Epigenetic changes regulating the epithelial-mesenchymal transition in human trophoblast differentiation.

The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both first trimester differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to two major placental pathologies, preeclampsia and placenta accreta spectrum, so characterization of the corresponding normal processes is crucial. In this report, our gene expression analysis, using purified human CTB and EVT cells, highlights an epithelial-mesenchymal transition (EMT) mechanism underlying CTB-EVT differentiation and provides a trophoblast-specific EMT signature.

Customizing EV-CATCHER to Purify Placental Extracellular Vesicles from Maternal Plasma to Detect Placental Pathologies.

Placenta Accreta Spectrum (PAS) is a life-threatening condition in which placental trophoblastic cells abnormally invade the uterus, often up to the uterine serosa and, in extreme cases, tissues beyond the uterine wall. Currently, there is no clinical assay for the non-invasive detection of PAS, and only ultrasound and MRI can be used for its diagnosis. Considering the subjectivity of visual assessment, the detection of PAS necessitates a high degree of expertise and, in some instances, can lead to its misdiagnosis.

Lipid profile of circulating placental extracellular vesicles during pregnancy identifies foetal growth restriction risk.

Small-for-gestational age (SGA) neonates exhibit increased perinatal morbidity and mortality, and a greater risk of developing chronic diseases in adulthood. Currently, no effective maternal blood-based screening methods for determining SGA risk are available. We used a high-resolution MS/MS shotgun lipidomic approach to explore the lipid profiles of small extracellular vesicles (sEV) released from the placenta into the circulation of pregnant individuals.

Ancestry dependent balancing selection of placental dysferlin at high-altitude.

The placenta mediates fetal growth by regulating gas and nutrient exchange between the mother and the fetus. The cell type in the placenta where this nutrient exchange occurs is called the syncytiotrophoblast, which is the barrier between the fetal and maternal blood. Residence at high-altitude is strongly associated with reduced 3rd trimester fetal growth and increased rates of complications such as preeclampsia.

Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry.

High-altitude hypoxia challenges reproduction; particularly in non-native populations. Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negatively impacted vitamin D levels, with the high-altitude Andeans having the lowest 25-OH-D levels and the high-altitude Europeans having the lowest 1α,25-(OH)-D levels.

Diminished trophoblast differentiation in early onset preeclampsia.

The mechanism by which human cytotrophoblast cells (CTB) differentiate into extravillous trophoblast cells (EVT) is an epithelial-mesenchymal transition (EMT). Polarized CTB, anchored in an epithelial layer, are transformed into motile, non-polar EVT which invade the uterus. Our previous research has shown that over gestation, invasive first trimester EVT are converted to a non-invasive phenotype showing a reduced degree of EMT.

Trophoblast invasion: Lessons from abnormally invasive placenta (placenta accreta).

The invasion of the uterine wall by extravillous trophoblast is acknowledged as a crucial component of the establishment of pregnancy however, the only part of this process that has been clearly identified is the differentiation of cytotrophoblast (CTB) into the invasive extravillous trophoblast (EVT). The control of invasion, both initiation and termination, have yet to be elucidated and even the mechanism of differentiation is unclear. This review describes our studies which are designed to characterize the intracellular mechanisms that drive differentiation.

Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs.

Background: Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.

Results: We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types.

3D Bioprinted GelMA Based Models for the Study of Trophoblast Cell Invasion.

Bioprinting is an emerging and promising technique for fabricating 3D cell-laden constructs for various biomedical applications. In this paper, we employed 3D bioprinted GelMA-based models to investigate the trophoblast cell invasion phenomenon, enabling studies of key placental functions. Initially, a set of optimized material and process parameters including GelMA concentration, UV crosslinking time and printing configuration were identified by systematic, parametric study.

Human placental GLUT1 glucose transporter expression and the fetal insulin-like growth factor axis in pregnancies complicated by diabetes.

We have previously described regulation of syncytial GLUT1 glucose transporters by IGF-I. Despite this, it is not clear what signal regulates transplacental glucose transport. In this report we asked whether changes in GLUT1 expression and glucose transport activity in diabetic pregnancies were associated with alterations in the fetal IGF axis.

IFPA meeting 2018 workshop report II: Abnormally invasive placenta; inflammation and infection; preeclampsia; gestational trophoblastic disease and drug delivery.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2018 there were nine themed workshops, five of which are summarised in this report. These workshops discussed new perspectives and knowledge in the following areas of research: 1) preeclampsia; 2) abnormally invasive placenta; 3) placental infection; 4) gestational trophoblastic disease; 4) drug delivery to treat placental dysfunction.

Human placental glucose transport in fetoplacental growth and metabolism.

While efficient glucose transport is essential for all cells, in the case of the human placenta, glucose transport requirements are two-fold; provision of glucose for the growing fetus in addition to the supply of glucose required the changing metabolic needs of the placenta itself. The rapidly evolving environment of placental cells over gestation has significant consequences for the development of glucose transport systems. The two-fold transport requirement of the placenta means also that changes in expression will have effects not only for the placenta but also for fetal growth and metabolism.

ZEB2, a master regulator of the epithelial-mesenchymal transition, mediates trophoblast differentiation.

