The interleukin (IL)-1 system plays a major role in immune responses and inflammation. The IL-1 system components include IL-1α, IL-1β, IL-1 receptor type 1 and IL-1 receptor type 2 (decoy receptor), IL-1 receptor accessory protein, and IL-1 receptor antagonist (IL-1Ra). These components have been shown to play a role in pregnancy, specifically in embryo-maternal communication for implantation, placenta development, and protection against infections. As gestation advances, maternal tissues experience increasing fetal demand and physical stress and IL-1β is induced. Dependent on the levels of IL-1Ra, which regulates IL-1β activity, a pro-inflammatory response may or may not occur. If there is an inflammatory response, prostaglandins are synthesized that may lead to myometrial contractions and the initiation of labor. Many studies have examined the role of the IL-1 system in pregnancy by independently measuring plasma, cervical, and amniotic fluid IL-1β or IL-1Ra levels. Other studies have tested for polymorphisms in IL-1β and IL-1Ra genes in women experiencing pregnancy complications such as early pregnancy loss, in vitro fertilization failure, pre-eclampsia and preterm delivery. Data from those studies suggest a definite role for the IL-1 system in successful pregnancy outcomes. However, as anticipated, the results varied among different experimental models, ethnicities, and disease states. Here, we review the current literature and propose that measurement of IL-1Ra in relation to IL-1 may be useful in predicting the risk of poor pregnancy outcomes.

Summary Sentence

The IL-1 system has been shown to have an important role in pregnancy, and an IL-1 system assay may be used as a method to screen for women who are more likely to have a high-risk pregnancy and pregnancy complications.

Despite sharing many common features, the relationship between ageing and parturition remains poorly understood. The decidua is a specialized lining of endometrial tissue, which develops in preparation for pregnancy. The structure and location of the decidua support its role as the physical scaffold for the growing embryo and placenta, and thus, it is vital to sustain pregnancy. Approaching term, the physical support properties of the decidua are naturally weakened to permit parturition. In this review, we hypothesize that the natural weakening of decidual tissue at parturition is promoted by the ageing process.

Studies of the ageing-related functional and molecular changes in the decidua at parturition are reviewed and classified using hallmarks of ageing as the framework. The potential roles of decidual mesenchymal stem/stromal cell (DMSC) ageing in labor are also discussed because, although stem cell exhaustion is also a hallmark of ageing, its role in labor is not completely understood. In addition, the potential roles of extracellular vesicles secreted by DMSCs in labor, and their parturition-related miRNAs, are reviewed to gain further insight into this research area.

In summary, the literature supports the notion that the decidua ages as the pregnancy progresses, and this may facilitate parturition, suggesting that ageing is the probable impetus of the gestational clocks in the decidua. This conceptual framework was developed to provide a better understanding of the natural ageing process of the decidua during parturition as well as to encourage future studies of the importance of healthy ageing for optimal pregnancy outcomes.

Summary Sentence

The decidua ages as the pregnancy progresses, and this may promote and/or facilitate parturition. Ageing is likely the impetus of the gestational clocks in the decidua.

Graphical Abstract

Intraovarianism refers to mechanisms within an ovary that affect the local follicle and luteal dynamics and is well-represented in heifers by greater frequency of ovulation from the right ovary (RO) than the left ovary (LO). On average, the RO has more 6-mm follicles than the LO before one follicle is selected to deviate in diameter and become the future ovulatory follicle. Therefore, the ovulatory follicle is more frequently selected from the RO. More follicles in the RO likely develop before birth as indicated by greater weight of the RO with more 0.3- to 4.8-mm follicles in recently born calves. It has been proposed that differences in intraovarianism between sides are a consequence of differences between sides in the inherent intraovarian angioarchitecture. The frequency of the pair of ovulations at the beginning and end of 900 interovulatory intervals (IOI) was lowest for the left/left (LL) pair (16%) and higher and similar among the RR, LR, and RL pairs (28% each). The lower frequency of LO ovulation was entirely a function of the LL pair as indicated by the lower frequency of the LL than RR pairs without a difference among the RR, LR, and RL pairs. Ovulations from the opposite sides at the beginning and end of an IOI (LR and RL pairs) would not have contributed to a difference in ovulation frequency between LO and RO. In conclusion, the greater frequency of RO (56%) than LO (44%) ovulation was mathematically and functionally a direct consequence of the low frequency of the LL pair of ovulations.

Summary sentence

The greater frequency of ovulation from the right ovary is mathematically and functionally attributable to the left ovary.

