Doxorubicin-Induced Cardiotoxicity May Be Alleviated by Bone Marrow Mesenchymal Stem Cell-Derived Exosomal lncRNA via Inhibiting Inflammation

Abstract

Chao Tian,1,* Yanyan Yang,2,* Bing Li,3 Meixin Liu,4 Xiangqin He,4 Liang Zhao,4 Xiaoxia Song,4 Tao Yu,4,5 Xian-Ming Chu1,6 1Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Immunology, Basic Medicine School, Qingdao University, Qingdao, People’s Republic of China; 3Department of Genetics, Basic Medicine School, Qingdao University, Qingdao, People’s Republic of China; 4Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 5Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 6Department of Cardiology, The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tao Yu, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China, Tel/Fax [phone], Email [email protected] Xian-Ming Chu, Department of Cardiology, the Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266100, People’s Republic of China, Tel [phone], Email [email protected]: To explore the therapeutic mechanism of bone marrow mesenchymal stem cells derived exosomes (BMSC-Exos) for doxorubicin (DOX)-induced cardiotoxicity (DIC) and identify the long noncoding RNAs’ (lncRNAs’) anti-inflammation function derived by BMSC-Exos.Materials and Methods: High-throughput sequencing and transcriptome bioinformatics analysis of lncRNA were performed between DOX group and BEC (bone marrow mesenchymal stem cells derived exosomes coculture) group. Elevated lncRNA (ElncRNA) in the cardiomyocytes of BEC group compared with DOX group were confirmed. Based on the location and co-expression relationship between ElncRNA and its target genes, we predicted two target genes of ElncRNA, named cis_targets and trans_targets. The target genes were analyzed by enrichment analyses. Then, we identified the key cellular biological pathways regulating DIC. Experiments were performed to verify the therapeutic effects of exosomes and the origin of lncRNAs in vitro and in vivo.Results: Three hundred and one lncRNAs were differentially expressed between DOX and BEC groups (fold change > 1.5 and p < 0.05), of which 169 lncRNAs were elevated in the BEC group compared with the DOX group. GO enrichment analysis of target genes of ElncRNAs showed that they were predominantly involved in inflammation-associated processes. KEGG analysis indicated that their regulatory pathways were mainly involved in oxidative stress-induced inflammation and proliferation of cardiomyocyte. The verification experiments in vitro showed that the oxidative stress and cell deaths were decreased in BEC groups. Moreover, from the top 10 ElncRNAs identified in the sequencing results, MSTRG.98097.4 and MSTRG.58791.2 were both decreased in the DOX group and elevated in BEC group. While in verification experiments in vivo, only the expression of MSTRG.58791.2 is consistent with the result in vitro.Conclusion: Our results show that ElncRNA, MSTRG.58791.2, is possibly secreted by the BMSC-Exos and able to alleviate DIC by suppressing inflammatory response and inflammation-related cell death.Keywords: doxorubicin-induced cardiotoxicity, exosomes, inflammation, transcriptome sequencing analysis

Keywords

• doxorubicin-induced cardiotoxicity
• exosomes
• inflammation
• transcriptome sequencing analysis