Female mouse embryonic stem cells (mESCs) contain two active X chromosomes, with one undergoing random inactivation upon differentiation. Schulz et al. (2014) now demonstrate that the presence of two active X chromosomes in mESCs prevents exit from pluripotency by blocking MAPK signaling, ensuring synchronization between X chromosome dosage compensation and development.

Background

Extracellular vesicles (EVs) are membrane-bound vesicles, found in biofluids, that carry and transfer regulatory molecules, such as microRNAs (miRNAs) and proteins, and may mediate intercellular communication between cells and tissues. EVs have been isolated from a wide variety of biofluids, including plasma, urine, and, relevant to this review, seminal, follicular and uterine luminal fluid. We conducted a systematic search of the literature to review and present the currently available evidence on the possible roles of EVs in follicular growth, resumption of oocyte development and maturation (meiosis), sperm maturation, fertilization and embryo implantation.

Methods

MEDLINE, Embase and Web of Science databases were searched using keywords pertaining to EVs, including 'extracellular vesicles', 'microvesicles', 'microparticles' and 'exosomes', combined with a range of terms associated with the period of development between fertilization and implantation, including 'oocyte', 'sperm', 'semen', 'fertilization', 'implantation', 'embryo', 'follicular fluid', 'epididymal fluid' and 'seminal fluid'. Relevant research articles published in English (both animal and human studies) were reviewed with no restrictions on publication date (i.e. from earliest database dates to July 2015). References from these articles were used to obtain additional articles.

Results

A total of 1556 records were retrieved from the three databases. After removing duplicates and irrelevant titles, we reviewed the abstracts of 201 articles, which included 92 relevant articles. Both animal and human studies unequivocally identified various types of EVs in seminal, follicular and ULFs. Several studies provided evidence for the roles of EVs in these biofluids. In men, EVs in seminal fluid were linked with post-testicular sperm maturation, including sperm motility acquisition and reduction of oxidative stress. In women, EVs in follicular fluid were shown to contain miRNAs with potential roles in follicular growth, resumption of oocyte meiosis, steroidogenesis and prevention of polyspermy after fertilization. EVs were also detected in the media of cultured embryos, suggesting that EVs released from embryos and the uterus may mediate embryo-endometrium cross-talk during implantation. It is important to note that many of the biologically plausible functions of EVs in reproduction discussed in the current literature have not yet been substantiated by conclusive experimental evidence.

Conclusions

A detailed understanding of the contributions of EVs in the series of events from gametogenesis to fertilization and then on to implantation, in both normal and pathological cases, may enable the development of valuable tools to advance reproductive health. Because of the early stage of the field, it is unsurprising that the current literature includes not only growing experimental evidence, but also as-yet unproven hypotheses pertaining to the roles of EVs in key reproductive processes. In this review, we present a comprehensive survey of the rapidly expanding literature on this subject, highlighting both relevant findings and gaps in knowledge.

The ability to culture pluripotent stem cells and direct their differentiation into specific cell types in vitro provides a valuable experimental system for modeling pluripotency, development and cellular differentiation. High-throughput profiling of the transcriptomes and epigenomes of pluripotent stem cells and their differentiated derivatives has led to identification of patterns characteristic of each cell type, discovery of new regulatory features in the epigenome and early insights into the complexity of dynamic interactions among regulatory elements. This work has also revealed potential limitations of the use of pluripotent stem cells as in vitro models of developmental events, due to epigenetic variability among different pluripotent stem cell lines and epigenetic instability during derivation and culture, particularly at imprinted and X-inactivated loci. This review focuses on the two most well-studied epigenetic mechanisms, DNA methylation and histone modifications, within the context of pluripotency and differentiation.

Background

Threatened preterm birth is the most common reason for antepartum hospitalization in the United States, accounting for approximately 50% of these admissions. However, fewer than 10% of patients with inpatient evaluation for signs or symptoms of preterm labor ultimately deliver before term.

Objective

This study aimed to generate predictive models to assess the risk of preterm delivery and time to delivery based on clinical signs and symptoms of patients evaluated in our institution for preterm labor concerns.

Study design

This was a retrospective cohort study of singleton pregnancies evaluated for signs and/or symptoms of preterm labor, including contractions, abdominal pain, vaginal bleeding, and short cervix, between 22 0/7 and 33 6/7 weeks of gestation. Inpatient evaluations were classified by patient presentation: (1) symptomatic with cervical findings (transvaginal cervical length of <2.5 cm or cervical dilation of ≥2.0 cm), (2) asymptomatic with cervical findings, and (3) symptomatic without cervical findings. The primary outcomes included incidence of spontaneous preterm birth and interval from presentation to delivery, compared between groups. The risk of preterm delivery was evaluated using log-binomial regression, and presentation to delivery timing was assessed by survival analysis and Cox proportional hazards modeling.

Results

Of 631 patients with preterm labor concerns, 96 (16%) were symptomatic with cervical findings on evaluation, 51 (8%) were asymptomatic with cervical findings, and 466 (76%) were symptomatic without cervical findings. The occurrence of preterm birth was significantly higher among symptomatic patients with cervical findings (49%) than among those with cervical findings alone (31%) or symptoms alone (11%) (P<.0001). In addition, symptomatic patients with cervical findings were significantly more likely to deliver within 48 hours (20%), 1 week (30%), 2 weeks (33%), and 1 month (43%) of presentation than patients with cervical findings alone (2%, 2%, 6%, and 10%, respectively) or symptoms alone (0.4%, 1%, 1.5%, and 5%, respectively) (P value for trend<.0001). Adjusted for gestational age at presentation and previous preterm birth, the overall risk of preterm delivery was significantly higher among patients with symptoms and cervical findings than among patients with cervical findings alone (relative risk, 2.81; 95% confidence interval, 1.74-4.54) or symptoms alone (relative risk, 4.39; 95% confidence interval, 3.16-6.09). Adjusted for the same variables, symptomatic patients with cervical findings were also at higher risk of delivery over time after assessment than patients with cervical findings alone (hazard ratio, 2.06; 95% confidence interval, 1.47-2.90) or symptoms alone (hazard ratio, 2.16; 95% confidence interval, 1.74-2.70). The negative predictive value of these models suggested that only 1% of patients with isolated symptoms or cervical findings are at risk of preterm delivery within 1 week of initial presentation.

Conclusion

Symptomatic patients with cervical findings suggestive of preterm labor were at the greatest risk of preterm birth and a shorter interval from presentation to delivery. The study findings supported a risk profile that may facilitate the selection of patients most appropriate for admission and targeted management. Nonetheless, as nearly 50% of patients meeting this risk profile subsequently deliver at term, future research is needed to identify which of these patients will require intervention.

The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications.