Key result
MIF-pretreated MSC exosomes attenuate doxorubicin-induced cardiac senescence and improve LVEF via the NEAT1/Sirt2 pathway.
Why the study?
Doxorubicin has high cardiotoxicity, and the role of exosomes derived from MIF-pretreated MSCs in treating doxorubicin-induced cardiomyopathy remained to be investigated.
Does treatment with exosomes derived from MIF-pretreated MSCs prevent doxorubicin-induced cardiac senescence and dysfunction in a mouse model?
Does treatment with exosomes derived from MIF-pretreated MSCs prevent doxorubicin-induced cardiac senescence and dysfunction in a mouse model?
Exosomes from MIF-pretreated MSCs protect against doxorubicin-induced cardiac senescence and dysfunction by transferring LncRNA-NEAT1, which sponges miR-221-3p to activate Sirt2.
AIMS: 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 exosomeMIF in the treatment of DIC. METHODS AND RESULTS: 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. 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. CONCLUSIONS: 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.
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Zhuang et al. (2020) studied Doxorubicin-induced cardiomyopathy. Exosomes derived from MIF-pretreated mesenchymal stem cells (exosomeMIF) vs. Doxorubicin alone or exosomes from untreated MSCs was evaluated on Cardiac function (LVEF and FS) and cellular senescence. Exosomes derived from MIF-pretreated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence and improved cardiac function through the LncRNA-NEAT1/miR-221-3p/Sirt2 pathway.
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