Exosomal LncRNA–NEAT1 Derived from MIF-Treated Mesenchymal Stem Cells Protected Against Doxorubicin-Induced Cardiac Senescence Through Sponging miR-221-3p

Abstract

Background: 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) (exosomeMIF) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). This study aimed to investigate the role of exosome MIF in the treatment of DIC. Method: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF). 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. Finding: It demonstrated that exosomesMIF 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 ruined the exosomeMIF -induced anti-senescent effect against Dox. Interpretation: The results indicated exosomeMIF serving as a promising anti-senescent effector against Dox-induced cardiotoxicity through LncRNA–NEAT1 transfer, thus sponging miR-221-3p and leading to Sirt2 activation. The study proposed that exosomeMIF might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy. Funding Statement: The present study was supported by the National Natural Science Foundation of China (grant nos. 81974186; 81671205 to STL), the Science and Technology Planning Project of Wenzhou (grant no. Y20190445 to LZ), and the Medical Science and Technology Project of Zhejiang Province (grant no. 2018KY517 to MH). Declaration of Interests: Not applicable. Ethics Approval Statement: All study procedures were approved by the Institutional Animal Care and Use Committee of Wenzhou Medical University. This study was conducted in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Academy Press (NIH, revised in 1996).