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Edinburgh Fertility and Reproductive Endocrine Centre, Simpson’s Centre for Reproductive Health, Edinburgh Royal Infirmary, Edinburgh, UK
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Elucidating the mechanisms underpinning fertilisation is essential to optimising IVF procedures. One of the critical steps involves paternal chromatin reprogramming, in which compacted sperm chromatin packed by protamines is removed by oocyte factors and new histones, including histone H3.3, are incorporated. HIRA is the main H3.3 chaperone governing this protamine-to-histone exchange. Failure of this step results in abnormally fertilised zygotes containing only one pronucleus (1PN), in contrast to normal two-pronuclei (2PN) zygotes. 1PN zygotes are frequently observed in IVF treatments, but the genotype-phenotype correlation remains elusive. We investigated the maternal functions of two other molecules of the HIRA complex, Cabin1 and Ubn1, in mouse. Loss-of-function Cabin1 and Ubn1 mouse models were developed: their zygotes displayed an abnormal 1PN zygote phenotype. We then studied human 1PN zygotes and found that the HIRA complex was absent in 1PN zygotes that lacked the male pronucleus. This shows that the role of the HIRA complex in male pronucleus formation potentially has coherence from mice to humans. Furthermore, rescue experiments in mouse showed that the abnormal 1PN phenotype derived from Hira mutants could be resolved by overexpression of HIRA. We have demonstrated that HIRA complex regulates male pronucleus formation in mice and is implicated in humans, that both CABIN1 and UBN1 components of the HIRA complex are equally essential for male pronucleus formation, and that rescue is feasible.
Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, New South Wales, Australia
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Maternal recognition of pregnancy (MRP) is a process by which an early conceptus signals its presence to the maternal system and prevents the lysis of the corpus luteum, thus ensuring a maternal milieu supportive of pregnancy continuation. It is a fundamental aspect of reproductive biology, yet in the horse, the mechanism underlying MRP remains unknown. This review seeks to address some of the controversies surrounding the evidence and theories of MRP in the equine species, such as the idea that the horse does not conform to the MRP paradigm established in other species or that equine MRP involves a mechanical, rather than chemical, signal. The review examines the challenges of studying this particularly clandestine phenomenon along with the new tools in scientific research that will drive this quest forward in coming years, and discusses the value of knowledge gleaned along this path in the context of clinical applications for improving breeding outcomes in the horse industry.
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We recently described two outbred mouse lines that were selected for large litter size at first delivery. However, lifetime fecundity appears to be economically more important for the husbandry of many polytocous species for which mouse lines might serve as bona fide animal models (e.g. for pigs). In the present study, we compared the lifetime fecundities of two highly fertile mouse lines (FL1 and FL2: >20 offspring/litter at first delivery) with those of an unselected control line (ctrl) and two lines that were selected for high body weight (DU6) and high protein mass (DU6P) without selection pressure on fertility. We tested the hypothesis that selection for large litter size at first parturition would also increase lifetime fecundity in mice, and we observed very large differences between lines. Whereas FL1 and ctrl delivered up to nine and ten litters, none of the DU6 and DU6P females gave birth to more than five litters. In line with this observation, FL1 delivered the most pups per lifetime (85.7/female). FL2 females produced the largest average litter sizes (20.4 pups/litter) in the first four litters; however, they displayed a reduced number of litters. With the exception of ctrl, litter sizes declined from litter to litter. Repeated delivery of litters with high offspring numbers did not affect the general health of FL females. The presented data demonstrate that two biodiverse, highly fertile mouse lines selected for large litter size at first delivery show different lifetime reproductive fitness levels. Thus, these mouse lines might serve as valuable mouse models for investigating lifetime productivity and longevity in farm animals.
Centre for Trophoblast Research, University of Cambridge, Cambridge, Cambridgeshire, UK
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Centre for Trophoblast Research, University of Cambridge, Cambridge, Cambridgeshire, UK
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Infertility is a common problem in modern societies with significant socio-psychological implications for women. Therapeutic interventions are often needed which, depending on the cause, can either be medical treatment, surgical procedures or assisted reproductive technology (ART). However, the treatment of infertility is not always successful due to our limited understanding of the preparation of the lining of the uterus, the endometrium, for pregnancy. The endometrium is of central importance for successful reproduction as it is the site of placental implantation providing the interface between the mother and her baby. Due to the dynamic, structural and functional changes the endometrium undergoes throughout the menstrual cycle, it is challenging to study. A major advancement is the establishment of 3D organoid models of the human endometrium to study this dynamic tissue in health and disease. In this review, we describe the changes that the human endometrium undergoes through the different phases of the menstrual cycle in preparation for pregnancy. We discuss defects in the processes of endometrial repair, decidualization and acquisition of receptivity that are associated with infertility. Organoids could be utilized to investigate the underlying cellular and molecular mechanisms occurring in non-pregnant endometrium and early pregnancy. These studies may lead to therapeutic applications that could transform the treatment of reproductive failure.
MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, Scotland
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NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol, Bristol, UK
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Ectopic pregnancy (EP) is defined as the implantation of an embryo outside of the uterus and is a leading cause of first trimester maternal mortality and morbidity. This article discusses a possible role for epithelial to mesenchymal transition in the pathogenesis of EP, given the notable similarity of protein expression between the two processes.
Guangdong Provincial Key Laboratory of Reproductive Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Guangdong Provincial Key Laboratory of Reproductive Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Reproductive Medicine Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
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Guangdong Provincial Key Laboratory of Reproductive Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Guangdong Provincial Key Laboratory of Reproductive Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Guangdong Provincial Key Laboratory of Reproductive Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Guangdong Provincial Key Laboratory of Reproductive Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Luteinization is the event of corpus luteum formation, a way of follicle cells transformation and a process of steroidogenesis alteration. As the core clock gene, Bmal1 was involved in the regulation of ovulation process and luteal function afterwards. Till now, the underlying roles of luteinization played by Bmal1 remain unknown. To explore the unique role of Bmal1 in luteal steroidogenesis and its underlying pathway, we investigated the luteal hormone synthesis profile in Bmal1 knockout female mice. We found that luteal hormone synthesis was notably impaired, and phosphorylation of PI3K/NfκB pathway was significantly activated. Then, the results were verified in in vitro cultured cells, including isolated Bmal1 interference granulosa cells (GCs) and theca cells (TCs), respectively. Hormones levels of supernatant culture media and mRNA expressions of steroidogenesis-associated genes (star, Hsd3β2, cyp19a1 in GCs, Lhcgr, star, Hsd3β2, cyp17a1 in TCs) were mutually decreased, while the phosphorylation of PI3K/NfκB was promoted during in vitro luteinization. After PI3K specific-inhibitor LY294002 intervention, mRNA expressions of Lhcgr and Hsd3β2 were partially rescued in Bmal1 interference TCs, together with significantly increased androstenedione and T synthesis. Further exploration in TCs demonstrated BMAL1 interacted directly but negatively with NfκB p65 (RelA), a subunit which was supposed as a mediator in Bmal1-governed PI3K signaling regulation. Taken together, we verified the novel role of Bmal1 in luteal steroidogenesis, achieving by negative interplay with RelA-mediated PI3K/NfκB pathway.
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Human placenta is a complex and heterogeneous organ interfacing between the mother and the fetus that supports fetal development. Alterations to placental structural components are associated with various pregnancy complications. To reveal the heterogeneity among various placenta cell types in normal and diseased placentas, as well as elucidate molecular interactions within a population of placental cells, a new genomics technology called single cell RNA-seq (or scRNA-seq) has been employed in the last couple of years. Here we review the principles of scRNA-seq technology, and summarize the recent human placenta studies at scRNA-seq level across gestational ages as well as in pregnancy complications, such as preterm birth and preeclampsia. We list the computational analysis platforms and resources available for the public use. Lastly, we discuss the future areas of interest for placenta single cell studies, as well as the data analytics needed to accomplish them.
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Failures during conceptus elongation are a major cause of pregnancy losses in ungulates, exerting a relevant economic impact on farming. The developmental events occurring during this period are poorly understood, mainly because this process cannot be recapitulated in vitro. Previous studies have established an in vitro post-hatching development (PHD) system that supports bovine embryo development beyond the blastocyst stage, based on agarose gel tunnels and serum- and glucose-enriched medium. Unfortunately, under this system embryonic disc formation is not achieved and embryos show notorious signs of apoptosis and necrosis. The objective of this study has been to develop an in vitro system able to support embryonic disc formation. We first compared post-hatching development inside agarose tunnels or free-floating over an agarose-coated dish in serum- and glucose-enriched medium (PHD medium). Culture inside agarose tunnels shaped embryo morphology by physical constriction, but it restricted embryo growth and did not provide any significant advantage in terms of development of hypoblast and epiblast lineages. In contrast to PHD medium, a chemically defined and enriched medium (N2B27) supported complete hypoblast migration and epiblast survival in vitro, even in the absence of agarose coating. Cells expressing the pluripotency marker SOX2 were observed in ~56% of the embryos and ~25% developed embryonic disc-like structures formed by SOX2+ cells. In summary, here we provide a culture system that supports trophectoderm proliferation, hypoblast migration and epiblast survival after the blastocyst stage.
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Endometriosis (EMs) is an estrogen (E2)-dependent inflammatory disorder. Although EMs is considered a benign disease, it presents with malignant characteristics, such as migration and invasion. An increasing number of studies have shown that aberrantly expressed circular RNAs (circRNAs) play an essential role in disease development and progression. However, the mechanisms by which circRNAs exert their pathological effects in EMs remain unclear. Hsa_circ_0001649, a novel cancer-associated circRNA, has been previously reported to be downregulated in several cancer types and related to cell migration and invasion. In the present study, real-time PCR (qRT-PCR) was carried out to measure hsa_circ_0001649 levels in human tissues, human primary endometrial stromal cells (ESCs) and a human endometrial stromal cell line (ThESCs). Matrix metalloproteinase 9 (MMP9) levels in ESCs and ThESCs were assessed by qRT-PCR and Western blotting, and the migration and invasion capacities of ThESCs were evaluated by transwell assay. As a result, hsa_circ_0001649 expression was significantly decreased in ectopic and eutopic endometrial samples compared with that in normal endometrial samples. E2 decreased hsa_circ_0001649 expression but increased MMP9 expression in ESCs and ThESCs. Furthermore, ThESCs were more invasive under E2 stimulation. However, these effects disappeared when ICI or hsa_circ_0001649 transfection was used. Collectively, our findings reveal that decreased hsa_circ_0001649 expression plays a role in E2-increased MMP9 expression through E2 receptors (ERs), which have critical functions in EMs.
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Adipokines emerged as regulators of metabolism and inflammation in several scenarios. This study evaluated the relationship between adipokines (adiponectin, chemerin and visfatin) and cytological (subclinical) endometritis, by comparing healthy (without), transient (recovered by 45 days postpartum (DPP)) and persistent (until 45 DPP) endometritis cows (n = 49). Cows with persistent endometritis had higher adiponectin concentrations in plasma (at 21 DPP, P < 0.05 and at 45 DPP, P < 0.01) and in uterine fluid (at 45 DPP, P < 0.001), and higher chemerin concentrations in plasma (P < 0.05) and uterine fluid (P < 0.01) at 45 DPP than healthy cows. Cows with persistent endometritis had higher gene transcription in the cellular pellet of uterine fluid and protein expression in the endometrium of these adipokines and their receptors than healthy cows. Adiponectin plasma concentrations allowed to discriminate healthy from persistent endometritis cows, in 87% (21 DPP) and 98% (45 DPP) of cases, and adiponectin and chemerin uterine fluid concentrations at 45 DPP allowed for this discrimination in 100% of cases. Cows with concentrations above the cutoff were a minimum of 3.5 (plasma 21 DPP), 20.4 (plasma 45 DPP), and 33.3 (uterine fluid 45 DPP) times more at risk of evidencing persistent endometritis at 45 DPP than cows with concentrations below the cutoff. Overall, results indicate a relationship between adipokine signalling and the inflammatory status of the postpartum uterus of dairy cows, evidencing that adipokines represent suitable biomarkers of subclinical endometritis, able to predict the risk of persistence of inflammation.
