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, 2017, 4150705

MiRNA-Sequence Indicates That Mesenchymal Stem Cells and Exosomes Have Similar Mechanism to Enhance Cardiac Repair

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MiRNA-Sequence Indicates That Mesenchymal Stem Cells and Exosomes Have Similar Mechanism to Enhance Cardiac Repair

Lianbo Shao et al. Biomed Res Int.

Abstract

Mesenchymal stem cells (MSCs) repair infarcted heart through paracrine mechanism. We sought to compare the effectiveness of MSCs and MSC-derived exosomes (MSC-Exo) in repairing infarcted hearts and to identify how MSC-Exo mediated cardiac repair is regulated. In a rat myocardial infarction model, we found that MSC-Exo inhibited cardiac fibrosis, inflammation, and improved cardiac function. The beneficial effects of MSC-Exo were significantly superior compared to that of MSCs. To explore the potential mechanisms underlying MSC-Exo's effects, we performed several in vitro experiments and miRNA-sequence analysis. MSC-Exo stimulated cardiomyocyte H9C2 cell proliferation, inhibited apoptosis induced by H2O2, and inhibited TGF-β induced transformation of fibroblast cell into myofibroblast. Importantly, novel miRNA sequencing results indicated that MSC-Exo and MSCs have similar miRNA expression profile, which could be one of the reasons that MSC-Exo can replace MSCs for cardiac repair. In addition, the expression of several miRNAs from MSC-Exo was significantly different from that of MSCs, which may explain why MSC-Exo has better therapeutic effect than MSCs. In conclusion, this study demonstrates that MSC-Exo could be used alone to promote cardiac repair and are superior to MSCs in repairing injured myocardium.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Characterization of MSCs and MSC-Exo. (a) The morphology of MSCs was observed under microscope; scale bar = 200 μm. (b) Flow-cytometric analyses showed that cultured MSCs from rats were positive for CD90 and negative for CD45 and CD11b. (c) The morphology of MSC-Exo was observed under an electron microscope. Bar = 100 nm. (d) The expression of exosome marker CD63 was identified by flow-cytometric analyses. (e) Western blot analysis of CD63 protein in MSC-Exo.
Figure 2
Figure 2
Analysis of rat myocardial function and inflammation after MSC-Exo and MSCs transplantation. (a) Representative echocardiography images of left ventricular ejection fraction (LVEF) and fraction shorting (FS) in the PBS, MSCs, and MSC-Exo-injected groups. LVEF and FS were measured preoperatively and at 1 and 7 days post-MI induction (n = 5/group). (b) MSC-Exo reduces inflammation in the peri-infarct myocardium. PBS control, MSCs, and MSC-Exo were injected into the peri-infarct zones and heart samples were harvested 1 week after injection. Heart sections were stained with anti-CD68 antibody (green) to detect inflammation in the peri-infarct zone. Bar = 50 μm. # represents MSCs group versus PBS group, P < 0.05; & represents MSC-Exo group versus PBS group, P < 0.05.
Figure 3
Figure 3
(a) miRNA expression profiling. Total RNA was extracted from MSC-Exo and MSCs using Qiagen miRNeasy Mini Kit. The sequence was detected by HiSeq 2500 platform. The RPKM stands for the miRNA expression. RPKM: read per kilobases per millionreads. (b) Heat map of miRNA sequencing data from MSC-Exo and MSCs. Green: downregulated. Red: upregulated.
Figure 4
Figure 4
Differentially expressed miRNAs, pathway analysis, and gene ontology (GO) in MSC-Exo compared with MSCs. (a) List of the differentially expressed miRNAs and the log2 fold-changes are indicated. (b) Pathways associated with increased expression of miRNAs in MSC-Exo. The vertical axis is the pathway category and the horizontal axis is the enrichment of pathways. (c) GO category associated with increased expression of miRNAs in MSC-Exo. The vertical axis is the GO category, and the horizontal axis is the enrichment of GO.

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