Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p.

Abstract

BACKGROUND:

Exosome transplantation is a promising cell-free therapeutic approach for the treatment of ischemic heart disease. The purpose of this study was to explore whether exosomes derived from Macrophage migration inhibitory factor (MIF) engineered umbilical cord MSCs (ucMSCs) exhibit superior cardioprotective effects in a rat model of AMI and reveal the mechanisms underlying it.

RESULTS:

Exosomes isolated from ucMSCs (MSC-Exo), MIF engineered ucMSCs (MIF-Exo) and MIF downregulated ucMSCs (siMIF-Exo) were used to investigate cellular protective function in human umbilical vein endothelial cells (HUVECs) and H9C2 cardiomyocytes under hypoxia and serum deprivation (H/SD) and infarcted hearts in rats. Compared with MSC-Exo and siMIF-Exo, MIF-Exo significantly enhanced proliferation, migration, and angiogenesis of HUVECs and inhibited H9C2 cardiomyocyte apoptosis under H/SD in vitro. MIF-Exo also significantly inhibited cardiomyocyte apoptosis, reduced fibrotic area, and improved cardiac function as measured by echocardiography in infarcted rats in vivo. Exosomal miRNAs sequencing and qRT-PCR confirmed miRNA-133a-3p significantly increased in MIF-Exo. The biological effects of HUVECs and H9C2 cardiomyocytes were attenuated with incubation of MIF-Exo and miR-133a-3p inhibitors. These effects were accentuated with incubation of siMIF-Exo and miR-133a-3p mimics that increased the phosphorylation of AKT protein in these cells.

CONCLUSION:

MIF-Exo can provide cardioprotective effects by promoting angiogenesis, inhibiting apoptosis, reducing fibrosis, and preserving heart function in vitro and in vivo. The mechanism in the biological activities of MIF-Exo involves miR-133a-3p and the downstream AKT signaling pathway.

• Authors: Wenwu Zhu, Ling Sun, Pengcheng Zhao, Yaowu Liu, Jian Zhang, Yuelin Zhang, Yimei Hong, Yeqian Zhu, Yao Lu, Wei Zhao, Xinguang Chen, Fengxiang Zhang
• Journal: Journal of nanobiotechnology (J Nanobiotechnology) Vol. 19 Issue 1 Pg. 61 (Feb 27 2021) ISSN: 1477-3155 [Electronic] England
• PMID: 33639970 (Publication Type: Journal Article)

Chemical References

• Macrophage Migration-Inhibitory Factors
• MicroRNAs
• Mirn133 microRNA, mouse
• Intramolecular Oxidoreductases
• Mif protein, rat

Topics

• Animals
• Apoptosis
• Cell Line
• Cell Proliferation
• Exosomes (metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Intramolecular Oxidoreductases
• Macrophage Migration-Inhibitory Factors (metabolism, pharmacology)
• Male
• Mesenchymal Stem Cells (drug effects, metabolism)
• MicroRNAs (metabolism)
• Myocardial Infarction (drug therapy, metabolism)
• Myocardium
• Myocytes, Cardiac (metabolism)
• Rats
• Signal Transduction
• Up-Regulation