF does not simply support survival and proliferation of melanocytes but also promotes differentiation of these cells. Unexpectedly, melanocyte stem cells independent of the c-Kit signal were maintained in the skin of the SLF transgenic mice. After the elimination of c-Kit-dependent melanoblasts by function-blocking anti-c-Kit antibody, these stem cells continued to proliferate and differentiate into mature melanocytes. These melanoblasts are able to migrate to cover most of the epidermis after several months. The SLF transgenic mice described in this report will be useful in the study of melanocyte biology.
Using the epidermis-specific cytokeratin 14 promoter to deliver HGF exclusively from epidermal keratinocytes, we have examined the potential of hepatocyte growth factor (HGF) secreted from the normal environment to control morphogenesis. The transgenic mice displayed a significant increase of the number of melanocytes and their precursors in embryos starting not later than 16.5 dpc, and then after birth an explosive increase of dermal melanocytes started within 1 week, and these melanocytes were maintained throughout the entire life of the mice. Thus, HGF acts as a paracrine agent to promote survival, proliferation and differentiation of melanocyte precursors in vivo, and eventually causes melanocytosis. Loss of E-cadherin expression in dermal melanocyte precursors suggests that HGF caused dermal localization of melanocytes and their precursors by down-regulation of E-cadherin molecules.
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.
The development of melanocytes from neural crest-derived precursor cells depends on signaling by the receptor tyrosine kinase KIT and the G protein-coupled endothelin receptor B (EDNRB) pathways. Loss-of-function mutations in either of these two signaling receptor molecules cause a loss or a marked reduction in the number of melanocyte precursors in the embryo and finally lead to loss of the coat color. Using cultures of embryonic stem (ES) cells to induce melanocyte differentiation in vitro, we investigated the requirement for EDNRB signaling during the entire developmental process of the melanocyte, in association with that for KIT signaling. During the 21-day period necessary for the induction of mature melanocytes from undifferentiated ES cells, endothelin 3 (EDN3), a ligand for EDNRB, increased the number of melanocytes in proportion to the period during which it was present. We tested the compensatory effect of EDNRB signaling on KIT signaling in vivo by using Kit(W-LacZ)/Kit(W-LacZ) ES cells and confirmed that the ectopic expression of EDN3 in the skin reduced the white spotting of Kit(W57)/Kit(W57)mice. KIT ligand (KITL) and EDN3 worked synergistically to induce melanocyte differentiation in vitro; however, the complete lack of EDNRB signaling attained by the use of EDN3-/- ES cells and an EDNRB antagonist, BQ788, revealed that the resulting failure of melanocyte development was not compensated by the further activation of KIT signaling by adding KITL. Simultaneous blockade of EDNRB and KIT signalings eliminated melanocyte precursors completely, suggesting that the maintenance or survival of early melanocyte precursors at least required the existence of either EDNRB or KIT signalings.
Neural crest (NC) cells are multipotent cells that can differentiate into melanocytes, neurons, glias and myofibroblasts. They migrate into the fetal thymus on embryonic day (E) 12 in mice and may participate in thymic organogenesis. Although the abnormality of migration and distribution of NC cells in the thymus results in immunodeficiency, the spatial and temporal presence of their progeny cells has not been defined in detail. In this study, we traced NC-derived cells based on the myelin protein zero gene promoter-Cre-mediated excision. We demonstrated that large numbers of NC-derived cells in the thymus were detected on E11.5 to E16.5 but rarely on E17.5. A colony formation assay of single thymic cells demonstrated that multipotent cells with the potential to differentiate into melanocytes, neurons and/or glias were present in the E14.5 and E15.5 but not in the E17.5 fetal thymus. Furthermore, we confirmed that these multipotent cells were NC-derived cells. Taken together, these findings imply that multipotent NC-derived cells are present in the developing thymus, but rarely in this organ at a later stage, suggesting that NC-derived cells may play roles in thymic organogenesis at an early embryonic stage.
It is crucial for the treatment of severe ocular surface diseases such as Stevens-Johnson syndrome (SJS) and ocular cicatricial pemphigoid (OCP) to find strategies that avoid the risks of allograft rejection and immunosuppression. Here, we report a new strategy for reconstructing the damaged corneal surface in a goat model of total limbal stem cell deficiency (LSCD) by autologous transplantation of epidermal adult stem cells (EpiASC).
EpiASC derived from adult goat ear skin by explant culture were purified by selecting single cell-derived clones. These EpiASC were cultivated on denuded human amniotic membrane (HAM) and transplanted onto goat eyes with total LSCD. The characteristics of both EpiASC and reconstructed corneal epithelium were identified by histology and immunohistochemistry. The clinical characteristic of reconstructed corneal surface was observed by digital camera.
Ten LSCD goats (10 eyes) were treated with EpiASC transplantation, leading to the restoration of corneal transparency and improvement of postoperative visual acuity to varying degrees in 80.00% (8/10) of the experimental eyes. The corneal epithelium of control groups either with HAM transplantation only or without any transplantation showed irregular surfaces, diffuse vascularization, and pannus on the entire cornea. The reconstructed corneal epithelium (RCE) expressed CK3, CK12, and PAX-6 and had the function of secreting glycocalyx-like material (AB-PAS positive). During the follow-up period, all corneal surfaces remained transparent and there were no serious complications. We also observed that the REC expressed CK1/10 weakly at six months after operation but not at 12 months after operation, suggesting that the REC was derived from grafted EpiASC.
Our results showed that EpiASC repaired the damaged cornea of goats with total LSCD and demonstrated that EpiASC can be induced to differentiate into corneal epithelial cell types in vivo, which at least in part correlated with down-regulation of CK1/10 and upregulation of PAX-6.
We have quantified the frequency and proliferation of five subsets of primitive hematopoietic cells, using the cobblestone area forming cell (CAFC) assay, in marrow of five strains of mice with lifespans ranging from about 500 to 800 days. Stem cell characteristics were determined in young (6 weeks) and old (12 months) mice. We report striking effects of both intrinsic strain lifespan and individual mouse age on stem cell populations. First, the relative and absolute numbers of the most primitive stem cell subsets was threefold to fourfold higher in old than in young mice. Second, a considerable strain-to-strain variation in the number of primitive cells was observed: when absolute frequencies were calculated, there was a trend for longer lifespan to be correlated with a larger stem cell pool. Third, stem cells from old mice had a far lower cycling activity than cells from young mice. However, this was highly strain dependent: short-lived C3H/He and CBA/J mice showed a stronger reduction in cycling activity during aging than long-lived C57BL/6 mice. Finally, a significant negative correlation was demonstrated in young mice between maximal lifespan and proliferative activity. These data show that aging has a major impact on the frequency and cell-cycle kinetics of primitive hematopoietic cell compartments. In addition, the observation that cycling activity of stem cells is related to the maximal lifespan of the mouse strain may open ways to identify the genetic mechanisms of both strain- and age-dependent variation in the structure of primitive hematopoietic cell compartments.
To address the fundamental question of whether or not stem cell populations age, we performed quantitative measurements of the cycling status and frequency of hematopoietic stem cells in long-lived C57BL/6 (B6) and short-lived DBA/2 (DBA) mice at different developmental and aging stages. The frequency of cobblestone area-forming cells (CAFC) day-35 in DBA fetal liver was twofold to threefold higher than in B6 mice, and by late gestation, the total stem cell number was nearly as large as that of young DBA adults. Following a further ≈50% increase in stem cells between 6 weeks and 1 year of age, numbers in old DBA mice dropped precipitously between 12 and 20 months of age. In marked contrast, this stem cell population in B6 mice increased at a constant rate from late gestation to 20 months of age with no signs of abatement. Throughout development an inverse correlation was observed between stem cell numbers and the percentage of cells in S-phase. Because a strong genetic component contributed to the changes in stem cell numbers during aging, we quantified stem cells of 20-month old BXD recombinant inbred (RI) mice, derived from B6 and DBA progenitor strains, thus permitting detailed interstrain genetic analysis. For each BXD strain we calculated the stem cell increase or decrease as mice aged from 2 to 20 months. Net changes in CAFC-day 35 numbers among BXD strains ranged from an ≈10-fold decrease to an ≈10-fold increase. A genome-wide search for loci associated with this quantitative trait was performed. Several loci contribute to the trait—putative loci map to chromosomes X, 2, and 14. We conclude that stem cell numbers fluctuate widely during aging and that this has a strong genetic basis.
The most comprehensive and integrated book on pigmentation. The Pigmentary System, Second Edition, gathers into one convenient, all-inclusive volume a wealth of information about the science of pigmentation and all the common and rare clinical disorders that affect skin color. The two parts, physiology (science) and pathophysiology (clinical disorders), are complementary and annotated so that those reading one part can easily refer to relevant sections in the other. For the clinician interested in common or rare pigment disorders or the principles of teaching about such disorders, this book provides an immediate and complete resource on the biologic bases for these disorders. For the scientist studying the biology of melanocyte function, the book provides a list of disorders that are related to basic biological functions of melanocytes. New features of this Second Edition include: Completely new section on the basic science of pigmentation - explaining the integration of melanocyte functions with other epidermal cells and with various organ systems like the immune system. New chapters on pigmentary disorders related to intestinal diseases, the malignant melanocyte, benign proliferations of melanocytes (nevi) and phototherapy with narrow band UV. All clinical chapters include the latest genetic findings and advances in therapy. More than 400 color images of virtually all clinical disorders. The book is ideal for all dermatologists and especially those interested in disorders of pigmentation. It is of particular use for pediatric dermatologists and medical geneticists caring for patients with congenital and genetic pigmentary disorders. This authoritative volume will fill the gap for dermatology training programs that do not have local experts on pigmentation. Basic and cosmetic scientists studying pigmentation and melanocytes will find the science and clinical correlations very useful in showing human significance and relevance to the results of their studies.
Preface.- Discovery and Origins: Discovery Embryological Origins Evolutionary Origins Agnathans.- Derivatives and Diversity: Amphibians Bony and Cartilaginous Fishes Reptiles and Birds Mammals.- Mechanisms and Malformations: Mechanisms of Migration Mechanisms of Differentiation Neurocristopathies Birth Defects.- References.- Index.
An important new perspective on AFFINE AND PROJECTIVE GEOMETRY. This innovative book treats math majors and math education students to a fresh look at affine and projective geometry from algebraic, synthetic, and lattice theoretic points of view. Affine and Projective Geometry comes complete with ninety illustrations, and numerous examples and exercises, covering material for two semesters of upper-level undergraduate mathematics. The first part of the book deals with the correlation between synthetic geometry and linear algebra. In the second part, geometry is used to introduce lattice theory, and the book culminates with the fundamental theorem of projective geometry. While emphasizing affine geometry and its basis in Euclidean concepts, the book: * Builds an appreciation of the geometric nature of linear algebra * Expands students' understanding of abstract algebra with its nontraditional, geometry-driven approach * Demonstrates how one branch of mathematics can be used to prove theorems in another * Provides opportunities for further investigation of mathematics by various means, including historical references at the ends of chapters. Throughout, the text explores geometry's correlation to algebra in ways that are meant to foster inquiry and develop mathematical insights whether or not one has a background in algebra. The insight offered is particularly important for prospective secondary teachers who must major in the subject they teach to fulfill the licensing requirements of many states. Affine and Projective Geometry's broad scope and its communicative tone make it an ideal choice for all students and professionals who would like to further their understanding of things mathematical. © 2010 M. Lynn Lamoreux, VA.
The neural crest is a multipotent and migratory cell type that forms transiently in the developing vertebrate embryo. These cells emerge from the central nervous system, migrate extensively and give rise to diverse cell lineages including melanocytes, craniofacial cartilage and bone, peripheral and enteric neurons and glia, and smooth muscle. A vertebrate innovation, the gene regulatory network underlying neural crest formation appears to be highly conserved, even to the base of vertebrates. Here, we present an overview of important concepts in the neural crest field dating from its discovery 150 years ago to open questions that will motivate future research.
Pigmentation of mammalian hairs is mediated by specialized pigment-producing cells referred as melanocytes. Hair pigmentation is tightly linked with hair regeneration cycles, where melanocytes proliferate and differentiate during the hair growth phase, but depleted by apoptosis during the regression phase. This periodical appearance of melanocytes is maintained by a small pool of immature stem cells residing in the hair follicle. Melanocyte stem cells offer an advantageous model by which to elucidate molecular basis of stem cell regulation, since genetic alterations affecting melanocyte regulation result in visible and yet viable phenotypes. Hence, by integrating melanocyte-specific in vivo gene manipulation approach and the subsequent phenotype analysis, melanocyte stem cell system provide an irresistible clue to identify key molecules for the stem cell regulation. Consolidation of such data would ultimately reveal an entire molecular network underlying the regulation of stem cells, which would not only contribute complete understanding of stem cell biology, but also provide valuable insights into medical application of stem cells.
Melanocytes are mainly found in the skin and more rarely in other parts of the body, including the heart. We analyzed the localization of heart melanocytes and their levels of pigmentation in a series of mutant mice presenting different numbers of melanocytes and pigmentation in the skin. We found that melanocytes were localized in the valves (mitral, tricuspid, and aortic) and septa (ventricular and atrial). Moreover, the numbers of melanocytes in the heart appears to reflect that of the skin. Mice having a high or low level of pigmented cells and/or melanin in valves and septa have similar lifespan. In this respect, melanocytes found in the valves and septa of the heart are probably not essential in a healthy and non-stressful environment.
Melanocyte stem cells (McSCs) intimately interact with epithelial stem cells (EpSCs) in the hair follicle bulge and secondary hair germ (sHG). Together, they undergo activation and differentiation to regenerate pigmented hair. However, the mechanisms behind this coordinated stem cell behavior have not been elucidated. Here, we identified Wnt signaling as a key pathway that couples the behavior of the two stem cells. EpSCs and McSCs coordinately activate Wnt signaling at the onset of hair follicle regeneration within the sHG. Using genetic mouse models that specifically target either EpSCs or McSCs, we show that Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes, while EpSC Wnt signaling not only dictates hair follicle formation but also regulates McSC proliferation during hair regeneration. Our data define a role for Wnt signaling in the regulation of McSCs and also illustrate a mechanism for regeneration of complex organs through collaboration between heterotypic stem cell populations.
Melanocyte stem cells in the bulge area of hair follicles are responsible for hair pigmentation, and defects in them cause hair graying. Here we describe the process of melanocyte stem cell entry into the quiescent state and show that niche-derived transforming growth factor beta (TGF-beta) signaling plays important roles in this process. In vitro, TGF-beta not only induces reversible cell cycle arrest, but also promotes melanocyte immaturity by downregulating MITF, the master transcriptional regulator of melanocyte differentiation, and its downstream melanogenic genes. In vivo, TGF-beta signaling is activated in melanocyte stem cells when they reenter the quiescent noncycling state during the hair cycle and this process requires Bcl2 for cell survival. Furthermore, targeted TGF-beta type II receptor (TGFbRII) deficiency in the melanocyte lineage causes incomplete maintenance of melanocyte stem cell immaturity and results in mild hair graying. These data demonstrate that the TGF-beta signaling pathway is one of the key niche factors that regulate melanocyte stem cell immaturity and quiescence.
The response of hair follicle melanoblasts to irradiation has been studied by two techniques at various stages of the hair growth cycle. Scoring of follicles without functional melanocytes in a growth phase after irradiation provides dose-response curves that have similarities to earlier depigmentation results. Melanoblast survival curves can also be obtained by scoring follicles with clones of functional melanocytes in a post-irradiation growth phase. A large difference in sensitivity is evident between resting and growing follicles. This difference seems to vary with different strains of mice. The sensitivities of the melanoblast survival curves also vary considerably through the hair growth cycle. The most sensitive cells are the resting Go melanoblasts. The dividing melanoblasts are more resistant, and the resistance is even greater, if the response is studied five days after plucking when the melanoblasts are reaching the end of the division phase and the beginning of the melanin synthetic phase.
The dorsal resting hair of C3H mice was shaved, activating the hair into the anagen stage. Hair regrowth in mice of different ages (10-20 mice in each group), whose hair cycles were in the telogen stage, were compared after shaving. In both groups of mice, new hair growth was not uniform, but irregular on the shaved areas. Delay in hair regrowth increased as the mice became older (20 < 66 < 188 < 312 day old mice). Furthermore, eighteen 59 day-old mice were used for biochemical analysis. Nine days after shaving, 30-50% of the shaved skin area was covered with new hair. After sacrifice, the dorsal skins were separated into hair re-growing, non-growing, and non-shaved control areas. Several enzyme activities in the extracts from the above-named areas were compared in terms of “per g of wet weight tissue”, “per mg DNA” and “per mg of soluble protein”. The activities of ornithine decarboxylase (ODC), transglutaminase (TGase) and alkaline phosphatase (Al-P) were remarkably high in the extract from the hair re-growing area as compared with that from the non-growing area. Comparison of the activities of the follicle-rich fractions from the hair re-growing area to those of the non-shaved area showed that ODC, TGase and Al-P activities were increased.
We have quantified the frequency and proliferation of five subsets of primitive hematopoietic cells, using the cobblestone area forming cell (CAFC) assay, in marrow of five strains of mice with lifespans ranging from about 500 to 800 days. Stem cell characteristics were determined in young (6 weeks) and old (12 months) mice. We report striking effects of both intrinsic strain lifespan and individual mouse age on stem cell populations. First, the relative and absolute numbers of the most primitive stem cell subsets was threefold to fourfold higher in old than in young mice. Second, a considerable strain-to-strain variation in the number of primitive cells was observed: when absolute frequencies were calculated, there was a trend for longer lifespan to be correlated with a larger stem cell pool. Third, stem cells from old mice had a far lower cycling activity than cells from young mice. However, this was highly strain dependent: short-lived C3H/He and CBA/J mice showed a stronger reduction in cycling activity during aging than long-lived C57BL/6 mice. Finally, a significant negative correlation was demonstrated in young mice between maximal lifespan and proliferative activity. These data show that aging has a major impact on the frequency and cell-cycle kinetics of primitive hematopoietic cell compartments. In addition, the observation that cycling activity of stem cells is related to the maximal lifespan of the mouse strain may open ways to identify the genetic mechanisms of both strain- and age-dependent variation in the structure of primitive hematopoietic cell compartments.
