Abstract
ObjectiveMesenchymal stromal cell–derived exosomes have been applied for the treatment of several immune diseases. This study aimed to explore the effect of human bone marrow–derived mesenchymal stem cell (hBMSC)–derived exosomes on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).MethodshBMSC were cultured, and the culture supernatants were then collected to prepare exosomes using total exosome isolation reagent from Invitrogen. Mouse aGVHD model was established by allogeneic cell transplantation and injected with hBMSC-derived exosomes (Msc-exo) via tail vein. Exosomes from human fibroblast (Fib-exo) were used as the treatment control. The effects of Msc-exo on dendritic cells, CD4+, and CD8+ T cells in aGVHD mice were analyzed through flow cytometry. The impact on inflammatory cytokines was tested by ELISA. Besides, the body weight, survival rate, and clinical score of treated mice were monitored.ResultsMsc-exo were successfully prepared. aGVHD mice injected with Msc-exo led to 7–8-fold increase of the CD8α+ conventional dendritic cells (cDCs) and CD11b+ cDCs compared with the controls. In addition, Msc-exo altered the T help and Treg subpopulation, and decreased the cytotoxicity and proliferation of cytotoxic T cells to favor inflammatory inhibition in aGVHD mice. Mice that received Msc-exo exhibited decreased weight loss and reduced aGVHD clinical score in a time-dependent manner as well as reduced lethality compared with Fib-exo treated or untreated control. Furthermore, the levels of IL-2, TNF-α, and IFN-γ were decreased, as well as the level of IL-10 was increased after Msc-exo treatment in vivo and in vitro.ConclusionhBMSC-derived exosomes could attenuate aGVHD damage and promote the survival of aGVHD mice by regulating the DC and T-cell subpopulation and function, and lead to inhibited inflammatory response in aGVHD mice.
Highlights
MATERIALS AND METHODSAs the only therapeutic method, allogeneic hematopoietic stem cell transplantation (HSCT) has been widely applied for the treatment of various hematological malignancies (Passweg et al, 2017)
We found that Msc-exo injection in acute graftversus-host disease (aGVHD) mice decreased the blood CD4+IL17+ T helper cells while increased the CD4+Foxp3+ Tregs compared with the fibroblast–derived exosomes (Fib-exo) group or untreated mice on day 10 after transplantation (Figures 4A,B)
We found Msc-exo injection resulted in decreased number of granzyme B or Ki-67 positive CD8+ T cells in aGVHD mice compared with Fib-exo treated or untreated mice
Summary
As the only therapeutic method, allogeneic hematopoietic stem cell transplantation (HSCT) has been widely applied for the treatment of various hematological malignancies (Passweg et al, 2017). Despite the substantial advances in transplant-related technologies such as donor lymphocyte infusion, novel immunosuppressive drugs, and supportive therapy, unsatisfactory prognosis and poor survival remain an issue due to the severe complications after allogeneic HSCT (Sahin et al, 2016). The prevention of aGVHD are mainly achieved by the utilization of a wide variety of drugs such as steroids and calcineurin inhibitors, and the prophylactic effect is poor (Lai et al, 2014). Previous clinical studies have suggested that MSC infusion can effectively prevent aGVHD after allogeneic HSCT (Wernicke et al, 2011; Chen et al, 2015; Zhao K. et al, 2015). The extent to which MSCs can improve patient outcomes remains unclear because of the significant heterogeneity in the details of disease diagnosis, treatment strategies, and MSC preparation method across clinical studies of MSCs (Rizk et al, 2016)
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