Mesenchymal stem cells‐derived exosomes improve pregnancy outcome through inducing maternal tolerance to the allogeneic fetus in abortion‐prone mating mouse

Abstract Recurrent pregnancy loss (RPL) is three or more times of consecutive spontaneous loss of pregnancy. The underlying cause is complicated and the etiology of over 50% of RPL patients is unclear. In the present study, bone marrow mesenchymal stem cells were isolated from CBA/J female mice and exosomes were isolated from cell culture medium by ultracentrifugation. CBA/J female mice were paired with male DBA/2 to generate abortion prone mouse model, and CBA/J females paired with male BALB/c mice were used as control. Exosomes were injected through uterine horns into pregnant CBA/J mice on day 4.5 of gestation in abortion‐prone matting. On day 13.5 of pregnancy, abortion rates were calculated and the level of transforming growth factor‐β (TGF‐β), interleukin 10 (IL‐10), interferon g (IFN‐γ), and tumor necrosis factor a (TNF‐α) in CD4+ T cells and macrophages in deciduas were evaluated by flow cytometry. Exosomes injection improved the pregnancy outcomes in abortion prone mice. The IL‐4 and IL‐10 levels on CD4+ T cells were upregulated in the maternal–fetal interface; meanwhile, the TNF‐α and IFN‐γ levels on CD4+ T cells were reduced. The IL‐10 level was increased and IL‐12 was reduced on the monocytes that separated from deciduas. miR‐101 level was increased in the CD4+ T cells in the deciduas. In conclusion, the treatment of ESCs‐derived exosomes modulates T cells' function and macrophages activities in the maternal–fetal interface that resulted in a decreased embryo resorption rate, and provides a therapeutic potential to treat RPL.