The regulatory roles of placenta-derived extracellular vesicles on monocyte/macrophage and endothelial cell functions

Abstract

Pregnancy involves a wide range of adaptions in the maternal body. Maternal immune tolerance towards the foreign fetus and spiral artery remodeling are the two fundamental changes within the first trimester of pregnancy. Monocytes and decidual macrophages are the primary antigen-presenting cells and phagocytic cells, which are critical in antigen processing and presentation. Meanwhile, the wellness of maternal endothelial cells is closely associated with hypertension, gestational diabetes mellitus and preeclampsia. Placenta-derived microvesicles (pMV) and exosomes (pEXO), extruded by the human placenta trophoblast, are small vesicles carrying biological active molecules. The functions of placenta-derived microvesicles and exosomes have been implicated in endothelial cell activation, smooth muscle cell migration, T cell apoptosis. However, it is still unknown that whether these vesicles could affect the maternal immune system and angiogenesis. In this study, pMV and pEXO were successfully isolated from our established placenta explant culture model. Our data showed that placenta-derived microvesicles and pEXO have different miRNAs profiles. Placenta-specific miRNAs, C19MC, were inclined to be enriched in the pMV but not in pEXO. pMV II compromised endothelial cell tube formation via miRNA-148a-3p-FLT1 axis pathway. Meanwhile, IL-6 secretion was reduced in the conditioned medium of microvesicles-treated endothelial cells. Decidual macrophages display dynamic changes alone during pregnancy progress. Here we reported that pEXO stimulated M2 macrophage polarization via exosomal miRNA-30d-5p. Mechanistically, miRNA-30d-5p polarized macrophages to M2 phenotype by inhibiting HDAC9 expression. Furthermore, the conditioned medium of pEXO-treated macrophages promoted trophoblast migration and invasion. By contrast, the conditioned medium impaired the ability of endothelial cell tube formation. Together, we demonstrated that pEXO polarizes macrophage into a decidua-like macrophage to promote trophoblast migration and invasion, endothelial cell migration, and endothelial cell tube formation attenuation. Systemic immune tolerance is a hallmark of a successful pregnancy. We reported that pEXO contributes to systemic immune tolerance by inducing Treg differentiation via the monocyte-dependent pathway. Specifically, the frequency of Treg cells was elevated after co-culture with autologous pEXO-treated monocytes. In addition, we identified that circulating monocytes are the primary cell type that uptake pEXO. The proliferation of CD4+ and CD8+ T cell was significantly suppressed when co-culture with pEXO-treated monocytes. Moreover, Th2 cytokines predominated the co-culture system with a decreased level of IFN-γ and TNF-α. Together, our results indicated that pEXO is a crucial modulator of maternal immune tolerance toward the semi-allograft fetus by promoting Treg differentiation via modulating circulating monocyte phenotype. In conclusion, this thesis reported a new insight into how placenta-derived extracellular vesicles influence maternal endothelial functions and immune cell activities. Our data demonstrated that placenta-derived extracellular vesicles are essential components in M2 macrophage polarization, Treg differentiation and spiral artery remodeling. The findings in this thesis indicated that placenta-derived extracellular vesicles could be used as potential biomarkers for the diagnosis of placenta-associated pregnancy complications.