Abstract
BackgroundExosome 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.ResultsExosomes 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.ConclusionMIF-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.
Highlights
Exosomes are small extracellular vesicles with a diameter of 30–150 nm and contain multifarious proteins, mRNAs, microRNAs and additional macromolecules [1]
Characterization of uMSCs and exosomes derived from umbilical cord mesenchymal stem cells (MSCs) (ucMSCs) Multiple differentiation potential of ucMSCs towards osteogenesis, adipogenesis, and chondrogenesis of ucMSCs were confirmed by Alcian blue staining, Oil red staining and Alizarin red staining (Fig. 1a). ucMSCs were positive for surface markers of CD44, CD73, CD105, and negative for markers of CD45, CD31 and CD34 (Fig. 1b)
Western blot showed that migration inhibitory factor (MIF) protein levels significantly decreased in siMIF-MSC compared with ucMSCs and MIF-MSC (Fig. 1d)
Summary
Exosomes are small extracellular vesicles with a diameter of 30–150 nm and contain multifarious proteins, mRNAs, microRNAs and additional macromolecules [1]. A growing number of research studies have shown the regulatory role of exosomes in biological processes, Zhu et al J Nanobiotechnol (2021) 19:61 including organ crosstalk and intercellular signaling [2,3,4]. They have anti-apoptotic effects and are used to treat animals in acute myocardial infarction (AMI) [2]. Included in the cargo of exosomes, microRNAs (miRNAs) have been demonstrated to control important processes that conduce to the pathological consequences of AMI [6]. 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
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