Abstract
The functional state of placental mesenchymal stem cells (PMSCs) plays a critical role in maintaining maternal-fetal interface homeostasis during the pathogenesis of preeclampsia (PE). Given the limitations associated with direct stem cell transplantation, this study aimed to investigate the therapeutic potential of PMSC-derived exosomes and their carried miR-146a-5p. Clinical sample analysis revealed a significant downregulation of miR-146a-5p in placental tissues from PE patients, accompanied by impaired proliferation, migration, and angiogenic dysfunction of PMSCs. In an in vitro model, exosome intervention effectively reversed hypoxia-induced trophoblast cell apoptosis and enhanced migratory capacity. Furthermore, it promoted macrophage polarization towards the anti-inflammatory M2 phenotype and markedly improved the inflammatory cytokine secretion profile. In a PE mouse model, exosome treatment reduced maternal blood pressure and proteinuria levels, alleviated fetal growth restriction, and up-regulated the expression of M2 macrophage markers in placental tissue. Mechanistically, miR-146a-5p targeted TRAF6 to suppress NF-κB pathway activation, an effect that could be reversed by specific inhibitors. This study is the first to demonstrate that PMSC-derived exosomes, via the miR-146a-5p/TRAF6 axis, concurrently ameliorate trophoblast dysfunction and correct macrophage polarization imbalance. The efficient intercellular delivery of miR-146a-5p by exosomes underscores their potential as a novel targeted therapeutic strategy for PE.