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.

[Retracted] Mesenchymal Stem Cell‐Derived Exosomes and Their Potential Agents in Hematological Diseases

“…Exosomes are 30 ∼ 150 nm extracellular vesicles (EVs) and membrane bound nanoparticles that contain bioactive substances like proteins, DNA, RNAs, and cytokines [ 20 – 22 ]. These bioactive components play key roles in intercellular, intertissue, and cross-species communications [ 20 ] and participate in formation and progression of tumor microenvironment (TME) remodeling, intracellular homeostasis, and drug resistance [ 23 , 24 ].…”

Exosomes Derived From miR-214-3p Overexpressing Mesenchymal Stem Cells Promote Myocardial Repair

“…Gene modi cation to produce exosomes is cheap, convenient and e cient, compared with electroporation and ultrasound methods. Exosomes derived from genetically modi ed stem cells have been used effectively to repair injured hearts as a new cell-free therapy [34][35][36] 37 . Our previous studies also showed that MIF engineered MSC-derived exosomes can reduce myocardial infarction size and improve cardiac function 9 .…”

Role of acetylation in doxorubicin-induced cardiotoxicity

“…MiR-221-3p is a target ceRNA of NEAT1 and its enrichment in aged myocardial tissues could impair myocardium regeneration by suppressing the sirtuin family [ [107] , [108] , [109] ]. MiR-221-3p interacts with the 3′-UTR of Sirt2 to inhibit Sirt2 expression at the post-transcriptional level, and Sirt2 activates AMPK to attenuate age-related cardiac hypotrophy and DOX-induced cardiotoxicity, implying that the exosome/NEAT1/miR-221-3p/Sirt2 pathway attenuates cardiomyocyte senescence [ 110 , 111 ].…”