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.
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(tm) 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 a, and IFN g; 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.
Stem cells and development