title: Extracellular Vesicles Released from Human Umbilical Cord-Derived Mesenchymal Stromal Cells Prevent Life-Threatening Acute Graft-Versus-Host Disease in a Mouse Model of Allogeneic Hematopoietic Stem Cell Transplantation.
abstract: Mesenchymal stromal cells (MSCs) are attractive agents for the prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, safety concerns remain about their clinical application. In this study, we explored whether extracellular vesicles released from human umbilical cord-derived MSCs (hUC-MSC-EVs) could prevent aGVHD in a mouse model of allo-HSCT. hUC-MSC-EVs were intravenously administered to recipient mice on days 0 and 7 after allo-HSCT, and the prophylactic effects of hUC-MSC-EVs were assessed by observing the in vivo manifestations of aGVHD, histologic changes in target organs, and recipient mouse survival. We evaluated the effects of hUC-MSC-EVs on immune cells and inflammatory cytokines by flow cytometry and ProcartaPlex™ Multiplex Immunoassays, respectively. The in vitro effects of hUC-MSC-EVs were determined by mitogen-induced proliferation assays. hUC-MSC-EVs alleviated the in vivo manifestations of aGVHD and the associated histologic changes and significantly reduced the mortality of the recipient mice. Recipients treated with hUC-MSC-EVs had significantly lower frequencies and absolute numbers of CD3+CD8+T cells; reduced serum levels of IL-2, TNF-α, and IFN-γ; a higher ratio of CD3+CD4+and CD3+CD8+T cells; and higher serum levels of IL-10. An in vitro experiment demonstrated that hUC-MSC-EVs inhibited the mitogen-induced proliferation of splenocytes in a dose-dependent manner, and the cytokine changes were similar to those observed in vivo. This study indicated that hUC-MSC-EVs can prevent life-threatening aGVHD by modulating immune responses. These data provide the first evidence that hUC-MSC-EVs represent an ideal alternative in the prophylaxis of aGVHD after allo-HSCT.
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .|2 Department of Hematology and Oncology, Laoshan Branch, No. 401 Hospital of Chinese PLA , Qingdao, China .
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Zhenyang
authors.initials: Z
authors.lastname: Gu
authors.affiliation: 3 Bone Marrow Transplantation Center , Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China .
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhao
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Feiyan
authors.initials: F
authors.lastname: Wang
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Ailing
authors.initials: A
authors.lastname: Deng
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Shasha
authors.initials: S
authors.lastname: Zhao
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Huaping
authors.initials: H
authors.lastname: Wei
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Lixun
authors.initials: L
authors.lastname: Guan
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Zhe
authors.initials: Z
authors.lastname: Gao
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Daihong
authors.initials: D
authors.lastname: Liu
authors.affiliation: 1 Department of Hematology, Chinese People's Liberation Army (PLA) General Hospital , Beijing, China .
authors.forename: Chunji
authors.initials: C
authors.lastname: Gao
mesh_terms: D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007165:Immunosuppression Therapy; D018836:Inflammation Mediators / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000166:cytology; D014184:Transplantation, Homologous / Q000009:adverse effects; D014470:Umbilical Cord / Q000166:cytology*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D018836:Inflammation Mediators
keywords: exosomes; extracellular vesicles; graft-versus-host disease; hematopoietic stem cell transplantation; mesenchymal stromal cells; microvesicles