Abstract
ObjectivesMesenchymal stem/stromal cells (MSCs) are widely investigated in regenerative medicine thanks to their immunomodulatory properties. They exert their anti-inflammatory function thanks to the secretion of a number of mediators, including proteins and miRNAs, which can be released in the extracellular environment or in the cargo of extracellular vesicles (EVs). However, the role of miRNAs in the suppressive function of MSCs is controversial. The aim of the study was to identify miRNAs that contribute to the immunomodulatory function of human bone marrow-derived MSCs (BM-MSCs).MethodsHuman BM-MSCs were primed by coculture with activated peripheral blood mononuclear cells (aPBMCs). High throughput miRNA transcriptomic analysis was performed using Human MicroRNA TaqMan® Array Cards. The immunosuppressive function of miRNAs was investigated in mixed lymphocyte reactions and the delayed type hypersensitivity (DTH) murine model.ResultsUpon priming, 21 out of 377 tested miRNAs were significantly modulated in primed MSCs. We validated the up-regulation of miR-29a, miR-146a, miR-155 and the down-regulation of miR-149, miR-221 and miR-361 in additional samples of primed MSCs. We showed that miR-155 significantly reduced the proliferation of aPBMCs in vitro and inflammation in vivo, using the DTH model. Analysis of miRNA-mRNA interactions revealed miR-221 as a potential target gene that is down-regulated by miR-155 both in primed MSCs and in aPBMCs.ConclusionHere, we present evidence that miR-155 participates to the immunosuppressive function of human BM-MSCs and down-regulates the expression of miR-221 as a possible inflammatory mediator.
Highlights
Multipotent mesenchymal stromal/stem cells (MSCs) are progenitor cells that have been identified and isolated from many tissues
We showed that miR-155 significantly reduced the proliferation of activated peripheral blood mononuclear cells (aPBMCs) in vitro and inflammation in vivo, using the delayed type hypersensitivity (DTH) model
Analysis of miRNA-mRNA interactions revealed miR-221 as a potential target gene that is down-regulated by miR-155 both in primed MSCs and in aPBMCs
Summary
Multipotent mesenchymal stromal/stem cells (MSCs) are progenitor cells that have been identified and isolated from many tissues. The main molecules that have been involved in their mechanism of action are indoleamine 2,3-dioxygenase (IDO) and inducible nitric oxide synthetase (iNOS) solely in human and murine MSCs, respectively, as well as prostaglandin E2 (PGE2), interleukin-6 (IL-6), transforming growth factor b1 (TGFb1), tumor necrosis factor-inducible gene 6 protein (TSG6), human leucocyte antigen-G5 (HLAG5) [1]. This is not a single molecule but rather a cocktail of molecules that support the immunosuppressive function of MSCs depending on the source, species and environmental context they encounter after in vivo implantation [2]. In addition to proteins and lipids, EV cargo contains mRNAs, lncRNAs and miRNAs, which have been identified as new players in the immunomodulatory activity of MSCs [4]
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