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

• Fujii, Sumie

  Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan・Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University

• Miura, Yasuo

  Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital・Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University

• Fujishiro, Aya

  Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital・Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science

• Shindo, Takero

  Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University

• Shimazu, Yutaka

  Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University

• Hirai, Hideyo

  Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital

• Tahara, Hidetoshi

  Department of Cellular and Molecular Biology, Institute of Biomedical & Health Sciences, Hiroshima University

• Takaori-Kondo, Akifumi

  Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University

• Ichinohe, Tatsuo

  Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University

• Maekawa, Taira

  Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital

Abstract

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.

Journal

• Stem Cells

  Stem Cells 36 (3), 434-445, 2018-02-22

  Wiley-Blackwell

Keywords

• Mesenchymal stem cells
• Graft-versus-host disease
• Extracellular vesicles
• microRNA
• Regulatory T cells
• Naive T cells
• Hematopoietic stem cell transplantation

Details

• CRID: 1050564285808304128
• NII Article ID: 120006454670
• ISSN: 10665099
• HANDLE: 2433/230431
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles