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Placental exosomes polarize human monocyte-derived macrophages to a decidual M2-like macrophage phenotype

ABSTRACT: Macrophages are abundant in uterine mucosa during the peri-implantation phase and early pregnancy. Decidual macrophages display dynamic changes alone with pregnancy progress: During the peri-implantation phase, macrophages displayed a pro-inflammatory phenotype which facilitates embryo implantation. While, In the late firster trimester and second trimester, decidual macrophages are anti-proinflammatory which are helpful to pregnancy maintenance. Alterations in the ratio of pro-inflammatory/anti-inflammatory decidual macrophages lead to abortion, preeclampsia, and preterm birth. Placenta-derived exosomes (pEXO) are critical in the immune cell modulation such as T cell apoptosis, NK activities, and T regulatory (Treg) differentiation. However, it is unknown whether placenta-derived exosomes contribute to decidual macrophage polarization during early pregnancy. Here we report that exosomes from the placenta explant stimulate 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, conditioned medium impaired the ability of endothelial cell tube formation. However, pEXO-treated macrophages have no impact on T cell proliferation. Together, we demonstrated that pEXO promoted trophoblast migration and invasion, endothelial cell migration, and attenuation of endothelial cell tube formation by polarizing macrophage to decidua-like macrophage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184194 | GEO | 2021/09/16

REPOSITORIES: GEO

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Project description:Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment, innate immune cells constitute a significant proportion of uterine cells prior to arrival of the embryo and throughout the first trimester in humans and animal models. Abnormal uterine immune cell function during implantation is believed to play a role in multiple adverse pregnancy outcomes. Current work in humans has focused on uterine immune cells present after pregnancy establishment, and limited in vitro models exist to explore unique functions of these cells. With single-cell RNA-sequencing (scRNAseq), we comprehensively compared the human uterine immune landscape of the endometrium during the window of implantation and the decidua during the first trimester of pregnancy. We uncovered global and cell-type-specific gene signatures for each timepoint. Immune cells in the endometrium prior to implantation expressed genes associated with immune metabolism, division, and activation. In contrast, we observed widespread interferon signaling during the first trimester of pregnancy. We also provide evidence of specific inflammatory pathways enriched in pre- and post-implantation macrophages and natural killer (NK) cells in the uterine lining. Using our novel implantation-on-a-chip (IOC) to model human implantation ex vivo, we demonstrate for the first time that uterine macrophages strongly promote invasion of extravillous trophoblasts (EVTs), a process essential for pregnancy establishment. Pre- and post-implantation uterine macrophages promoted EVT invasion to a similar degree as pre- and post-implantation NK cells on the IOC. This work provides a foundation for further investigation of the individual roles of uterine immune cell subtypes present prior to embryo implantation and during early pregnancy, which will be critical for our understanding of pregnancy complications associated with abnormal trophoblast invasion and placentation.

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Placental exosomes polarize human monocyte-derived macrophages to a decidual M2-like macrophage phenotype

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