TY - JOUR
T1 - 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
AU - Fujii, Sumie
AU - Miura, Yasuo
AU - Fujishiro, Aya
AU - Shindo, Takero
AU - Shimazu, Yutaka
AU - Hirai, Hideyo
AU - Tahara, Hidetoshi
AU - Takaori-Kondo, Akifumi
AU - Ichinohe, Tatsuo
AU - Maekawa, Taira
N1 - Funding Information:
We thank Yoko Nakagawa (Kyoto University) and Ikuko Fukuba (Hiroshima University) for their excellent technical assistance. We also thank Drs. Mariko Ikuo and Shigeyuki Teranishi (Hiroshima University) for their EV analysis. This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (#15K09453, #16K07171, and #17H04264 to Y.M., T.M., and T.I., respectively) and from the Japan Agency for Medical Research and Development (AMED) (17ek0510022s0601, to T.I.). This work was also supported in part by the Program of the Network-Type Joint Usage/Research Disaster Medical Science of Hiroshima University, Nagasaki University, and Fukush-ima Medical University (Y.M., S.F., and T.I.).
Funding Information:
H.H. received research funding from Kyowa Hakko Kirin and Novartis Pharma. H.T. is a founder and the chairman/chief executive officer of MiRTeL Co. LTD., and owns stock in MiRTeL Co. LTD. T.M. received research funding from Bristol-Meyers Squibb. The other authors indicated no potential conflicts of interest.
PY - 2018/3
Y1 - 2018/3
N2 - 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. Stem Cells 2018;36:434–445.
AB - 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. Stem Cells 2018;36:434–445.
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U2 - 10.1002/stem.2759
DO - 10.1002/stem.2759
M3 - Article
C2 - 29239062
AN - SCOPUS:85039168838
VL - 36
SP - 434
EP - 445
JO - Stem Cells
JF - Stem Cells
SN - 1066-5099
IS - 3
ER -