Seminal Exosomal miR-181a-5p Protects from Early Pregnancy Loss Via Promoting the Biological Function of Trophoblast Cells Through PROX1/Notch1 Signaling Pathway

Background: Early pregnancy loss is the most common complication in pregnancy. Recently, semen has been identified as regulator of female reproductive function. Here, we investigate latent promising seminal exosomal miRNA as a clinically applicable bio-regulator that can promote the biological function of trophoblast cells in early pregnancy.  Objective: To study the regulation and mechanism of semen on embryonic trophoblasts.  Methods: Compare the expression of Notch1 in fetal villi of in vitro fertilization-embryo transfer (IVF-ET)-conceived and intercourse-conceived by immunohistochemical staining. Seminal exosome (SE) and miR-181a-5p highly expressed in SE were co-cultured with trophoblast cell line HTR-8/Svneo cells to detect the effect and mechanism of SE and miR-181a-5p on the biological functions of trophoblasts.  Results: The expression of Notch1 in the villi tissue from IVF (in vitro fertilization)-conceived women was significantly decreased compared with that from intercourse-conceived women, this may be the reason why IVF pregnancy complications are higher than natural pregnancy. In vitro experiments, we found that both SE and miR-181a-5p significantly increased the migration, invasion and angiogenesis of HTR-8/Svneo cells through inhibiting the expression of PROX1 and then activating Notch1 signaling pathway in HTR-8/Svneo cells.  Conclusions: We found that the decreased expression of villous Notch1 may be one of the causes of early pregnancy loss (EPL) in IVF. Semen exosomes can protect the establishment and maintenance of pregnancy by promoting the biological function of trophoblast cells through the miR181-PROX1-Notch1 signaling pathway. Funding: This study was supported by the National Natural Science Foundation of China (CSFC) (grant No. 81471455 and No. 81100418). Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Research Ethics Committee of Renmin Hospital of Wuhan University (No. WDRY2021-K044).