It has become a staple assumption of biology that there is an intrinsic fixed limit to the number of divisions that normal vertebrate cells can undergo before they senesce, and this limit is in some way related to aging of the organism. The notion of such a limited replicative lifespan arose from the often repeated observation that diploid fibroblasts cannot proliferate indefinitely in monolayer culture, and that the number of divisions before senescence is directly related to the in vivo lifespan of different species. The in vitro evidence is countered by estimates that the number of cell divisions in some organs of rodents and man are one or more orders of magnitude higher than the in vitro limit, with no indication of the degenerative changes seen in culture. Serial transplantation experiments in animals also exhibit many more cell divisions than the in vitro studies, with some indicating an indefinite replicative lifespan. I present evidence that vertebrate cells are severely stressed by enzymatic dispersion and sustain cumulative damage during serial subcultivations. The evidence includes large increases in cell size and its heterogeneity, reductions in replicative efficiency at low seeding densities, appearance of abnormal structures in the cytoplasm, changes in metabolism to a common cell culture type, continuous loss of methyl groups and reiterated sequences from DNA, and a constant rate of decline of growth rate with passage. This evidence is complemented by the reduction induced in the replicative life span of diploid cells by a large array of treatments which have different primary targets in the cells. The most consistent and general observation of cell behavior in aging animals, with only a few exceptions, is a reduction in the rate of cell proliferation. This reduction is perpetuated when the cells are grown in culture, indicating it is an enduring and intrinsic property of the cells rather than a systemic effect of the aging organism. A similar heritable reduction in growth rate can be induced in established cell lines by prolonged incubation at quiescence. The reduction can be exaggerated by subculturing the quiescent cells under suboptimal conditions, just as the effects of age are exaggerated under stress. The constant decline of growth rate that occurs during serial passage of diploid cells may represent a similar decay of cell function. I propose that the limit on replicative lifespan is an artifact that reflects the failure of diploid cells to adapt to the trauma of dissociation and the radically foreign environment of cell culture. It is, however, a useful artifact that has given us much information about cell behavior under stressful conditions. The overall evidence indicates cell in vivo accumulate damage over a lifetime that results in gradual loss of differentiated function and growth rate accompanied by an increased probability for the development of cancer. Such changes are normally held to a minimum by the organized state of the tissues and homeostatic regulation of the organism. The rejection of an intrinsic limit on the number of cell divisions eliminates the need for a cellular clock, such as telomere length, that counts mitoses. I offer a heuristic explanation for the gradual reduction of cell function and growth capacity with age based on a cumulative discoordination of interacting pathways within and between cells and tissues. I also make a case for the use of established cell lines as model systems for studying heritable damage to cell populations that simulates the effects of aging in vivo, and represents a relatively unexplored area of cell biology.
The development of neural crest-derived melanocytes, as well as haematopoietic and germ cells, is affected by mutations of the Kit and Mgf genes, which lead to dominant spotting (W) or steel (Sl) phenotypes. Mgf codes for the ligand of the receptor tyrosine kinase encoded by the Kit locus. KitW-v, a point mutation exerting a dominant negative effect, causes a substantial reduction in tyrosine kinase activity of the Kit receptor and leads to a characteristic pigmentation phenotype, namely dilute coat colour and a white ventral and head spot with reduced pigmentation of the feet and tail in the heterozygous animal, as well as slight anaemia. Homozygous animals lack coat pigmentation and are severely anaemic and infertile. Dct is a marker for cells of the melanoblast lineage. In order to study these cells in detail we have generated transgenic mouse lines carrying the lacZ reporter under the control of the Dct promoter and have used the embryonic expression of the reporter to identify early melanoblasts before they begin to produce pigment. Our transgenic lines have simplified the study of melanoblasts in the mouse embryo, and by crossing our mice with KitW-v mutants we have been able to identify the midgestation stages at which melanoblasts rely critically on Mgf/Kit interactions. We conclude that the survival of immature melanoblasts depends crucially upon Kit signalling up until E11, and later in development Kit plays a vital role in melanoblast proliferation. Our data do not describe a dependence upon Kit for melanoblast migration or differentiation.
