Mesenchymal stem cell-derived extracellular vesicles regulate M1 and M2 macrophages

Mesenchymal stem cells (MSCs) can respond to micrenvironmental cues to exert immune suppression or stimulation. Both MSCs and macrophages (MΦs) are part of the bone marrow microenvironment. Separately, both cell types can influence the behavior of breast cancer cells towards dormancy and reverse dormancy. This study assessed the MΦ−ΜSC axis, specifically determined how activated MSCs could influence the type of MΦ. The toll like receptor 4 (TLR4) on MSCs was activated with LPS and then used to assess how this influence the type of MΦ. We demonstrated that activated MSCs can convert M2 MΦs to M1 type and vice versa. Interestingly, the transition is not stable showing re-transition to the original type. This suggested the ability of activated and inactivated MSCs to maintain homeostasis by dictating the MΦ type. We quantitated cytokine levels in the media from activated and inactivated MSCs without evidence of significant changes. Using siRNA and pharmacological inhibitors, the results supported a role for MSC derived extracellular vesicles (EVs) as mediators of MΦ transition. We assessed our published miRNA arrays from cancer activated MSCs and identified one of four potential miRNAs that has been reported to regulate myeloid cells. We further investigated molecular changes with RNA-Seq using extracts from activated and inactivated MSCs, and EVs from M1 and M2 MΦs