Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction

Stella Victorelli, Anthony Lagnado, Jessica Halim, Will Moore, Duncan Talbot, Karen Barrett, James Chapman, Jodie Birch, Mikolaj Ogrodnik, Alexander Meves, Jeff S. Pawlikowski, Diana Jurk, Peter D. Adams, Diana van Heemst, Marian Beekman, P. Eline Slagboom, David A. Gunn, João F. Passos

Research output: Contribution to journalArticle

14 Scopus citations

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 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.

Original languageEnglish (US)
Article numbere101982
JournalEMBO Journal
Volume38
Issue number23
DOIs
StatePublished - Dec 2 2019

Keywords

  • melanocytes
  • SASP
  • senescence
  • skin ageing
  • telomeres

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Victorelli, S., Lagnado, A., Halim, J., Moore, W., Talbot, D., Barrett, K., Chapman, J., Birch, J., Ogrodnik, M., Meves, A., Pawlikowski, J. S., Jurk, D., Adams, P. D., van Heemst, D., Beekman, M., Slagboom, P. E., Gunn, D. A., & Passos, J. F. (2019). Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO Journal, 38(23), [e101982]. https://doi.org/10.15252/embj.2019101982