Jia Haoyuan, Liu Wanzhu, Zhang Bin, Wang Juanjuan, Wu Peipei, Tandra Nitin, Liang Zhaofeng, Ji Cheng, Yin Lei, Hu Xinyuan, Yan Yongmin, Mao Fei, Zhang Xu, Yu Jing, Xu Wenrong, Qian Hui
Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, P. R. China.
Department of Emergency, The Affiliated People's Hospital of Jiangsu University8 Dianli Road, Zhenjiang 212002, Jiangsu, P. R. China.
Am J Transl Res. 2018 Jan 15;10(1):101-113. eCollection 2018.
The clinical application of cisplatin is restricted by its side effects of nephrotoxicity. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-ex) have an important effect in tissue injury repair. Our previous work discovered that pretreatment with human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-ex) alleviated cisplatin-induced acute kidney injury (AKI) by activating autophagy both and . In this study, we further explored the mechanisms of hucMSC-ex in autophagy for preventing cisplatin-induced nephrotoxicity. We discovered that 14-3-3ζ was contained in hucMSC-ex, and knockdown and overexpression 14-3-3ζ reduced and enhanced the autophagic activity respectively. Furthermore, Knockdown of 14-3-3ζ alleviated the preventive effect of hucMSC-ex. In contrast, overexpression of 14-3-3ζ enhanced the effect. Further results confirmed that hucMSC-ex increased ATG16L expression and that 14-3-3ζ interacted with ATG16L, promoting the localization of ATG16L at autophagosome precursors. In this study, we revealed that hucMSC-ex-delivered 14-3-3ζ interacted with ATG16L to activate autophagy. Our findings suggest that 14-3-3ζ is a novel mechanism for MSC-exosomes-activated autophagy and provides a new strategy for the prevention of cisplatin-induced nephrotoxicity.
顺铂的临床应用受到其肾毒性副作用的限制。人脐带间充质干细胞来源的外泌体（hucMSC-ex）在组织损伤修复中具有重要作用。我们之前的研究发现，用人脐带间充质干细胞来源的外泌体（hucMSC-ex）预处理可通过激活自噬减轻顺铂诱导的急性肾损伤（AKI）。在本研究中，我们进一步探讨了hucMSC-ex在自噬中预防顺铂诱导的肾毒性的机制。我们发现hucMSC-ex中含有14-3-3ζ，敲低和过表达14-3-3ζ分别降低和增强了自噬活性。此外，敲低14-3-3ζ减轻了hucMSC-ex的预防作用。相反，过表达14-3-3ζ增强了该作用。进一步的结果证实，hucMSC-ex增加了ATG16L的表达，并且14-3-3ζ与ATG16L相互作用，促进了ATG16L在自噬体前体处的定位。在本研究中，我们揭示了hucMSC-ex传递的14-3-3ζ与ATG16L相互作用以激活自噬。我们的研究结果表明，14-3-3ζ是MSC外泌体激活自噬的一种新机制，并为预防顺铂诱导的肾毒性提供了一种新策略。
