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 exosomeMIF in the treatment of DIC.

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 decreased 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 inhibiting 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.

• Authors: Lei Zhuang, Wenzheng Xia, Didi Chen, Yijia Ye, Tingting Hu, Shiting Li, Meng Hou
• Journal: Journal of nanobiotechnology (J Nanobiotechnology) Vol. 18 Issue 1 Pg. 157 (Oct 31 2020) ISSN: 1477-3155 [Electronic] England
• PMID: 33129330 (Publication Type: Journal Article)

Chemical References

• MIRN221 microRNA, human
• Macrophage Migration-Inhibitory Factors
• MicroRNAs
• NEAT1 long non-coding RNA, human
• RNA, Long Noncoding
• Doxorubicin
• SIRT2 protein, human
• Sirtuin 2
• Intramolecular Oxidoreductases
• MIF protein, human

Topics

• Animals
• Cardiotoxicity (prevention & control)
• Doxorubicin (adverse effects, pharmacology)
• Exosomes (chemistry)
• Gene Expression Regulation
• Heart Injuries (chemically induced, genetics, prevention & control)
• Humans
• Intramolecular Oxidoreductases (chemistry)
• Macrophage Migration-Inhibitory Factors (chemistry)
• Male
• Mesenchymal Stem Cells (chemistry, cytology)
• Mice
• MicroRNAs (metabolism)
• Myocytes, Cardiac (drug effects)
• RNA, Long Noncoding (metabolism)
• Signal Transduction
• Sirtuin 2 (metabolism)