Placenta-derived extracellular vesicles as liquid biopsy for placental transfer

A growing body of evidence supports the idea that placenta-derived extracellular vesicles (pEV) ensure successful pregnancy progression. Conversely, pregnancy adversities have been linked to placental dysfunction as indicated by altered pEV production. Clinically, placental dysfunction manifests in an impaired maternofetal transfer of nutrients and hormones. Recent studies further link placental dysfunction to an altered transplacental transfer of maternal microchimeric cells (MMc) to the fetus. We investigated whether pEV serve as a proxy for transplacental cellular transfer in healthy and SARS-CoV-2 infected women. EV from third trimester serum samples of healthy pregnant women and pregnant women upon SARS-CoV-2 infection were isolated via cushion-ultracentrifugation. Using placenta-specific antibody staining, pEV were identified by Imaging Flow Cytometry analysis. Further, pEV were correlated with MMc numbers from matching neonatal cord blood samples. Finally, differential quantitative proteomic is was used to identify possible markers on pEV that are associated with an adequate placental transfer of MMc. SARS-CoV-2 infection results in strongly reduced numbers of MMc but leads to significantly higher frequencies of pEV in the maternal serum. In healthy mothers, proteomic analysis of pEV show clustering between samples with high or low placental transfer of MMc, which was absent in SARS-CoV-2 infected mothers. Reduced transfer of MMc following maternal infection is associated with an excessive production of pEV indicating a dysregulation in placental function. By using proteomic analysis, we demonstrate that pEV are an indicator of placental transfer during healthy pregnancies, by expressing a unique protein profile that is altered during infection.