Abstract
Mesenchymal stem/stromal cells (MSCs) represent a promising tool to treat cardiovascular diseases. One mode of action through which MSCs exert their protective effects is secretion of extracellular vesicles (EVs). Recently, we demonstrated that rat adipose-derived MSC-overexpressing stem cell factor (SCF) can induce endogenous regenerative processes and improve cardiac function. In the present work, we isolated EVs from intact, GFP- or SCF-overexpressing rat MSC and analyzed microarray datasets of their miRNA cargo. We uncovered a total of 95 differentially expressed miRNAs. We did not observe significant differences between EVs from GFP-MSC and SCF-MSC that may indicate intrinsic changes in MSC after viral transduction. About 80 miRNAs were downregulated in EVs from both SCF- or GFP-MSC. We assembled the miRNA-based network and found several nodes of target genes among which Vim Sept3 and Vsnl1 are involved in regulation of cellular migration that is consistent with our previous EVs data. Topological analyses of the network also revealed that among the downregulated miRNA-rno-miRNA-128-3p that regulates plenty of targets is presumably associated with chemokine signaling pathways. Overall, our data suggest that genetic modification of MSC has a great impact on their miRNA composition and provide novel insights into the regulatory networks underlying EV effects.
Highlights
During the last decade, enormous research in the field of extracellular vesicles (EV) has been carried out
Mesenchymal stem/stromal cells (MSCs) are often genetically engineered with viral vectors to overexpress specific miRNAs or proteins that are incorporated into the EV cargo (Xin et al, 2013; Yu et al, 2015; O’Brien et al, 2018; Sun et al, 2020; Zilun et al, 2020)
Being aware that MSCs are very sensitive to their microenvironment and given the importance of miRNAs in regulating multiple cellular responses, we aimed at characterizing the expression profile of miRNAs in EVs from MSCs
Summary
Enormous research in the field of extracellular vesicles (EV) has been carried out. Beneficial therapeutic effects of MSC-secretome are miRNA Alteration in EVs mediated at least in part by extracellular vesicles (Nooshabadi et al, 2018). This finding contributed to the development of MSC-based cell-free approach using MSC-derived EVs as therapeutic agents itself or as carrier particles. The engineering of EV as drug delivery vehicles requires loading strategies different from those used for liposomes, such as overexpression of proteins and miRNAs into parental cells. Comprehensive studies like this are needed for quality control of EV cargo compositions and the safety and efficacy assessment of EVs from genetically modified MSC before they can be used in clinical applications
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