YAP prevents senescence of dermal fibroblast and inhibits melanogenesis via paracrine effect of DKK1

IF 3.5 3区医学 Q1 DERMATOLOGY Experimental Dermatology Pub Date : 2024-05-14 DOI:10.1111/exd.15093

Tong Li, Yimei Xiong, Longjun Xian, Lidan Xiong, Li Li

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Abstract

Senile skin hyperpigmentation displays remarkable histopathological features of dermal aging. The crosstalk between melanocytes and dermal fibroblasts plays crucial roles in aging-related pigmentation. While senescent fibroblasts can upregulate pro-melanogenic factors, the role of anti-melanogenic factors, such as dickkopf1 (DKK1), and the upstream regulatory mechanism during aging remain obscure. This study investigated the roles of yes-associated protein (YAP) and DKK1 in the regulation of dermal fibroblast senescence and melanogenesis. Our findings demonstrated decreased YAP activity and DKK1 levels in intrinsic and extrinsic senescent fibroblasts. YAP depletion induced fibroblast senescence and downregulated the expression and secretion of DKK1, whereas YAP overexpression partially reversed the effect. The transcriptional regulation of DKK1 by YAP was supported by dual-luciferase reporter and chromatin immunoprecipitation assays. Moreover, YAP depletion in fibroblasts upregulated Wnt/β-catenin in melanocytes and stimulated melanogenesis, which was partially rescued by the re-supplementation of DKK1. Conversely, overexpression of YAP in senescent fibroblasts decreased Wnt/β-catenin levels in melanocytes and inhibited melanogenesis. Additionally, reduced levels of YAP and DKK1 were verified in the dermis of solar lentigines. These findings suggest that, during skin aging, epidermal pigmentation may be influenced by YAP in the dermal microenvironment via the paracrine effect of DKK1.

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YAP 可防止真皮成纤维细胞衰老，并通过 DKK1 的旁分泌效应抑制黑色素生成

老年性皮肤色素沉着显示了皮肤老化的显著组织病理学特征。黑色素细胞和真皮成纤维细胞之间的相互作用在与衰老有关的色素沉着中起着至关重要的作用。虽然衰老的成纤维细胞能上调促黑色素生成因子，但抗黑色素生成因子（如dickkopf1（DKK1））在衰老过程中的作用和上游调控机制仍不清楚。本研究探讨了YAP和DKK1在调控真皮成纤维细胞衰老和黑色素生成中的作用。我们的研究结果表明，内在和外在衰老成纤维细胞中的YAP活性和DKK1水平均有所下降。YAP耗竭会诱导成纤维细胞衰老，并下调DKK1的表达和分泌，而YAP过表达可部分逆转这种效应。双荧光素酶报告和染色质免疫沉淀实验证实了YAP对DKK1的转录调控。此外，成纤维细胞中 YAP 的缺失会上调黑色素细胞中的 Wnt/β-catenin 并刺激黑色素生成，而 DKK1 的重新补充可部分缓解这一现象。相反，在衰老成纤维细胞中过表达 YAP 会降低黑色素细胞中的 Wnt/β-catenin 水平，抑制黑色素生成。此外，日光性色斑真皮层中的 YAP 和 DKK1 水平降低也得到了证实。这些发现表明，在皮肤老化过程中，表皮色素沉着可能受到真皮微环境中 YAP 通过 DKK1 的旁分泌效应的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental Dermatology 医学-皮肤病学

CiteScore

6.70

自引率

5.60%

发文量

201

审稿时长

2 months

期刊介绍： Experimental Dermatology provides a vehicle for the rapid publication of innovative and definitive reports, letters to the editor and review articles covering all aspects of experimental dermatology. Preference is given to papers of immediate importance to other investigators, either by virtue of their new methodology, experimental data or new ideas. The essential criteria for publication are clarity, experimental soundness and novelty. Letters to the editor related to published reports may also be accepted, provided that they are short and scientifically relevant to the reports mentioned, in order to provide a continuing forum for discussion. Review articles represent a state-of-the-art overview and are invited by the editors.