Exosomes Derived from miR-146a-5p-Enriched Mesenchymal Stem Cells Protect the Cardiomyocytes and Myocardial Tissues in the Polymicrobial Sepsis through Regulating MYBL1

Abstract

Background. At present, the study has confirmed that the mesenchymal stem cell-derived exosomes (MCSs-Exo) possess cardio-protection in sepsis. Nevertheless, the molecular mechanism of the protection of MSCs-Exo in sepsis remains unknown. Therefore, this research is aimed at studying the molecular mechanism. Methods. The effects of MSCs-Exo and miR-146a-5p in LPS-induced cardiomyocytes (H9C2 cells) in vitro were verified by CCK-8, EdU assay, flow cytometry, Western blot assay, and RT-qPCR. The effect of MSCs-Exo in vivo was evaluated by CLP-induced sepsis model. The potential gene in MSCs-Exo was verified by bioinformatics analysis, and the potential target of miR-146a-5p was identified by bioinformatics analysis and luciferase reporter assay. At last, the function of miR-146a-5p and its target genes on LPS-induced cardiomyocytes (H9C2 cells) in vitro was validated by recuse experiment. Results. Our findings revealed that MSCs-Exo could effectively protect cardiomyocytes of inflammation model in vitro and myocardial tissues of sepsis model in vivo. Meanwhile, we found that miR-146a-5p was a potential gene in MSCs-Exo, and MYBL1 was the target gene of miR-146a-5p and negatively regulated by miR-146a-5p. In addition, miR-146a-5p overexpression promoted proliferation and inhibited apoptosis of LPS-induced cardiomyocytes. The rescue experiment demonstrated that miR-146a-5p could effectively repress the inflammatory response of cardiomyocytes via decreasing MYBL1 expression. Conclusion. This study suggests that miR-146a-5p-bearing MSC-derived exosomes may become an effective treatment for sepsis.

MiR‐146a‐5p accelerates sepsis through dendritic cell activation and glycolysis via targeting ATG7

“…[25] Liu et al found that miR-146a-5p overexpression promoted LPS-induced cardiomyocyte proliferation and inhibited their apoptosis, and effectively inhibited the inflammatory response of cardiomyocytes and the progression of sepsis by decreasing the expression of MYBL1. [26] Nevertheless, the function of miR-146a-5p in DCs of sepsis was largely unknown. Autophagy-related gene 7 (ATG7) is a ubiquitin E1-like activating enzyme that has been validated to be implicated in some diseases' autophagy process.…”

Senescence of mesenchymal stem cells: implications in extracellular vesicles, miRNAs and their functional and therapeutic potentials

“…In a mouse model of allergic airway inflammation, MSC-EV suppresses the function of group 2 innate lymphoid cells, reducing inflammatory infiltration and T helper 2 cytokines production by transporting miR-146a-5p [115]. MSC-EV effectively represses the inflammatory response of cardiomyocytes by delivering miR-146a-5p to reduce v-myb myeloblastosis viral oncogene homolog-like 1 (MYBL1) expression [116].…”

Mesenchymal Stem Cell-Derived Exosomes in Cardioprotection: A Novel Application to Prevent Myocardial Injury

“…The characteristics and molecular mechanisms of all the related studies mentioned above are shown in Table 1 (Ref. [31][32][33][34][35][36][40][41][42][43][44][45][46][47]54,55,61,64,71,72]).…”

“…MiR-125b increased the expression of the p53 and BAK1 mRNA [ 41 ]. Upregulating miR-221–3p and miR-146a-5p also inhibited the apoptosis of cardiomyocytes [ 44 , 45 ]. MSC-Exos pretreated with macrophage migration inhibitory factor showed a strong cardioprotective effect.…”