Membrane particles generated from mesenchymal stromal cells modulate immune responses by selective targeting of pro-inflammatory monocytes

Mesenchymal stromal cells (MSC) are a promising therapy for immunological disorders. However, culture expanded MSC are large and get trapped in the capillary networks of the lungs after intravenous infusion, where they have a short survival time. Hypothetically, living cells are a risk for tumor formation. To reduce risks associated with MSC infusion and improve the distribution in the body, we generated membrane particles (MP) of MSC and MSC stimulated with IFN-gamma (MP gamma). Tracking analysis and electron microscopy indicated that the average size of MP was 120 nm, and they showed a round shape. MP exhibited ATPase, nucleotidase and esterase activity, indicating they are enzymatically active. MP and MP gamma did not physically interact with T cells and had no effect on CD4(+) and CD8(+) T cells proliferation. However, MP and MP gamma selectively bound to monocytes and decreased the frequency of pro-inflammatory CD14(+) CD16(+) monocytes by induction of selective apoptosis. MP and MP gamma increased the percentage of CD90 positive monocytes, and MP gamma but not MP increased the percentage of antiinflammatory PD-L1 monocytes. MP gamma increased mRNA expression of PD-L1 in monocytes. These data demonstrate that MP have immunomodulatory properties and have potential as a novel cell-free therapy for treatment of immunological disorders.