Graphical Abstract

During pregnancy, cell senescence at the maternal–fetal interface is required for maternal well-being, placental development, and fetal growth. However, recent reports have shown that aberrant cell senescence is associated with multiple pregnancy-associated abnormalities, such as preeclampsia, fetal growth restrictions, recurrent pregnancy loss, and preterm birth. Therefore, the role and impact of cell senescence during pregnancy requires further comprehension. In this review, we discuss the principal role of cell senescence at the maternal–fetal interface, emphasizing its “bright side” during decidualization, placentation, and parturition. In addition, we highlight the impact of its deregulation and how this “dark side” promotes pregnancy-associated abnormalities. Furthermore, we discuss novel and less invasive therapeutic practices associated with the modulation of cell senescence during pregnancy.

Summary Sentence

An overview of the recent discoveries on the physiology role of cell senescence in successful pregnancies and pathology role of excessive cell senescence in complicated pregnancy.

Graphical Abstract

The differences between males and females begin shortly after birth, continue throughout prenatal development, and eventually extend into childhood and adult life. Male embryos and fetuses prioritize proliferation and growth, often at the expense of the fetoplacental energy reserves. This singular focus on growth over adaptability leaves male fetuses and neonates vulnerable to adverse outcomes during pregnancy and birth and can have lasting impacts throughout life. Beyond this prioritization of growth, male placentas and fetuses also respond to infection and inflammation differently than female counterparts. Pregnancies carrying female fetuses have a more regulatory immune response, whereas pregnancies carrying male fetuses have a stronger inflammatory response. These differences can be seen as early as the innate immune response with differences in cytokine and chemokine signaling. The sexual dimorphism in immunity then continues into the adaptive immune response with differences in T-cell biology and antibody production and transfer. As it appears that these sex-specific differences are amplified in pathologic pregnancies, it stands to reason that differences in the placental, fetal, and maternal immune responses in pregnancy contribute to increased male perinatal morbidity and mortality. In this review, we will describe the genetic and hormonal contributions to the sexual dimorphism of fetal and placental immunity. We will also discuss current research efforts to describe the sex-specific differences of the maternal–fetal interface and how it impacts fetal and maternal health.

Summary Sentence

Fetal sex influences the fetal, placental, and maternal immune response during pregnancy.

Vitrification is an important assisted reproductive technology, although it induces mitochondrial dysfunction in embryos. Herein, we aimed to investigate whether age-associated accumulation of advanced glycation end-products (AGEs) in oocytes impairs the recovery of embryos from cryopreservation-induced mitochondrial dysfunction/damage. Mouse eight-cell stage embryos developed in vitro were vitrified and warmed and incubated up to the blastocyst stage. AGE levels in oocytes were higher in both aged mice and AGE accumulation mouse models (MGO-mice) than those in young and control mice. In addition, the level of SIRT1 upregulation was lower for embryos of aged and MGO-mice than that for embryos of young and control mice. The highest mitochondrial DNA (mtDNA) content was detected in blastocysts derived from vitrified embryos of aged and MGO-mice. The spent culture medium of blastocysts derived from both aged and MGO-mice contained higher mtDNA content than that of the blastocysts derived from young and control mice. EX527 increased mtDNA content in the spent culture medium of vitrified embryos derived from young mice. In addition, p62 aggregate levels were higher in vitrified embryos of control mice than those in vitrified embryos of MGO-mice. The SIRT1 activator, resveratrol, increased p62 aggregation levels in vitrified embryos derived from young and aged mice, whereas vitrification did not affect p62 aggregation levels in embryos from aged mice. Therefore, age-associated AGE accumulation induces decreased responsive SIRT1 upregulation following vitrified–warmed treatment and impairs mitochondrial quality control activity in vitrified embryos.

Summary Sentence

Accumulation of AGEs inhibits responsive SIRT1 upregulation after vitrification and warming, which negatively affects mitochondrial quality control system in embryos.

Graphical Abstract

In vitro maturation of mammalian oocytes is an important means in assisted reproductive technology. Most bovine immature oocytes complete nuclear maturation, but less than half develop to the blastocyst stage after fertilization. Thus, inefficient in vitro production is mainly caused by a suboptimal in vitro culture process, in which oocyte quality appears to be the limiting factor. In our study, a potential maternal regulator, C-XC motif chemokine ligand 12, was identified by analyzing transcriptome data. C-X-C motif chemokine ligand 12 supplementation promoted the developmental potential of oocytes by improving protein synthesis and reorganizing cortical granules and mitochondria during in vitro maturation, which eventually increased blastocyst formation efficiency and cell number after parthenogenesis, fertilization, and cloning. All these promoting effects by C-X-C motif chemokine ligand 12 were achieved by activating SH2 domain-containing tyrosine phosphatase 2, thereby promoting the mitogen-activated protein kinase signaling pathway. These findings provide an in vitro maturation system that closely resembles the maternal environment to provide high-quality oocytes for in vitro production.

Summary Sentence

CXCL12 improves the developmental potential of bovine oocytes by activating SHP2 during maturation.

