Decidual stromal cells-derived exosomes incured insufficient migration and invasion of trophoblast because of abnormal ubiquitination and degradation of Snail mediated by miR-92b-3p/USP28.

BACKGROUND: Recent findings have demonstrated that inadequate trophoblast migration and invasion are often responsible for the unsuccessful communication between the mother and fetus, contributing to URSA (unexplained recurrent spontaneous abortion). Effective intercellular communication at the maternal-fetal interface is crucial for maintaining trophoblast invasion and migration. Decidual stromal cells (DSCs), which are predominant at the maternal-fetal interface, have been identified as key regulators of the epithelial-mesenchymal transition (EMT) of trophoblasts, which facilitates their migration and invasion. However, the underlying biological mechanisms remain largely unexplored and constitute the central focus of this study.

RESULTS: The inhibition of trophoblast EMT by URSA-DSC-derived exosomes (URSA-DSC-exos) resulted in decreased migration and invasion abilities in vitro. MicroRNA sequencing revealed that miR-92b-3p were the most significantly upregulated microRNA in trophoblasts treated with URSA-DSC-exos. Further functional experiments demonstrated that URSA-DSC-exos inhibited trophoblast migration and invasion by transferring miR-92b-3p. Mechanistically, miR-92b-3p in URSA-DSC-exos suppressed trophoblast migration and invasion by directly downregulating USP28 expression at the post-transcriptional level. Overexpression of USP28 rescue the inhibitory effect of miR-92b-3p mimics on the expression of USP28 and restored the invasion and migration capabilities of HTR-8/SVneo cells. Furthermore, in vivo experiment suggested that URSA-DSC-exos led to increased embryo absorption in mice. Clinically, alterations in USP28 and EMT-related molecule expressions were observed in URSA patients, and a negative correlation was noted between miR-92b-3p and USP28 levels.

CONCLUSION: Our findings has demonstrated that the induction of insufficient migration and invasion of trophoblast by URSA-DSC-exos is due to abnormal ubiquitination degradation, which is mediated by the low expression of USP28, which is suppressed by miR-92b-3p at the post-transcriptional level. Reversing this disorder sheds light on a novel mechanism in DSC regulation of trophoblasts, highlighting their significant role in URSA.