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Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Leads to Downregulation of Cytokine‐Induced Leukocyte Recruitment

Mesenchymal stem cells (MSC) have immunomodulatory properties, but their effects on endothelial cells (EC) and recruitment of leukocytes are unknown. We cocultured human bone marrow‐derived MSC with EC and found that MSC could downregulate adhesion of flowing neutrophils or lymphocytes and their subsequent transendothelial migration. This applied for EC treated with tumor necrosis factor‐α (TNF), interleukin‐1β (IL‐1), or TNF and interferon‐γ combined. Supernatant from cocultures also inhibited endothelial responses. This supernatant had much higher levels of IL‐6 than supernatant from cultures of the individual cells, which also lacked inhibitory functions. Addition of neutralizing antibody against IL‐6 removed the bioactivity of the supernatant and also the immunomodulatory effects of coculture. Studies using siRNA showed that IL‐6 came mainly from the MSC in coculture, and reduction in production in MSC alone was sufficient to impair the protective effects of coculture. Interestingly, siRNA knockdown of IL‐6‐receptor expression in MSC as well as EC inhibited anti‐inflammatory effects. This was explained when we detected soluble IL‐6R receptor in supernatants and showed that receptor removal reduced the potency of supernatant. Neutralization of transforming growth factor‐β indicated that activation of this factor in coculture contributed to IL‐6 production. Thus, crosstalk between MSC and EC caused upregulation of production of IL‐6 by MSC which in turn downregulated the response of EC to inflammatory cytokines, an effect potentiated by MSC release of soluble IL‐6R. These studies establish a novel mechanism by which MSC might have protective effects against inflammatory pathology and cardiovascular disease. Stem Cells 2013;31:2690–2702