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

doi:10.15252/embj.2019101982

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 journal › Article › peer-review

27 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 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.

Original language	English (US)
Article number	e101982
Journal	EMBO Journal
Volume	38
Issue number	23
DOIs	https://doi.org/10.15252/embj.2019101982
State	Published - Dec 2 2019

Keywords

SASP
melanocytes
senescence
skin ageing
telomeres

ASJC Scopus subject areas

General Neuroscience
Molecular Biology
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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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), Article e101982. https://doi.org/10.15252/embj.2019101982

Victorelli, S, Lagnado, A, Halim, J, Moore, W, Talbot, D, Barrett, K, Chapman, J, Birch, J, Ogrodnik, M, Meves, A, Pawlikowski, JS, Jurk, D, Adams, PD, van Heemst, D, Beekman, M, Slagboom, PE, Gunn, DA & Passos, JF 2019, 'Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction', EMBO Journal, vol. 38, no. 23, e101982. https://doi.org/10.15252/embj.2019101982

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title = "Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction",

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.",

keywords = "SASP, melanocytes, senescence, skin ageing, telomeres",

author = "Stella Victorelli and Anthony Lagnado and Jessica Halim and Will Moore and Duncan Talbot and Karen Barrett and James Chapman and Jodie Birch and Mikolaj Ogrodnik and Alexander Meves and Pawlikowski, {Jeff S.} and Diana Jurk and Adams, {Peter D.} and {van Heemst}, Diana and Marian Beekman and Slagboom, {P. Eline} and Gunn, {David A.} and Passos, {Jo{\~a}o F.}",

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doi = "10.15252/embj.2019101982",

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AU - Lagnado, Anthony

AU - Halim, Jessica

AU - Moore, Will

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AU - Barrett, Karen

AU - Chapman, James

AU - Birch, Jodie

AU - Ogrodnik, Mikolaj

AU - Meves, Alexander

AU - Pawlikowski, Jeff S.

AU - Jurk, Diana

AU - Adams, Peter D.

AU - van Heemst, Diana

AU - Beekman, Marian

AU - Slagboom, P. Eline

AU - Gunn, David A.

AU - Passos, João F.

PY - 2019/12/2

Y1 - 2019/12/2

N2 - 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.

AB - 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.

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Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction

Abstract

Keywords

ASJC Scopus subject areas

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