Graphical Abstract

Melatonin is important for oocyte maturation, fertilization, early embryonic development, and embryo implantation, but less knowledge is available regarding its role in decidualization. The present study found that melatonin did not alter the proliferation of human endometrial stromal cells (ESCs), as well as cell cycle progress, but suppressed stromal differentiation after binding to the melatonin receptor 1B (MTNR1B), which was visualized in decidualizing ESCs. Further analysis evidenced that application of melatonin resulted in the diminishment for NOTCH1 and RBPJ expression. Supplementation of recombinant NOTCH1 protein (rNOTCH1) counteracted the impairment of stromal differentiation conferred by melatonin, while the addition of the NOTCH signaling pathway inhibitor DAPT aggravated the differentiation progress. Meanwhile, melatonin might restrain the expression and transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2), whose blockage accelerated the fault of stromal differentiation under the context of melatonin, but this restraint was subsequently ameliorated by rNOTCH1. Forkhead box O 1 (FOXO1) was identified as a downstream target of melatonin in decidualization. Repression of NRF2 antagonized the retrieval of rNOTCH1 due to aberrant FOXO1 expression elicited by melatonin. Moreover, melatonin brought about the occurrence of oxidative stress accompanied by an obvious accumulation of intracellular reactive oxygen species and a significant reduction in glutathione (GSH) content, as well as enzymatic activities of glutathione peroxidase and glutathione reductase, whereas supplementation of rNOTCH1 improved the above-mentioned effects. Nevertheless, this improvement was disrupted by the blockage of NRF2 and FOXO1. Furthermore, addition of GSH rescued the defect of stromal differentiation by melatonin. Collectively, melatonin might impair endometrial decidualization by restraining the differentiation of ESCs dependent on NOTCH1–NRF2–FOXO1–GSH pathway after binding to the MTNR1B receptor.

Summary Sentence

Melatonin impaired endometrial decidualization by restraining the differentiation of stromal cells dependent on the NOTCH1–NRF2–FOXO1–GSH pathway after binding to the MTNR1B receptor.

Graphical Abstract

Progesterone (P4), estradiol (E2), and expression of their receptors (PGR and ESR1, respectively) by cells of the uterus regulate reproductive performance of mammals through effects on secretion and transport of nutrients into the uterine lumen. This study investigated the effect of changes in P4, E2, PGR, and ESR1 on expression of enzymes for the synthesis and secretion of polyamines. Suffolk ewes (n = 13) were synchronized to estrus (Day 0) and then, on either Day 1 (early metestrus), Day 9 (early diestrus), or Day 14 (late diestrus) of the estrous cycle, maternal blood samples were collected, and ewes were euthanized before obtaining uterine samples and uterine flushings. Endometrial expression of MAT2B and SMS mRNAs increased in late diestrus (P < 0.05). Expression of ODC1 and SMOX mRNAs decreased from early metestrus to early diestrus, and expression of ASL mRNA was lower in late diestrus than in early metestrus (P < 0.05). Immunoreactive PAOX, SAT1, and SMS proteins were localized to uterine luminal, superficial glandular, and glandular epithelia, stromal cells, myometrium, and blood vessels. Concentrations of spermidine and spermine in maternal plasma decreased from early metestrus to early diestrus and decreased further in late diestrus (P < 0.05). The abundances of spermidine and spermine in uterine flushings were less in late diestrus than early metestrus (P < 0.05). These results indicate that synthesis and secretion of polyamines are affected by P4 and E2, as well as the expression of PGR and ESR1 in the endometria of cyclic ewes.

Summary Sentence

Synthesis and secretion of polyamines are regulated by changes in progesterone (P4), estradiol (E2), and expression of their receptors (PGR and ESR1, respectively) in uterine epithelia of ewes during the estrous cycle.

Graphical Abstract

Progesterone, estradiol, and the expression of their receptors in uterine luminal, superficial glandular, and glandular epithelia affect changes in the polyamine pathway during the estrous cycle. Changes in the concentrations and abundances of polyamines in plasma and uterine flushings, respectively, and cell-specific expression of enzymes involved in polyamine synthesis in the uteri of ewes occur in response to changes in circulating levels of progesterone, estradiol, and the expression of their receptors (PGR and ESR1) in the uteri of cyclic ewes.

Infertility is a public health concern worldwide. Asthenozoospermia is a common cause of male infertility and is characterized by decreased motility. Sperm motility ensures that sperm migrate to complete fertilization. Macrophages are an essential component of innate immunity in the female reproductive tract. Macrophage extracellular traps are induced by various microorganisms to capture and mediate the clearance of microorganisms. The relationship between sperm and macrophage extracellular traps is unclear. The human monocyte leukemia (THP-1) cells differentiated by phorbol myristate acetate (PMA) are widely used as surrogate of human macrophages. This study investigated sperm-induced macrophage extracellular trap formation and clarified some of the mechanisms affecting macrophage extracellular trap production. Sperm-induced macrophage extracellular traps were visualized and components of macrophage extracellular traps were identified by immunofluorescence analyses and scanning electron microscopy. By inhibiting macrophage extracellular trap production and macrophage phagocytosis, the relationship between macrophage phagocytosis and macrophage extracellular trap production was analyzed. Sperm could trigger PMA-differentiated THP-1 macrophages to produce extracellular traps. Sperm-triggered macrophage extracellular traps are dependent on phagocytosis and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Sperm from asthenozoospermia donors are more likely to be phagocytosed by macrophages than sperm from healthy donors, which induce more macrophage extracellular trap release. These data confirm the phenomenon and partial mechanism of sperm-induced macrophage extracellular trap formation in vitro. These may partly provide evidence to explain the mechanisms of clearing abnormally morphological or hypomotile sperm in the female reproductive tract and the rationale for the decreased probability of successful fertilization in asthenozoospermia.

Summary Sentence

Sperm-triggered macrophage extracellular traps are dependent on phagocytosis and NADPH oxidase in phorbol myristate acetate-differentiated THP-1 macrophages. Sperm from asthenozoospermia donors are more likely to be phagocytosed than sperm from healthy donors, which induce more macrophage extracellular trap release.

Graphical Abstract