Human Trophoblast Cell-Derived Extracellular Vesicles Facilitate Preeclampsia by Transmitting miR-1273d, miR-4492, and miR-4417 to Target HLA-G.

Abstract

Extracellular vesicles (EVs) can intercellularly transmit a wide range of bioactive molecules, and these cargoes may potentially serve as therapeutic biomarkers for preeclampsia. Herein, the current study aims to elucidate the mechanism underlying the human trophoblast cell-derived EV-mediated miRNA-mRNA network that could potentially influence the development of preeclampsia based on microarray datasets from publicly available GEO databases. Preeclampsia-related genes were retrieved from the GeneCards and CTD databases, which were then subjected to GO and KEGG enrichment analyses in an effort to identify key pathways in preeclampsia. The obtained results suggested an important role of the immune- and inflammation-related pathways in preeclampsia. Infiltration proportion of 22 immune cells was subsequently analyzed using the CIBERSORT algorithm. Placental tissues of patients with preeclampsia presented with increased proportion of resting NK cells and resting dendritic cells, while there was a reduction in the proportion of activated NK cells. Differentially expressed mRNAs were additionally predicted in the preeclampsia-related datasets retrieved from the GEO database, and then intersected with preeclampsia-related genes to identify the key genes. HLA-G was indicated as a key target gene in the development of preeclampsia and further associated with hypoxia, immune, and inflammatory pathways. The upstream microRNAs (miRNAs/miRs) of the key genes were further predicted and intersected with differentially expressed miRNAs in the human trophoblast cell-derived EV-related datasets from the GEO database to obtain the key miRNAs. EVs secreted by human trophoblast cells under hypoxic conditions were associated with 3 key upstream miRNAs of HLA-G, namely miR-1273d, miR-4492, and miR-4417, which might be implicated in the development of preeclampsia via targeting of HLA-G. Collectively, our findings highlighted that EVs secreted by human trophoblast cells under hypoxic conditions transferred miR-1273d, miR-4492, and miR-4417, all of which targeted HLA-G, thus orchestrating immune- and inflammation-related pathways and consequently promoting the development of preeclampsia.