Zhuang Lei, Xia Wenzheng, Chen Didi, Ye Yijia, Hu Tingting, Li Shiting, Hou Meng
Department of Hepatobiliary Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
J Nanobiotechnology. 2020 Oct 31;18(1):157. doi: 10.1186/s12951-020-00716-0.
The chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers. However, its high cardiotoxicity hampered its clinical use. Exosomes derived from stem cells showed a therapeutic effect against Dox-induced cardiomyopathy (DIC). Previous studies reported that exosomes derived from mesenchymal stem cells (MSCs) pretreated with macrophage migration inhibitory factor (MIF) (exosome) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). This study aimed to investigate the role of exosome in the treatment of DIC.
Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosome). Regulatory lncRNAs activated by MIF pretreatment were explored using genomics approaches. Fluorescence-labeled exosomes were tracked in vitro by fluorescence imaging. In vivo and in vitro, miR-221-3p mimic transfection enforced miR-221-3p overexpression, and senescence-associated β-galactosidase assay was applied to test cellular senescence. Exosomal delivering LncRNA-NEAT1 induced therapeutic effect in vivo was confirmed by echocardiography. It demonstrated that exosomes recovered the cardiac function and exerted the anti-senescent effect through LncRNA-NEAT1 transfer against Dox. TargetScan and luciferase assay showed that miR-221-3p targeted the Sirt2 3'-untranslated region. Silencing LncRNA-NEAT1 in MSCs, miR-221-3p overexpression or Sirt2 silencing in cardiomyocytes decreased the exosome-induced anti-senescent effect against Dox.
The results indicated exosome serving as a promising anti-senescent effector against Dox-induced cardiotoxicity through LncRNA-NEAT1 transfer, thus inhibiting miR-221-3p and leading to Sirt2 activation. The study proposed that exosome might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy.
化疗药物阿霉素（Dox）被广泛用于治疗多种癌症。然而，其高心脏毒性阻碍了它的临床应用。来源于干细胞的外泌体对阿霉素诱导的心肌病（DIC）显示出治疗效果。先前的研究报道，用巨噬细胞迁移抑制因子（MIF）预处理的间充质干细胞（MSCs）来源的外泌体（exosome）通过调节长链非编码RNA/微小RNA（lncRNAs/miRs）发挥心脏保护作用。本研究旨在探讨外泌体在DIC治疗中的作用。
从对照MSCs（exosome）和MIF预处理的MSCs中分离出外泌体。使用基因组学方法探索由MIF预处理激活的调控lncRNAs。通过荧光成像在体外追踪荧光标记的外泌体。在体内和体外，转染miR-221-3p模拟物可增强miR-221-3p的过表达，并应用衰老相关β-半乳糖苷酶检测来测试细胞衰老。超声心动图证实外泌体递送LncRNA-NEAT1在体内具有治疗效果。结果表明，外泌体可恢复心脏功能，并通过LncRNA-NEAT1转移对阿霉素发挥抗衰老作用。TargetScan和荧光素酶检测表明，miR-221-3p靶向Sirt2的3'-非翻译区。在MSCs中沉默LncRNA-NEAT1、在心肌细胞中过表达miR-221-3p或沉默Sirt2可降低外泌体对阿霉素诱导的抗衰老作用。
结果表明，外泌体通过LncRNA-NEAT1转移，作为一种有前景的抗衰老效应物对抗阿霉素诱导的心脏毒性，从而抑制miR-221-3p并导致Sirt2激活。该研究提出，外泌体在癌症化疗期间可能有潜力作为一种心脏保护治疗剂。
