Exosomes perform important functions for intercellular communication through extracellular signaling pathways, leading to the regulation of important biological processes, including cell proliferation, but also systemic dysfunctions such as preeclampsia (PE). However, the inhibitory effects of mesenchymal stem cell (MSCs)-derived exosomes in PE remain largely unknown. Thus, we assessed the possibility that exosomes could transport long non-coding RNA H19 and the correlation between H19 and the apoptosis of trophoblast cells. The expression of microRNA let-7b and forkhead box protein O1 (FOXO1) was characterized in placental tissues of PE patients. Gain- and loss-of-function experiments were performed to examine the roles of FOXO1 and let-7b in trophoblast cells. Interactions between let-7b and H19 as well as between let-7b and FOXO1 were confirmed by a dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation. HTR-8/SVneo cells were co-cultured with exosomes derived from MSCs overexpressing H19, followed by invasion, migration, and apoptosis assessments of trophoblast cells. We found that let-7b was highly expressed and FOXO1 was poorly expressed in placental tissues of PE patients. Furthermore, H19 acts as a competitive endogenous RNA against let-7b, and let-7b directly targeted FOXO1. Moreover, H19 could be transferred to trophoblast cells via MSC-secreted exosomes. MSC-derived exosomes overexpressing H19 decreased let-7b, increased FOXO1, and activated the protein kinase B (AKT) signaling pathway, thus increasing invasion and migration and inhibiting apoptosis of trophoblast cells. These results suggest that MSC-derived exosomes overexpressing H19 may be a novel direction for therapeutic strategies against PE.

中文翻译：

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MSC 分泌的外泌体 H19 通过下调 let-7b 和上调 FOXO1 促进滋养层细胞侵袭和迁移


外泌体通过细胞外信号通路对细胞间通讯发挥重要作用，从而调节重要的生物过程，包括细胞增殖，以及先兆子痫（PE）等全身功能障碍。然而，间充质干细胞（MSC）来源的外泌体在 PE 中的抑制作用仍然很大程度上未知。因此，我们评估了外泌体转运长链非编码RNA H19的可能性以及H19与滋养层细胞凋亡之间的相关性。对 PE 患者胎盘组织中 microRNA let-7b 和叉头盒蛋白 O1 (FOXO1) 的表达进行了表征。进行功能获得和丧失实验来检查 FOXO1 和 let-7b 在滋养层细胞中的作用。通过双荧光素酶报告基因测定、RNA pull-down 和 RNA 免疫沉淀证实了 let-7b 和 H19 之间以及 let-7b 和 FOXO1 之间的相互作用。 HTR-8/SVneo 细胞与源自过表达 H19 的 MSC 的外泌体共培养，然后评估滋养层细胞的侵袭、迁移和凋亡。我们发现在PE患者的胎盘组织中let-7b高表达而FOXO1低表达。此外，H19作为let-7b的竞争性内源RNA，而let-7b直接靶向FOXO1。此外，H19 可以通过 MSC 分泌的外泌体转移到滋养层细胞。 MSC来源的外泌体过表达H19会减少let-7b，增加FOXO1，并激活蛋白激酶B（AKT）信号通路，从而增加侵袭和迁移并抑制滋养层细胞的凋亡。这些结果表明，过度表达 H19 的 MSC 衍生的外泌体可能是针对 PE 治疗策略的新方向。