Graphical Abstract

Regulatory mechanisms of germline differentiation have generally been explained via the function of signaling pathways, transcription factors, and epigenetic regulation; however, little is known regarding proteomic and metabolomic regulation and their contribution to germ cell development. Here, we conducted integrated proteomic and metabolomic analyses of fetal germ cells in mice on embryonic day (E)13.5 and E18.5 and demonstrate sex- and developmental stage-dependent changes in these processes. In male germ cells, RNA processing, translation, oxidative phosphorylation, and nucleotide synthesis are dominant in E13.5 and then decline until E18.5, which corresponds to the prolonged cell division and more enhanced hyper-transcription/translation in male primordial germ cells and their subsequent repression. Tricarboxylic acid cycle and one-carbon pathway are consistently upregulated in fetal male germ cells, suggesting their involvement in epigenetic changes preceding in males. Increased protein stability and oxidative phosphorylation during female germ cell differentiation suggests an upregulation of aerobic energy metabolism, which likely contributes to the proteostasis required for oocyte maturation in subsequent stages. The features elucidated in this study shed light on the unrevealed mechanisms of germ cell development.

Summary Sentence

Integrated proteomic and metabolomic analysis of mouse fetal germline revealed its sex- and developmental stage-dependent characteristics on protein and metabolic regulation.

Maternal obesity increases the risk of offspring to become obese and develop related pathologies. Exposure to maternal high-fat diet (HFD) only during lactation increases the risk of obesity-related diseases, suggesting that factors in milk affect long-term health. We hypothesized that prepregnancy obesity induced by HFD alters milk lipidome, and in turn, alterations may affect neonate serum lipidome. The objective of this study was to determine the effect of prepregnancy obesity induced by HFD on circulating lipids in dams and neonates and in milk. Female mice were fed an HFD (60% kcal fat) or control diet (CON, 10% kcal fat) beginning 4 weeks before breeding. On postnatal day 2 (PND2), pups were cross-fostered to create pup groups exposed to HFD during pregnancy, lactation, or both or exposed to CON. On PND12, dams were milked and then euthanized along with pups to collect blood. Serum and milk were processed for multiple reaction monitoring (MRM) lipidomics profiling to quantify the relative expression of lipid classes. Lipidome of HFD dam serum and milk had increased proportion of C18:2 free fatty acid and fatty acyl residues in all lipid classes. Lipidome of serum from pups exposed to maternal HFD during lactation was similarly affected. Thus, maternal HFD induced redistribution of fatty acyl residues in the dam's circulation, which was associated with modification in milk and suckling neonate's lipidome. Further studies are needed to determine if increased circulating levels of C18:2 in neonate affects development and predisposes offspring to obesity and metabolic syndrome.

Graphical Abstract

Summary Sentence

Maternal prepregnancy obesity induced by high-fat diet significantly impacts circulating lipids and similarly modifies the lipid composition of milk and circulating lipid of suckling neonates.

Uterine smooth muscle cells differentiate from mesenchymal cells, and gap junctions connect the muscle cells in the myometrium. At the neonatal stage, a uterine smooth muscle layer is situated away from the epithelium when smooth muscle cells are grafted near the epithelium, suggesting that the epithelium plays an important role in differentiation, proliferation, and/or migration of smooth muscle cells. In this study, developmental mechanisms regulating the formation of the smooth muscle layers in the mouse uterus were analyzed using an in vitro culture model. Differentiation of smooth muscle cells occurs at a neonatal stage because ACTA2 gene expression was increased at the outer layer, and GJA1 was not expressed in cellular membranes of uterine smooth muscle cells by postnatal day 15. To analyze the effects of the epithelium on the differentiation of smooth muscle cells, a bulk uterine mesenchymal cell line was established from p53^–/– mice at postnatal day 3 (P3US cells). Co-culture with Müllerian ductal epithelial cells (E1 cells) induced repulsive migration of ACTA2-positive cells among bulk P3US cells from E1 cells, but it had no effects on the migration of any of 100% ACTA2-positive or negative smooth muscle cell lines cloned from P3US cells. Thus, uterine epithelial cells indirectly affected the repulsive migration of smooth muscle cells via mesenchymal cells. Conditioned medium by E1 cells inhibited differentiation into smooth muscle cells of clonal cells established from P3US cells. Therefore, the uterine epithelium inhibits the differentiation of stem-like progenitor mesenchymal cells adjacent to the epithelium into smooth muscle cells.

Summary Sentence

Factors derived from Müllerian epithelial cells inhibited differentiation into smooth muscle cells and migration of uterine mesenchymal cells.