Study Question: Does the upregulation of the zinc finger E-box binding homeobox 2 (ZEB2) transcription factor in human trophoblast cells lead to alterations in gene expression consistent with an epithelial-mesenchymal transition (EMT) and a consequent increase in invasiveness?

Summary Answer: Overexpression of ZEB2 results in an epithelial-mesenchymal shift in gene expression accompanied by a substantial increase in the invasive capacity of human trophoblast cells.

What Is Known Already: In-vivo results have shown that cytotrophoblast differentiation into extravillous trophoblast involves an epithelial-mesenchymal transition. The only EMT master regulatory factor which shows changes consistent with extravillous trophoblast EMT status and invasive capacity is the ZEB2 transcription factor.

Human trophoblast epithelial-mesenchymal transition in abnormally invasive placenta.

Differentiation of first trimester human placental cytotrophoblast (CTB) from an anchorage-dependent epithelial phenotype into the mesenchymal-like invasive extravillous trophoblast (EVT) is crucial in the development of the maternal-fetal interface. We showed previously that differentiation of first trimester CTB to EVT involves an epithelial-mesenchymal transition (EMT). Here we compare the epithelial-mesenchymal characteristics of CTB and EVT derived from normal third trimester placenta or placenta previa versus abnormally invasive placenta (AIP).

Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling.

Introduction: The BCRP/ABCG2 efflux transporter protects the developing fetus by limiting the transplacental transfer of drugs and chemicals and prevents the apoptosis of trophoblasts. The purpose of this study was to determine whether hypoxia-related signaling alters placental BCRP expression and function in vitro and in human pregnancies.

Methods: Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic, cobalt chloride (CoCl), or 3% oxygen for 24-48 h.

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Although much progress is being made in understanding the molecular pathways in the placenta that are involved in the pathophysiology of pregnancy-related disorders, a significant gap exists in the utilization of this information for the development of new drug therapies to improve pregnancy outcome. On March 5-6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a 2-day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given to the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways.

Differentiation of first trimester cytotrophoblast to extravillous trophoblast involves an epithelial-mesenchymal transition.

The transformation of cytotrophoblast (CTB) to extravillous trophoblast (EVT) is an essential process for placental implantation. EVT generated at the tips of the anchoring villi migrate away from the placenta and invade the endometrium and maternal spiral arteries, where they modulate maternal immune responses and remodel the arteries into high-volume conduits to facilitate uteroplacental blood flow. The process of EVT differentiation has several factors in common with the epithelial-to-mesenchymal transition (EMT) observed in embryonic development, wound healing and cancer metastasis.

Three-Dimensional Power Doppler Ultrasonography for Diagnosing Abnormally Invasive Placenta and Quantifying the Risk.

Objective: To test an objective ultrasound marker for diagnosing the presence and severity of abnormally invasive placenta.

Methods: Women at risk of abnormally invasive placenta underwent a three-dimensional power Doppler ultrasound scan. The volumes were examined offline by a blinded observer.

Regulation of human trophoblast GLUT1 glucose transporter by insulin-like growth factor I (IGF-I).

Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression.

Maternal and fetoplacental hypoxia do not alter circulating angiogenic growth effectors during human pregnancy.

One causal model of preeclampsia (PE) postulates that placental hypoxia alters the production of angiogenic growth effectors (AGEs), causing an imbalance leading to maternal endothelial cell dysfunction. We tested this model using the natural experiment of high-altitude (HA) residence. We hypothesized that in HA pregnancies 1) circulating soluble fms-like tyrosine kinase 1 (sFlt-1) is increased and placental growth factor (PlGF) decreased, and 2) AGE concentrations correlate with measures of hypoxia.

Maternal and fetal outcomes in placenta accreta after institution of team-managed care.

Introduction: Placenta accreta significantly contributes to maternal morbidity and mortality. We evaluated whether planned delivery and experienced, team-managed surgical intervention results in improved outcomes. We also examined whether risk factors differed for accreta, increta, and percreta and evaluated whether excess lower segment uterine vascularity correlates with disease severity.

Asymmetric syncytial expression of GLUT9 splice variants in human term placenta and alterations in diabetic pregnancies.

Glucose transport from the maternal to fetal side of the placenta is critical for fetal growth and development due to the absence of fetal gluconeogenesis. Human GLUT9, existing as 2 isoforms, is a novel member of the transporter family. This study investigated the localization and relative expression levels of these isoforms in the human term placenta from both control and diabetic patients.

Hypoglycemia and the origin of hypoxia-induced reduction in human fetal growth.

Background: The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies.

Placental metabolic reprogramming: do changes in the mix of energy-generating substrates modulate fetal growth?

Insufficient oxygen leads to the cessation of growth in favor of cellular survival. Our unique model of high-altitude human pregnancy indicates that hypoxia-induced reductions in fetal growth occur at higher levels of oxygen than previously described. Fetal PO(2) is surprisingly high and fetal oxygen consumption unaffected by high altitude, whereas fetal glucose delivery and consumption decrease.

Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude.

Fetal growth is decreased at high altitude (> 2700 m). We hypothesized that variation in fetal O(2) delivery might account for both the altitude effect and the relative preservation of fetal growth in multigenerational natives to high altitude. Participants were 168 women of European or Andean ancestry living at 3600 m or 400 m.