Translational research : the journal of laboratory and clinical medicine. 2025 May 20:S1931-5244(25)00052-0. doi: 10.1016/j.trsl.2025.05.002 Q15.92025
Mechanism of adipose-derived stem cell-derived extracellular vesicles affecting macrophage efferocytosis by mediating ADAM17/MerTK in the apoptosis of tubular epithelial cells after sepsis-associated acute kidney injury
脓毒症相关急性肾损伤后间充质干细胞来源的细胞外囊泡通过介导ADAM17/Mertk影响肾小管上皮细胞凋亡中巨噬细胞胞葬作用的机制研究 翻译改进
Zhixiang Bian 1, Xiangxiang Wang 1, Xiaoxuan Su 1, Ming Yang 1, Rui Zhu 1, Shunjie Chen 2
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DOI: 10.1016/j.trsl.2025.05.002 PMID: 40403963
摘要 中英对照阅读
目标： 本研究探讨了脂肪源性干细胞衍生的细胞外囊泡（ADSC-EVs）通过调节ADAM17/MerTK介导的巨噬细胞摄取凋亡细胞，从而改善脓毒症相关急性肾损伤（S-AKI）管状上皮细胞（TEC）凋亡的分子机制。
方法： 通过结肠系膜和穿刺建立S-AKI小鼠模型，并静脉注射ADSC-EVs。将小鼠肾脏巨噬细胞与LPS培养，同时转染oe-ADAM17或si-MerTK，并与Jurkat细胞共孵育。使用比色法、免疫组化、Western blot和ELISA测定小鼠血清尿素和肌酐、efferocytosis相关蛋白、促炎因子、细胞因子以及可溶性MerTK (sMerTK)水平。通过HE染色、TUNEL染色、免疫荧光和流式细胞术分别评估肾小管损伤、TEC凋亡、巨噬细胞摄取和M1/M2极化水平。进行了体内验证实验。
结果： S-AKI小鼠血清尿素、肌酐、KIM-1、促炎因子、促凋亡蛋白以及ADAM17蛋白水平升高，抗凋亡蛋白和MerTK蛋白水平降低，并且M2极化程度减弱。ADSC-EVs在S-AKI小鼠肾组织和LPS诱导的小鼠肾脏巨噬细胞中下调了ADAM17和sMerTK水平，增加了细胞膜上的MerTK、巨噬细胞对凋亡细胞的识别及摄取以及M2极化，表明ADSC-EVs通过调节ADAM17/MerTK介导的巨噬细胞efferocytosis促进了M2极化。敲低MerTK部分逆转了ADSC-EVs调节LPS诱导的小鼠肾脏巨噬细胞efferocytosis和M2极化。体内实验中，上调ADAM17部分抵消了ADSC-EVs对S-AKI后小鼠肾组织TEC凋亡的调控作用。
结论： 通过调节ADAM17促进巨噬细胞efferocytosis和减轻S-AKI后的TEC凋亡及炎症，ADSC-EVs下调了sMerTK水平并上调了肾组织中巨噬细胞膜上的MerTK蛋白水平。
关键词： A disintegrin and metalloprotease protein-17；脂肪源性干细胞衍生的细胞外囊泡；efferocytosis；Myeloid-epithelial-reproductive tyrosine kinase；脓毒症相关急性肾损伤。
版权 © 2025。Elsevier Inc.出版。
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Mechanism of adipose-derived stem cell-derived extracellular vesicles affecting macrophage efferocytosis by mediating ADAM17/MerTK in the apoptosis of tubular epithelial cells after sepsis-associated acute kidney injury