Mechanisms of implantation such as determination of the attachment pole, fetal-maternal communication, and underlying causes of implantation failure are largely unexplored. Here, we performed single-cell RNA sequencing on peri-implantation embryos from both humans and mice to explore trophectoderm (TE) development and embryo-endometrium cross-talk. We found that the transcriptomes of polar and mural TE diverged after embryos hatched from the zona pellucida in both species, with polar TE being more mature than mural TE. The implantation poles show similarities in cell cycle activities, as well as in expression of genes critical for implantation and placentation. Embryos that either fail to attach in vitro or fail to implant in vivo show abnormalities in pathways related to energy production, protein metabolism, and 18 S ribosomal RNA m ⁶ A methylation. These findings uncover the gene expression characteristics of humans and mice TE differentiation during the peri-implantation period and provide new insights into embryo implantation.

Secreted by the anterior pituitary gland, growth hormone (GH) is a peptide that plays a critical role in regulating cell growth, development, and metabolism in multiple targeted tissues. Studies have shown that GH and its functional receptor are also expressed in the female reproductive system, including the ovaries and uterus. The experimental data suggest putative roles for GH and insulin-like growth factor 1 (IGF-1, induced by GH activity) signaling in the direct control of multiple reproductive functions, including activation of primordial follicles, folliculogenesis, ovarian steroidogenesis, oocyte maturation, and embryo implantation. In addition, GH enhances granulosa cell responsiveness to gonadotropin by upregulating the expression of gonadotropin receptors (follicle-stimulating hormone receptor and luteinizing hormone receptor), indicating crosstalk between this ovarian regulator and the endocrine signaling system. Notably, natural gene mutation of GH and the age-related decline in GH levels may have a detrimental effect on female reproductive function, leading to several reproductive pathologies, such as diminished ovarian reserve, poor ovarian response during assisted reproductive technology (ART), and implantation failure. Association studies using clinical samples showed that mature GH peptide is present in human follicular fluid, and the concentration of GH in this fluid is positively correlated with oocyte quality and the subsequent embryo morphology and cleavage rate. Furthermore, the results obtained from animal experiments and human samples indicate that supplementation with GH in the in vitro culture system increases steroid hormone production, prevents cell apoptosis, and enhances oocyte maturation and embryo quality. The uterine endometrium is another GH target site, as GH promotes endometrial receptivity and pregnancy by facilitating the implantation process, and the targeted depletion of GH receptors in mice results in fewer uterine implantation sites. Although still controversial, the administration of GH during ovarian stimulation alleviates age-related decreases in ART efficiency, including the number of oocytes retrieved, fertilization rate, embryo quality, implantation rate, pregnancy rate, and live birth rate, especially in patients with poor ovarian response and recurrent implantation failure.

Polycystic ovary syndrome (PCOS) is a complex disorder associated with multiple metabolic disturbance, including defective glucose metabolism and insulin resistance. The altered metabolites caused by the related metabolic disturbance may affect ovarian follicles, which can be reflected in follicular fluid composition. The aim of this study is to investigate follicular fluid metabolic profiles in women with PCOS using an advanced sequential window acquisition of all theoretical fragment-ion spectra (SWATH) mass spectrometry. Nineteen women with PCOS and twenty-one healthy controls undergoing IVF/ET were recruited, and their follicular fluid samples were collected for metabolomic study. Follicular fluid metabolic profiles, including steroid hormones, free fatty acids, bioactive lipids, and amino acids were analyzed using the principal component analysis (PCA) and partial least squares to latent structure-discriminant analysis (PLS-DA) model. Levels of free fatty acids, 3-hydroxynonanoyl carnitine and eicosapentaenoic acid were significantly increased (P < 0.05), whereas those of bioactive lipids, lysophosphatidylcholines (LysoPC) (16:0), phytosphingosine, LysoPC (14:0) and LysoPC (18:0) were significantly decreased in women with PCOS (P < 0.05). Additionally, levels of steroid hormone deoxycorticosterone and two amino acids, phenylalanine and leucine were higher in the PCOS patients (P < 0.05). Women with PCOS display unique metabolic profiles in their follicular fluid, and this data may provide us with important biochemical information and metabolic signatures that enable a better understanding of the pathogenesis of PCOS.

Early pregnancy is a complex and well-orchestrated differentiation process that involves all the cellular elements of the fetal-maternal interface. Aberrant trophoblast-decidual interactions can lead to miscarriage and disorders that occur later in pregnancy, including preeclampsia, intrauterine fetal growth restriction, and preterm labor. A great deal of research on the regulation of implantation and placentation has been performed in a wide range of species. However, there is significant species variation regarding trophoblast differentiation as well as decidual-specific gene expression and regulation. Most of the relevant information has been obtained from studies using mouse models. A comprehensive understanding of the physiology and pathology of human implantation and placentation has only recently been obtained because of emerging advanced technologies. With the derivation of human trophoblast stem cells, 3D-organoid cultures, and single-cell analyses of differentiated cells, cell type-specific transcript profiles and functions were generated, and each exhibited a unique signature. Additionally, through integrative transcriptomic information, researchers can uncover the cellular dysfunction of embryonic and placental cells in peri-implantation embryos and the early pathological placenta. In fact, the clinical utility of fetal-maternal cellular trafficking has been applied for the noninvasive prenatal diagnosis of aneuploidies and the prediction of pregnancy complications. Furthermore, recent studies have proposed a viable path toward the development of therapeutic strategies targeting placenta-enriched molecules for placental dysfunction and diseases.