Theranostics 2018; 8(17):4620-4632. doi:10.7150/thno.26975

Research Paper

Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo

Jung Eun Yoon1,4, Yeongeun Kim2,4, Soohyun Kwon2, Misun Kim2, Young Hwa Kim1, Jang-Hee Kim3, Tae Jun Park1,4,5,✉, Hee Young Kang2,4,✉

1. Department of Biochemistry and Molecular Biology, Ajou University, School of Medicine, Suwon, 443-721, Korea
2. Department of Dermatology, Ajou University School of Medicine, Suwon, 443-721, Korea
3. Department of Pathology, Ajou University School of Medicine, Suwon, 443-721, Korea
4. Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon,443-721, Korea
5. Institute on Ageing, Ajou University Medical Center, Suwon, 443-721, Korea

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Citation:
Yoon JE, Kim Y, Kwon S, Kim M, Kim YH, Kim JH, Park TJ, Kang HY. Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo. Theranostics 2018; 8(17):4620-4632. doi:10.7150/thno.26975. Available from https://www.thno.org/v08p4620.htm

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Abstract

Cutaneous ageing is an important extrinsic process that modifies the pigmentary system. Because cellular senescence is a fundamental ageing mechanism, we examined the role of senescent cells in ageing pigmentation.

Methods: Biopsies obtained from senile lentigo and perilesional normal skin were assayed for a marker of cellular senescence, p16INK4A. To determine the secretory phenotypes of senescent fibroblasts, we performed microarray, RNA sequencing and methylation array analyses in senile lentigo and senescent fibroblasts. To further investigate the impact of senescent cells on ageing-related pigmentation, an intervention that targeted senescent cells using radiofrequency was performed.

Results: In vivo, senescent fibroblasts accumulated at the sites of age-related pigmentation. Phenotype switching of the cells resulted in the repression of stromal-derived factor 1 (SDF1) by promoter methylation. SDF1 induced melanocyte differentiation via stromal-epithelial interactions, ultimately driving skin pigmentation. Furthermore, the elimination of senescent fibroblasts from pigmented skin using radiofrequency was accompanied by skin lightening, rendering it a potential target for treatment.

Conclusion: Aged pigmented skin contains an increasing proportion of senescent fibroblasts. Cells with phenotype switching exhibited a loss of SDF1, which stimulates the melanogenic process and thereby contributes to aging pigmentation. These data may promote the development of new therapeutic paradigms, such as a stroma-targeting therapy for pigmentary disorders.

Keywords: Skin pigmentation, senile lentigo, SDF1, senescent fibroblasts