In vitro oogenesis is key to elucidating the mechanism of human female germ‐cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell‐like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single‐cell transcriptomes among humans, monkeys, and mice unravels primate‐specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia‐to‐oocyte transition and the latter including two active X chromosomes with little X‐chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates.
Preeclampsia is one of the leading causes of maternal and neonatal mortality and morbidity worldwide. We have previously reported that magnesium sulfate therapy is effective for early-onset (EO) preeclampsia. To investigate the molecular mechanisms underlying this favorable effect, metabolomics analysis of magnesium sulfate–treated preeclamptic placentas was performed using capillary electrophoresis time of flight mass spectrometry. There were significant metabolic differences between EO-preeclamptic placentas (n=7) and other placentas (late-onset preeclampsia [n=3], normal pregnancies [n=10]). In EO-preeclamptic placentas, the glutathione metabolism pathway was markedly upregulated, whereas single-sample gene-set enrichment analysis using a publicly available microarray dataset (GSE75010) showed that the glutathione metabolism pathway was significantly downregulated in EO-preeclamptic placentas compared with nonpreeclamptic controls. Metabolomic profiles showed that magnesium sulfate significantly promoted glutathione production in an immortalized trophoblast cell line under oxidative stress conditions but not under normal conditions. Magnesium sulfate suppressed hydrogen peroxide–induced production of reactive oxygen species. Exploratory analysis revealed that urinary 8-isoprostane was decreased in all 5 women treated with magnesium sulfate for preeclampsia with severe features. These findings suggest that magnesium sulfate is effective for treating EO-preeclampsia partly because of its antioxidant effects on trophoblasts.
Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal–embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph–ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.
This study demonstrated that the Eph-ephrin A system can promote intercellular dissociation in Ishikawa cells suggesting an important role in the initial step of embryo implantation by opening the endometrial epithelial cell barrier.
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