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A substantial proportion of patients with acute graft‐versus‐host disease (aGVHD) respond to cell therapy with culture‐expanded human bone marrow mesenchymal stromal/stem cells (BM‐MSCs). However, the mechanisms by which these cells can ameliorate aGVHD‐associated complications remain to be clarified. We show here that BM‐MSC‐derived extracellular vesicles (EVs) recapitulated the therapeutic effects of BM‐MSCs against aGVHD. Systemic infusion of human BM‐MSC‐derived EVs prolonged the survival of mice with aGVHD and reduced the pathologic damage in multiple GVHD‐targeted organs. In EV‐treated GVHD mice, CD4+ and CD8+ T cells were suppressed. Importantly, the ratio of CD62L‐CD44+ to CD62L + CD44‐ T cells was decreased, suggesting that BM‐MSC‐derived EVs suppressed the functional differentiation of T cells from a naive to an effector phenotype. BM‐MSC‐derived EVs also preserved CD4 + CD25 + Foxp3+ regulatory T cell populations. In a culture of CD3/CD28‐stimulated human peripheral blood mononuclear cells with BM‐MSC‐derived EVs, CD3+ T cell activation was suppressed. However, these cells were not suppressed in cultures with EVs derived from normal human dermal fibroblasts (NHDFs). NHDF‐derived EVs did not ameliorate the clinical or pathological characteristics of aGVHD in mice, suggesting an immunoregulatory function unique to BM‐MSC‐derived EVs. Microarray analysis of microRNAs in BM‐MSC‐derived EVs versus NHDF‐derived EVs showed upregulation of miR‐125a‐3p and downregulation of cell proliferative processes, as identified by Gene Ontology enrichment analysis. Collectively, our findings provide the first evidence that amelioration of aGVHD by therapeutic infusion of BM‐MSC‐derived EVs is associated with the preservation of circulating naive T cells, possibly due to the unique microRNA profiles of BM‐MSC‐derived EVs. S tem  C ells   2018;36:434–445

stem cells

Graft‐Versus‐Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell‐Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations