Cardiac Senescence

NEAT1[LncRNA]

miR-221-3p[miRNA]

Sirt2[mRNA]

mesenchymal stem cells

Homo sapiens (human)

J Nanobiotechnology. 2020 Oct 31;18(1):157. doi: 10.1186/s12951-020-00716-0.

Exosomal LncRNA-NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p.

luciferase assay;

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) (exosome(MIF)) 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. RESULTS: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosome(MIF)). 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(MIF) 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(MIF)-induced anti-senescent effect against Dox. CONCLUSIONS: The results indicated exosome(MIF) 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(MIF) might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy.