miR-155 Contributes to the Immunoregulatory Function of Human Mesenchymal Stem Cells

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.

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“…miR-181c in UC-MSC-EVs repressed inflammation by suppressing TLR4 ( 110 ). miR-155 has been shown to significantly reduce the proliferation of activated PBMCs, by targeting miR-221 as a potential inflammation mediator ( 111 ). miR-223 in MSC-EVs could also restrain adhesion and migration of T cells ( 112 ).…”

Engineering Extracellular Matrix‐Bound Nanovesicles Secreted by Three‐Dimensional Human Mesenchymal Stem Cells

“…Another possible reason is the miRNAs, for instance, miR‐21 and miR‐155, participating in immunomodulation. [ 54,56 ] Moreover, variations in other cargo such as the non‐coding Y RNAs (83–112 nucleotides) provide additional explanation, because Y RNAs regulate macrophage polarization via cytokine IL‐10. [ 57 ] In addition, different signaling pathways being activated could lead to the difference.…”

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“…Although not demonstrated to be directly related, the detection of TGFBI/BIGH3 in the cargo of both small and large size EVs might explain the protective role of EVs in OA as seen by the group of D. Noël* ( Ruiz et al, 2020 ). Priming MSCs was shown to modify their proteome and secretome as well as their content in miRNAs, thereby modulating their functional properties, in particular their immunoregulatory function as described by the group of D. Noël* ( Pers et al, 2021 ). Parental cell priming also impacts the cargo of EVs and inflammatory priming was reported to modulate cytokine and miRNA levels in EVs and enhance their anti-inflammatory potency ( Ragni et al, 2020 ).…”