Abstract
Exosomes, extracellular nanovesicles secreted by various cell types, modulate the bone marrow (BM) microenvironment by regulating angiogenesis, cytokine release, immune response, inflammation, and metastasis. Interactions between bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells play crucial roles in MM development. We previously reported that BMSC-derived exosomes directly promote MM cell growth, whereas the other possible mechanisms for supporting MM progression by these exosomes are still not clear. Here, we investigated the effect of BMSC-derived exosomes on the MM BM cells with specific emphasis on myeloid-derived suppressor cells (MDSCs). BMSC-derived exosomes were able to be taken up by MM MDSCs and induced their expansion in vitro. Moreover, these exosomes directly induced the survival of MDSCs through activating STAT3 and STAT1 pathways and increasing the anti-apoptotic proteins Bcl-xL and Mcl-1. Inhibition of these pathways blocked the enhancement of MDSC survival. Furthermore, these exosomes increased the nitric oxide release from MM MDSCs and enhanced their suppressive activity on T cells. Taken together, our results demonstrate that BMSC-derived exosomes activate MDSCs in the BM through STAT3 and STAT1 pathways, leading to increased immunosuppression which favors MM progression.
Highlights
Exosomes are nanometric membrane vesicles derived from late endosomes, released by normal and tumor cells
The mean fluorescence intensity of DIO or RNASelect green fluorescent cell stain (RGFCS) in CD11b+ cells was significantly higher than in the other subpopulations, as well as in total bone marrow (BM) cells (Supplementary Figure S1E and S1F), suggesting a greater capacity for taking up www.impactjournals.com/oncotarget exosomes. These results indicate that BM stromal cells (BMSCs) exosomes are taken up by MM cells, and by the other BM cells such as myeloid-derived suppressor cells (MDSCs)
Since MM develops in the BM, we sought to investigate the effect of BMSCderived exosomes on MDSC activation
Summary
Exosomes are nanometric membrane vesicles derived from late endosomes, released by normal and tumor cells. The exosome, as a communicator, can educate the bone marrow (BM) microenvironment by targeting various cell types in the BM, including macrophages [3], dendritic cells [3], B cells [4, 5], T cells [4, 6], mesenchymal stem cells (MSCs) [7], BM stromal cells (BMSCs) [8], myeloid-derived suppressor cells (MDSCs) [9, 10], as well as tumor cells [8, 11]. We previously reported that exosomes derived from BMSCs could mediate the communication between stromal cells and www.impactjournals.com/oncotarget
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