Abstract
Canities (or hair greying) is an age-linked loss of the natural pigment called melanin from hair. While the specific cause(s) underlying the loss of melanogenically-active melanocytes from the anagen hair bulbs of affected human scalp remains unclear, oxidative stress sensing appears to be a key factor involved. In this study, we examined the follicular melanin unit in variably pigmented follicles from the aging human scalp of healthy individuals (22–70 years). Over 20 markers were selected within the following categories: melanocyte-specific, apoptosis, cell cycle, DNA repair/damage, senescence and oxidative stress. As expected, a reduction in melanocyte-specific markers in proportion to the extent of canities was observed. A major finding of our study was the intense and highly specific nuclear expression of Ataxia Telangiectasia Mutated (ATM) protein within melanocytes in anagen hair follicle bulbs. ATM is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks and functions as an important sensor of reactive oxygen species (ROS) in human cells. The incidence and expression level of ATM correlated with pigmentary status in canities-affected hair follicles. Moreover, increased staining of the redox-associated markers 8-OHdG, GADD45 and GP-1 were also detected within isolated bulbar melanocytes, although this change was not clearly associated with donor age or canities extent. Surprisingly, we were unable to detect any specific change in the expression of other markers of oxidative stress, senescence or DNA damage/repair in the canities-affected melanocytes compared to surrounding bulbar keratinocytes. By contrast, several markers showed distinct expression of markers for oxidative stress and apoptosis/differentiation in the inner root sheath (IRS) as well as other parts of the hair follicle. Using our in vitro model of primary human scalp hair follicle melanocytes, we showed that ATM expression increased after incubation with the pro-oxidant hydrogen peroxide (H2O2). In addition, this ATM increase was prevented by pre-incubation of cells with antioxidants. The relationship between ATM and redox stress sensing was further evidenced as we observed that the inhibition of ATM expression by chemical inhibition promoted the loss of melanocyte viability induced by oxidative stress. Taken together these new findings illustrate the key role of ATM in the protection of human hair follicle melanocytes from oxidative stress/damage within the human scalp hair bulb. In conclusion, these results highlight the remarkable complexity and role of redox sensing in the status of human hair follicle growth, differentiation and pigmentation.
Highlights
Canities or hair greying is associated with the aging process and characterised by new growth of unpigmented hair fibre within hair follicles[1]
One of the major findings of this study was that of all the biomarkers tested, only Ataxia-Telangiectasia mutated (ATM) was found to be exclusively expressed within hair bulb melanocytes and so correlated with hair follicle pigmentation status
Investigations on primary hair follicle melanocytes (HFM) in vitro showed that total levels of ATM were upregulated after exposure to hydrogen peroxide that increased oxidative stress
Summary
Canities or hair greying is associated with the aging process and characterised by new growth of unpigmented hair fibre within hair follicles[1]. Studies (albeit predominantly in mice) have pointed to a number of factors including increased oxidative stress in the hair follicle[9], depletion of melanoblast stem cells from the niche[10], apoptosis of differentiated matrix melanocyte in the hair bulb[11] and DNA damage repair (DDR) abnormalities, that all may contribute in part to hair g reying[12]. ROS or pigmentation markers in both pigmented and canities affected hair follicles, information on the collective status, expression and distribution of selected cell cycle, DNA damage, apoptosis and ROS metabolising anti-oxidant markers in aging human scalp follicles is limited. In this study we have analysed the protein expression of over 20 markers of cell cycle, DNA damage, apoptosis, senescence and oxidative stress in hair bulb melanocytes and in the wider growth scalp hair follicle in normal healthy individuals across six decades. ATM appears to play a role in protecting human hair follicle melanocytes from oxidative stress/damage, and maintenance of its expression within the follicle microenvironment along with other redox markers may be important for hair bulb melanocyte survival in canities-prone scalp hair follicles
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