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Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.

Published on Oct 21, 2019in The EMBO Journal11.227
· DOI :10.15252/embj.2019101982
Stella Victorelli4
Estimated H-index: 4
(Newcastle University),
Anthony Lagnado3
Estimated H-index: 3
(Newcastle University)
+ 15 AuthorsJoão F. Passos29
Estimated H-index: 29
(Newcastle University)
Sources
Abstract
Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16(INK4A) during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.
  • References (68)
  • Citations (2)
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References68
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#1Nan Liu (Tokyo Medical and Dental University)H-Index: 1
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Stem cells underlie tissue homeostasis, but their dynamics during ageing—and the relevance of these dynamics to organ ageing—remain unknown. Here we report that the expression of the hemidesmosome component collagen XVII (COL17A1) by epidermal stem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis, and that the resulting differential expression of COL17A1 in individual stem cells generates a driving force for cell competition. In vivo clonal analysis in mice a...
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#1Rhys Anderson (Newcastle University)H-Index: 7
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Abstract Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age‐related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post‐mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age‐related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent‐like phenotype characterised by pe...
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There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life- and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extrac...
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Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here...
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Senescent cells are more prevalent in aged human skin compared to young, but evidence that senescent cells are linked to other biomarkers of aging is scarce. We counted cells positive for the tumor suppressor and senescence associated protein p16INK4a in sun-protected upper-inner arm skin biopsies from 178 participants (aged 45-81 years) of the Leiden Longevity Study. Local elastic fiber morphology, facial wrinkles, and perceived facial age were compared to tertiles of p16INK4a counts, while adj...
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Melanoma is a highly malignant and is a life-threatening disease with no effective treatment currently. This study aims to evaluate the significance of TUSC3, an endoplasmic reticulum stress (ERS)-inducible gene and explore its relationship with AKT/GSK3-beta/beta-catenin signalling pathway in melanoma cell WM451. We investigated TUSC3 expression in melanoma cell by qRT-PCR, CCK-8 and clonal formation assays were utilized to evaluate cell proliferation. Wound healing and transwell experiments de...
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