miR-1246过表达外泌体通过抑制GSK3β激活自噬，改善紫外线诱导的光老化

IF 2.7 3区化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Photochemical & Photobiological Sciences Pub Date : 2024-04-13 DOI:10.1007/s43630-024-00567-w

Wei Gao, Limin Yuan, Yue Zhang, Fangzhou Huang, Chen Ai, Tianci Lv, Jiale Chen, Hui Wang, Yixin Ling, Yu-shuai Wang

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引用次数: 0

摘要

干细胞旁分泌物在皮肤伤口修复和光老化治疗中具有潜在的应用价值。我们之前的研究表明，从脂肪源性干细胞（ADSCs）中分离出的miR-1246高表达外泌体（OE-EXs）对紫外线诱导的光老化具有比载体更好的光保护作用，但其潜在机制尚不清楚。同时进行的生物信息学分析表明，miR-1246 显示了与 GSK3β 的潜在结合位点，而 GSK3β 是自噬的负调控因子。本研究旨在探讨OE-EX是否能通过靶向GSK3β激活自噬而改善皮肤光老化。结果表明，OE-EXs能显著降低GSK3β的表达，增强自噬通量和自噬相关蛋白（如LC3II），同时抑制p62的表达。同时，OE-EXs 能明显逆转 UVB 照射引起的人皮肤成纤维细胞内 ROS、MMP-1、I 型胶原和 DNA 损伤水平，但当引入 3-Methyladenine (3-MA) 阻断自噬途径时，其改善效果会受到明显抑制。此外，OE-EXs 还能逆转 UVB 引起的昆明小鼠皱纹、表皮增生和胶原纤维减少，但与 3-MA 合用时，OE-EXs 的治疗效果会减弱。总之，OE-EXs可通过靶向GSK3β激活自噬，从而治疗UVB诱导的皮肤光老化。

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miR-1246-overexpressing exosomes improve UVB-induced photoaging by activating autophagy via suppressing GSK3β

Stem cell paracrine has shown potential application in skin wound repair and photoaging treatment. Our previous study demonstrated that miR-1246-overexpressing Exosomes (OE-EXs) isolated from adipose-derived stem cells (ADSCs) showed superior photo-protecting effects on UVB-induced photoaging than that of the vector, however, the underlying mechanism was unclear. The simultaneous bioinformatics analysis indicated that miR-1246 showed potential binding sites with GSK3β which acted as a negative regulator for autophagy. This study was aimed to explore whether OE-EXs ameliorate skin photoaging by activating autophagy via targeting GSK3β. The results demonstrated that OE-EXs significantly decreased GSK3β expression, enhanced autophagy flux and autophagy-related proteins like LC3II, while suppressed p62 expression. Meanwhile, OE-EXs markedly reversed the levels of intracellular ROS, MMP-1, procollagen type I and DNA damage in human skin fibroblasts caused by UVB irradiation, but the ameliorating effects were significantly inhibited when 3-Methyladenine (3-MA) was introduced to block the autophagy pathway. Further, OE-EXs could reverse UVB-induced wrinkles, epidermal hyperplasia, and collagen fibers reduction in Kunming mice, nevertheless, the therapeutical effects of OE-EXs were attenuated when it was combinative treated with 3-MA. In conclusion, OE-EXs could cure UVB induced skin photoaging by activating autophagy via targeting GSK3β.