The endometrium, composed of epithelial and stromal cell compartments, is tightly regulated by the ovarian steroid hormones estrogen (E2) and progesterone (P4) during early pregnancy. Through the progesterone receptor (PGR), steroid receptor coactivators, and other transcriptional coregulators, progesterone inhibits E2-induced cell proliferation and induces the differentiation of stromal cells in a process called decidualization to promote endometrial receptivity. Although interleukin-13 receptor subunit alpha-2 (Il13ra2) is expressed in the human and mouse endometrium, its potential role in the steroid hormone regulation of the endometrium has not been thoroughly examined. In this study, we employed PGR knockout mice and steroid receptor coactivator-1 knockout mice (SRC-1^–/–) to profile the expression of Il13ra2 in the murine endometrium and determine the role of these transcriptional regulators in the hormone-responsiveness of Il13ra2 expression. Furthermore, we utilized a well-established decidualization-inducing steroidogenic cocktail and a siRNA-based knockdown of IL13RA2 to determine the importance of IL13RA2 in the decidualization of primary human endometrial stromal cells. Our findings demonstrate that Il13ra2 is expressed in the subepithelial stroma of the murine endometrium in response to ovarian steroid hormones and during early pregnancy in a PGR- and SRC-1-dependent manner. Furthermore, we show that knockdown of IL13RA2 before in vitro decidualization of primary human endometrial stromal cells partially compromises the full decidualization response. We conclude that Il13ra2 is a downstream target of progesterone through PGR and SRC-1 and plays a role in mediating the stromal action of ovarian steroid hormones.

Summary Sentence

Expression of Il13ra2 is induced by progesterone in the murine uterine stroma through the progesterone receptor and steroid receptor coactivator-1, and it is involved in human stromal cell decidualization.

The reproductive process is usually controlled by the hypothalamic-pituitary-gonad axis in vertebrates, while Kiss/gonadotropin-releasing hormone (GnRH) system in the hypothalamus is required for mammalian reproduction but dispensable for fish reproduction. The regulation of follicle stimulating hormone/luteinizing hormone (LH) expression in fish species is still unknown. Here, we identified miR-200s on chromosome 23 (chr23-miR-200s) as important regulators for female zebrafish reproduction. Knockout of chr23-miR-200s (chr23-miR-200s-KO) resulted in dysregulated expression of luteinizing hormone beta lhb (luteinizing hormone beta) and some hormone genes in the pituitary as revealed by comparative transcriptome profiling, leading to failure of oocyte maturation and ovulation as well as defects in reproductive duct development. Chr23-miR-200s mainly expressed in the pituitary and regulated lhb expression by targeting the transcription repressor wt1a. Injection of human chorionic gonadotropin (hCG) could rescue the defects of oocyte maturation in chr23-miR-200s-KO zebrafish, whereas GnRH or LHRH-A2 could not, suggesting that Chr23-miR-200s regulated lhb expression in a GnRH-independent pathway. It was remarkable that either injection of carp pituitary extraction, or co-injection of hCG with synthetic oxytocin and vasotocin could greatly rescue the defects of both oocyte maturation and ovulation in chr23-miR-200s-KO zebrafish. Altogether, our findings highlight an important function of chr23-miR-200s in controlling oocyte maturation by regulation LH expression, and oxytocin and vasotocin are potentially responsible for the ovulation in fish species.

Fibrinogen alpha chain (FGA), a cell adhesion molecule, contains two arginyl-glycyl-aspartic acid (RGD) cell adhesion sequences. Our previous study demonstrated that FGA, as an upregulated protein in endometriosis (EM), was closely related to disease severity and involved in the development of EM. However, the biological functions and underlying mechanism of FGA in EM have not been fully understood. To explore the roles of FGA in EM, we analyzed the effects of FGA on the biological behaviors of human primary eutopic endometrial stromal cells (EuESC). The results indicated FGA knockdown suppressed the migration and invasion ability of EuESC, which also altered the distribution of cytoskeletal filamentous and cell morphology. Western blot analysis demonstrated that knockdown of FGA attenuated the migration-related protein levels of vimentin and matrix metallopeptidase 2 (MMP-2), but not integrin subunit alpha V (ITGAV) and integrin subunit beta 3 (ITGB3). Meanwhile, integrin-linked transduction pathways were detected. We found FGA knockdown significantly suppressed the expression of focal adhesion kinase (FAK) level and protein kinase B (AKT) phosphorylation, without extracellular-signal-regulated kinase (ERK) dependent pathways. Treatment with the AKT inhibitor MK2206 or RGD antagonist highly decreased the effects of FGA on the migration and invasion of EuESC. RGD antagonist treatment strongly inhibited FAK- and AKT-dependent pathways, but not ERK pathways. Our data indicated that FGA may enhance the migration and invasion of EuESC through RGD sequences binding integrin and activating the FAK/AKT/MMP-2 signaling pathway. This novel finding suggests that FGA may provide a novel potential approach to the treatment of EM, which provides a new way to understand the pathogenesis of EM.

Summary Sentence

FGA enhanced the migration and invasion ability of endometrial stromal cells through RGD sequences binding integrin and activating the FAK/AKT/MMP-2 signaling pathway in endometriosis.