To address the fundamental question of whether or not stem cell populations age, we performed quantitative measurements of the cycling status and frequency of hematopoietic stem cells in long-lived C57BL/6 (B6) and short-lived DBA/2 (DBA) mice at different developmental and aging stages. The frequency of cobblestone area-forming cells (CAFC) day-35 in DBA fetal liver was twofold to threefold higher than in B6 mice, and by late gestation, the total stem cell number was nearly as large as that of young DBA adults. Following a further approximately 50% increase in stem cells between 6 weeks and 1 year of age, numbers in old DBA mice dropped precipitously between 12 and 20 months of age. In marked contrast, this stem cell population in B6 mice increased at a constant rate from late gestation to 20 months of age with no signs of abatement. Throughout development an inverse correlation was observed between stem cell numbers and the percentage of cells in S-phase. Because a strong genetic component contributed to the changes in stem cell numbers during aging, we quantified stem cells of 20-month old BXD recombinant inbred (RI) mice, derived from B6 and DBA progenitor strains, thus permitting detailed interstrain genetic analysis. For each BXD strain we calculated the stem cell increase or decrease as mice aged from 2 to 20 months. Net changes in CAFC-day 35 numbers among BXD strains ranged from an approximately 10-fold decrease to an approximately 10-fold increase. A genome-wide search for loci associated with this quantitative trait was performed. Several loci contribute to the trait-putative loci map to chromosomes X, 2, and 14. We conclude that stem cell numbers fluctuate widely during aging and that this has a strong genetic basis.
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.
Hair graying is the most obvious sign of aging in humans, yet its mechanism is largely unknown. Here, we used melanocyte-tagged
transgenic mice and aging human hair follicles to demonstrate that hair graying is caused by defective self-maintenance of
melanocyte stem cells. This process is accelerated dramatically with Bcl2 deficiency, which causes selective apoptosis of melanocyte stem cells, but not of differentiated melanocytes, within the
niche at their entry into the dormant state. Furthermore, physiologic aging of melanocyte stem cells was associated with ectopic
pigmentation or differentiation within the niche, a process accelerated by mutation of the melanocyte master transcriptional
regulator Mitf.
The neural crest origin of pigment-producing melanocytes has been carefully traced and documented. Melanoblasts, the precursors to melanocytes, originate in the neural crest and travel to their destinations, including the hair follicle, where they differentiate into melanocytes that produce the pigment melanin. In the hair follicle, the life of a melanocyte is tightly integrated with the cyclical nature of the follicle. The hair follicle cycle consists of a finite period of hair fiber production and growth (anagen), followed by a brief regression period (catagen) and a resting period of little activity (telogen). In mice and most other mammals, the anagen growth phase occurs in a wave-like pattern across the skin surface, whereas, in humans, each follicle cycles independently of its neighbors. The activity of melanocytes in the hair matrix is also under cyclical control where melanogenesis and anagen are tightly coupled; melanocytes in the hair bulb are terminally differentiated and die in early catagen by an unknown mechanism.
The appearance of hair plays an important role in people's overall physical appearance and self-perception. With today's increasing life-expectations, the desire to look youthful plays a bigger role than ever. The hair care industry has become aware of this and is delivering active products directed towards meeting this consumer demand. The discovery of pharmacological targets and the development of safe and effective drugs also indicate strategies of the drug industry for maintenance of healthy and beautiful hair. Hair aging comprises weathering of the hair shaft, decrease of melanocyte function, and decrease in hair production. The scalp is subject to intrinsic and extrinsic aging. Intrinsic factors are related to individual genetic and epigenetic mechanisms with interindividual variation: prototypes are familial premature graying, and androgenetic alopecia. Currently available pharmacologic treatment modalities with proven efficacy for treatment of androgenetic alopecia are topical minoxidil and oral finasteride. Extrinsic factors include ultraviolet radiation and air pollution. Experimental evidence supports the hypothesis that oxidative stress also plays a role in hair aging. Topical anti-aging compounds include photoprotectors and antioxidants. In the absence of another way to reverse hair graying, hair colorants remain the mainstay of recovering lost hair color. Topical liposome targeting for melanins, genes, and proteins selectively to hair follicles are currently under investigation.
Cell aging in vivo and in vitro
- Rubin