Abstract
BackgroundSepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches. Encouragingly, mesenchymal stromal cells (MSCs) and their produced extracellular vesicles (EVs) have been shown to elicit anti-inflammatory effects in multiple inflammatory conditions including sepsis. However, EVs are generally released from mammalian cells in relatively low amounts, and high-yield isolation of EVs is still challenging due to a complicated procedure. To get over these limitations, vesicles very similar to EVs can be produced by serial extrusions of cells, after which they are called nanovesicles (NVs). We hypothesized that MSC-derived NVs can attenuate the cytokine storm induced by bacterial outer membrane vesicles (OMVs) in mice, and we aimed to elucidate the mechanism involved.MethodsNVs were produced from MSCs by the breakdown of cells through serial extrusions and were subsequently floated in a density gradient. Morphology and the number of NVs were analyzed by transmission electron microscopy and nanoparticle tracking analysis. Mice were intraperitoneally injected with Escherichia coli-derived OMVs to establish sepsis, and then injected with 2 × 109 NVs. Innate inflammation was assessed in peritoneal fluid and blood through investigation of infiltration of cells and cytokine production. The biodistribution of NVs labeled with Cy7 dye was analyzed using near-infrared imaging.ResultsElectron microscopy showed that NVs have a nanometer-size spherical shape and harbor classical EV marker proteins. In mice, NVs inhibited eye exudates and hypothermia, signs of a systemic cytokine storm, induced by intraperitoneal injection of OMVs. Moreover, NVs significantly suppressed cytokine release into the systemic circulation, as well as neutrophil and monocyte infiltration in the peritoneum. The protective effect of NVs was significantly reduced by prior treatment with anti-interleukin (IL)-10 monoclonal antibody. In biodistribution study, NVs spread to the whole mouse body and localized in the lung, liver, and kidney at 6 h.ConclusionsTaken together, these data indicate that MSC-derived NVs have beneficial effects in a mouse model of sepsis by upregulating the IL-10 production, suggesting that artificial NVs may be novel EV-mimetics clinically applicable to septic patients.
Highlights
Sepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches
We have previously shown that outer membrane vesicles (OMVs) provoke a sepsis-like inflammatory response and activate cardiomyocytes resulting in sepsis-associated cardiac dysfunction [26, 27]
In this study, we show that NVs derived from mesenchymal stromal cells (MSCs) are enriched in proteins released by natural extracellular vesicles (EVs) and have protective immunomodulatory effects in vitro as well as in a mouse model of sepsis provoked by bacterial OMVs
Summary
Sepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches. We hypothesized that MSC-derived NVs can attenuate the cytokine storm induced by bacterial outer membrane vesicles (OMVs) in mice, and we aimed to elucidate the mechanism involved Advanced infectious diseases such as sepsis are associated with excessive release of cytokines into the systemic circulation, induced by an aggressive host immune response to an infection [1]. Treatment of patients with sepsis with MSCs of various origins has resulted in reduced mortality and improved myocardial function in a mouse sepsis model [6, 7] This protective effect of MSCs has been mainly ascribed to the interaction of MSCs with immune cells such as macrophages in biological fluids and tissues, resulting in a diminished secretion of pro-inflammatory cytokines [6, 7]
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