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Extracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSCs) have been proposed to be a key mechanistic link in the therapeutic efficacy of cells in response to cellular injuries through paracrine effects. We hypothesize that inflammatory stimulation of MSCs results in the release of EVs that have greater anti-inflammatory effects. The present study evaluates the immunomodulatory abilities of EVs derived from inflammation-stimulated and naive MSCs (MSCEv 1 and MSCEv, respectively) isolated using a current Good Manufacturing Practice-compliant tangential flow filtration system. Detailed characterization of both EVs revealed differences in protein composition, cytokine profiles, and RNA content, despite similarities in size and expression of common surface markers. MSCEv 1 further attenuated release of pro-inflammatory cytokines in vitro when compared to MSCEv, with a distinctly different pattern of EV-uptake by activated primary leukocyte subpopulations. The efficacy of EVs was partially attributed to COX2/PGE 2 expression. The present study demonstrates that inflammatory stimulation of MSCs renders release of EVs that have enhanced anti-inflammatory properties partially due to COX2/PGE 2 pathway alteration. STEM CELLS 2018;36:79-90 SIGNIFICANCE STATEMENTPrevious work has identified mesenchymal stromal cell-derived extracellular vesicles (MSCEv) as mediators of cell-cell communication and effectors of cellular/tissue change. This study isolated MSCEv using a clinically propitious filtration system after stimulation with inflammatory cytokines, characterized their composition, and evaluated their effect on inflammation, along with their potential mechanism of action and interaction with potential target cells. This study identified important compositional differences between control and stimulated MSCEv in cytokine and RNA content. Furthermore, stimulated MSCEv attenuate TNF-a and IFN-g release from activated splenocytes compared to standard MSCEv (and liposomal controls). The nature of MSCEv interaction with cells likely involves cellular internalization, so this study fluorescently labeled MSCEv prior to coculture with activated leukocytes to determine changes in uptake activity in response to several antigens. These studies demonstrate a specific anti-inflammatory, MSCEvmediated response and the capacity to change efficacy in response to inflammatory cues, creating the foundation for enhancing the efficacy of translational efforts using MSCEv for targeting inflammatory injuries and diseases. This represents a new paradigm for generation of extracellular vesicles targeting specific pathologies.

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This study was done to discover the underlying mechanism of the inhibitory effect of sericin against colon tumorigenesis. Mice were fed a diet with 30 g/kg sericin for 115 d, and given a weekly injection of 1,2-dimethylhydrazine (10 mg/kg body weight) for the initial 10 wk. Dietary supplemental sericin caused a 62% reduction in the incidence of colonic adenoma (P<0.05), but did not affect the incidence of colonic adenocarcinoma. Sericin intake significantly reduced the number of colon adenomas. Consumption of sericin significantly reduced the BrdU labeling index of colonic proliferating cells and the expression of colonic c-myc and c-fos. The levels of colonic 8-hydroxydeoxyguanosine, 4-hydroxynonenal, and inducible nitric oxide synthase protein were significantly suppressed by sericin. The results suggest that dietary sericin suppresses the development of colon tumors by reducing oxidative stress, cell proliferation, and nitric oxide production.