Dataset Information

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

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.

SUBMITTER: Yoon JE

PROVIDER: S-EPMC6160768 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Yoon Jung Eun JE Kim Yeongeun Y Kwon Soohyun S Kim Misun M Kim Young Hwa YH Kim Jang-Hee JH Park Tae Jun TJ Kang Hee Young HY

Theranostics 20180909 17

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. <b>Methods:</b> Biopsies obtained from senile lentigo and perilesional normal skin were assayed for a marker of cellular senescence, p16<sup>INK4A</sup>. To determine the secretory phenotypes of senescent fibroblasts, we performed microarray, RNA sequencing and methylation array analy ...[more]

PMID: 30279727

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Project description:Excessive exposure to ultraviolet (UV) light is known to induce photoaging in the skin, necessitating the development of effective anti-photoaging strategies to mitigate the adverse effects of UV radiation. Understanding the biofunctional characteristics of diverse skin cell types and unraveling the molecular modifications implicated in the aging process are pivotal in comprehending the intricacies of photoaging in human skin. Such insights are essential for paving the way for innovative interventions to counteract the deleterious impact of UV radiation on the skin. The single-cell RNA sequencing data of UVB-irradiated and normal control mouse skin in GSE173385 were downloaded from the Gene Expression Omniniub (GEO) database. First, cell types were identified using Seurat for normalization, dimensionality reduction and clustering. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were executed on these cell subpopulations. Using FindAllMarkers in the Seurat package to identify differential gene expression and Monocle2 cell trajectory analysis, we screened out hub genes related to the development trajectory of senescent fibroblasts during photoaging, and then combined it with 307 aging-related genes collected in the HAGR library, we finally identified two biomarkers. The efficiency of biomarkers in diagnosing UV radiation photoaging was also evaluated in the dataset. Concurrently, the immune infiltration of identified biomarkers under UV radiation has also been further explored. Moreover, we employed the Enrichr platform to conduct a comprehensive screening of drug molecules associated with the identified biomarkers. Our comprehensive analysis, employing Seurat for normalization, dimensionality reduction, and clustering, successfully identified ten distinct cell types within the samples. Then GO functional enrichment analysis showed that senescent fibroblasts are mainly involved in the regulation of immune effector processes such as cytokine-mediated signaling pathways, regulation of epithelial cell proliferation and intercellular adhesion. Afterwards, KEGG analysis determined the main biological pathways are: IL-17 signaling pathway, Cytokine-cytokine receptor interaction, Metabolism of xenobiotics by cytochrome P450. After differential gene expression and Monocle2 cell trajectory analysis, we matched the obtained hub genes with the aging-related genes collected in the HAGR library, and finally screened out two relevant biomarkers: Apoe and Gdf15 which are related to the development trajectory of senescent fibroblasts during photoaging. Meanwhile, the immune infiltration further implied that the expression of these two biomarkers was significantly correlated with immune cells. In addition, the Enrichr platform was used to screen the drug molecules related to these biomarkers. This strategic approach aimed to pinpoint effective molecular targets for the prevention and treatment of photoaging. Our investigation has effectively characterized biomarkers associated with fibroblast senescence during photoaging at the single-cell level, We have validated their correlation with cellular immune inflammation and identified potential drug targets through the utilization of the Enrichr platform. This foundational research establishes a robust basis for the development of therapeutic interventions targeting skin diseases resulting from photoaging.

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

Publications

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

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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