Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.,The EMBO Journal

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Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-10-21 , DOI: 10.15252/embj.2019101982
Stella Victorelli _{1,

2,

3} , Anthony Lagnado _{1,

2,

3} , Jessica Halim _{1,

2} , Will Moore _{1,

2} , Duncan Talbot ₄ , Karen Barrett ₄ , James Chapman _{1,

2} , Jodie Birch _{1,

2} , Mikolaj Ogrodnik ₃ , Alexander Meves ₅ , Jeff S Pawlikowski ₆ , Diana Jurk _{1,

2,

3} , Peter D Adams _{7,

8} , Diana van Heemst _{9,

10} , Marian Beekman ₁₁ , P Eline Slagboom _{11,

12} , David A Gunn ₄ , João F Passos _{1,

2,

3}

Affiliation

Ageing Research Laboratories, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK.
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
Unilever Discover, Colworth Science Park, Sharnbrook, Bedfordshire, UK.
Department of Dermatology, Mayo Clinic, Rochester, MN, USA.
Vanderbilt University Medical Center, Nashville, TN, USA.
Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
Netherlands Consortium for Healthy Aging, Leiden University Medical Center, Leiden, The Netherlands.
Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Max Planck Institute for Biology of Ageing, Cologne, Germany.

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 p16INK4A 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.

中文翻译：

衰老的人类黑素细胞通过旁分泌端粒功能障碍导致皮肤衰老。

细胞衰老已被证明会导致皮肤老化。然而，黑素细胞在此过程中的作用尚未得到充分研究。我们的数据表明，黑素细胞是人类皮肤衰老过程中唯一表达衰老标志物 p16INK4A 的表皮细胞类型。老化的黑素细胞还表现出额外的衰老标志物，例如 HMGB1 减少和端粒功能障碍，但未检测到端粒缩短。此外，衰老黑素细胞 SASP 以旁分泌方式诱导端粒功能障碍，并通过激活 CXCR3 依赖性线粒体 ROS 限制周围细胞的增殖。最后，使用 3D 人类表皮等效物进行体外实验，衰老的黑素细胞会损害基底角质细胞增殖并导致表皮萎缩。至关重要的是，使用抗衰老药物 ABT737 清除衰老黑素细胞或使用靶向线粒体的抗氧化剂 MitoQ 治疗可抑制这种效应。总之，我们的研究提供了概念验证证据，表明衰老的黑素细胞影响角质形成细胞功能并充当人类皮肤衰老的驱动因素。

更新日期：2019-12-02

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