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Placenta Sep 2023The future health of the offspring can be influenced by longstanding maternal anxiety and depression disorders during pregnancy. The present study aimed to explore the...
INTRODUCTION
The future health of the offspring can be influenced by longstanding maternal anxiety and depression disorders during pregnancy. The present study aimed to explore the effect of psychiatric disorders during pregnancy on placental epigenetics.
METHODS
We measured DNA methylation patterns in term-placentas of women either suffering longstanding anxiety and depression symptoms (Index group, with overt symptoms), or a healthy population (Control, none/only mild symptoms). Whole genome DNA methylation profiling was performed using the TruSeq® Methyl Capture EPIC Library Prep Kit (Illumina, San Diego, CA, USA) for library preparation and NGS technology for genomic DNA sequencing.
RESULTS
The results of high-throughput DNA methylation analysis revealed that the Index group had differential DNA methylation at epigenome-wide significance (p < 0.05) in 226 genes in the placenta. Targeted enrichment analyses identified hypermethylation of genes associated with psychiatric disorders (BRINP1, PUM1), and ion homeostasis (COMMD1), among others. The ECM (extracellular matrix)-receptor interaction pathway was significantly dysregulated in the Index group compared to the Control. In addition, DNA methylation/mRNA integration analyses revealed that four genes with key roles in neurodevelopment and other important processes (EPB41L4B, BMPR2, KLHL18, and UBAP2) were dysregulated at both, DNA methylation and transcriptome levels in the Index group compared to Control.
DISCUSSION
The presented results increase our understanding of how maternal psychiatric disorders may affect the newborn through placental differential epigenome, suggesting DNA methylation status as a biomarker when aiming to design new preventive techniques and interventions.
Topics: Infant, Newborn; Humans; Pregnancy; Female; Placenta; Depression; Epigenesis, Genetic; DNA Methylation; Anxiety; RNA-Binding Proteins
PubMed: 37549439
DOI: 10.1016/j.placenta.2023.07.298 -
Placenta Aug 2023Spatial transcriptomics (ST) maps RNA level patterns within a tissue. This technology has not been previously applied to human placental tissue. We demonstrate analysis...
Spatial transcriptomics (ST) maps RNA level patterns within a tissue. This technology has not been previously applied to human placental tissue. We demonstrate analysis of human placental samples with ST. Unsupervised clustering revealed that distinct RNA patterns were found corresponding to different morphological structures. Additionally, when focusing upon terminal villi and hemoglobin associated structures, RNA levels differed between placentas from full term healthy pregnancies and those complicated by preeclampsia. The results from this study can provide a benchmark for future ST studies in placenta.
Topics: Pregnancy; Humans; Female; Placenta; RNA; Transcriptome; Pre-Eclampsia; Gene Expression Profiling
PubMed: 37481829
DOI: 10.1016/j.placenta.2023.07.004 -
Placenta Sep 2023The human placenta is a vital connection between maternal and fetal tissues, allowing for the exchange of molecules and modulation of immune interactions during... (Review)
Review
The human placenta is a vital connection between maternal and fetal tissues, allowing for the exchange of molecules and modulation of immune interactions during pregnancy. Interestingly, some of the placenta's unique functions can be attributed to transposable elements (TEs), which are DNA sequences that have mobilised into the genome. Co-option throughout mammalian evolution has led to the generation of TE-derived regulators and TE-derived genes, some of which are expressed in the placenta but silenced in somatic tissues. TE genes encompass both TE-derived genes with a repeat element in the coding region and TE-derived regulatory regions such as alternative promoters and enhancers. Placental-specific TE genes are known to contribute to the placenta's unique functions, and interestingly, they are also expressed in some cancers and share similar functions. There is evidence to support that aberrant activity of TE genes may contribute to placental pathologies, cancer and autoimmunity. In this review, we highlight the crucial roles of TE genes in placental function, and how their dysregulation may lead to pre-eclampsia, a common and dangerous placental condition. We provide a summary of the functional TE genes in the placenta to offer insight into their significance in normal and abnormal human development. Ultimately, this review highlights an opportunity for future research to investigate the potential dysregulation of TE genes in the development of placental pathologies such as pre-eclampsia. Further understanding of TE genes and their role in the placenta could lead to significant improvements in maternal and fetal health.
Topics: Animals; Female; Humans; Pregnancy; DNA Transposable Elements; Placenta; Pre-Eclampsia; Promoter Regions, Genetic; Mammals
PubMed: 37301654
DOI: 10.1016/j.placenta.2023.05.017 -
The Journal of Maternal-fetal &... Dec 2024Preeclampsia, one of the most serious obstetric complications, is a heterogenous disorder resulting from different pathologic processes. However, placental oxidative...
OBJECTIVE
Preeclampsia, one of the most serious obstetric complications, is a heterogenous disorder resulting from different pathologic processes. However, placental oxidative stress and an anti-angiogenic state play a crucial role. Mitochondria are a major source of cellular reactive oxygen species. Abnormalities in mitochondrial structures, proteins, and functions have been observed in the placentae of patients with preeclampsia, thus mitochondrial dysfunction has been implicated in the mechanism of the disease. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a newly characterized bi-organellar protein with pleiotropic functions. In the mitochondria, this protein regulates cytochrome oxidase activity and reactive oxygen species production, whereas in the nucleus, it regulates the transcription of a number of genes including response to tissue hypoxia and inflammatory signals. Since MNRR1 expression changes in response to hypoxia and to an inflammatory signal, MNRR1 could be a part of mitochondrial dysfunction and involved in the pathologic process of preeclampsia. This study aimed to determine whether the plasma MNRR1 concentration of women with preeclampsia differed from that of normal pregnant women.
METHODS
This retrospective case-control study included 97 women with preeclampsia, stratified by gestational age at delivery into early (<34 weeks, = 40) and late (≥34 weeks, = 57) preeclampsia and by the presence or absence of placental lesions consistent with maternal vascular malperfusion (MVM), the histologic counterpart of an anti-angiogenic state. Women with an uncomplicated pregnancy at various gestational ages who delivered at term served as controls ( = 80) and were further stratified into early ( = 25) and late ( = 55) controls according to gestational age at venipuncture. Maternal plasma MNRR1 concentrations were determined by an enzyme-linked immunosorbent assay.
RESULTS
1) Women with preeclampsia at the time of diagnosis (either early or late disease) had a significantly higher median (interquartile range, IQR) plasma MNRR1 concentration than the controls [early preeclampsia: 1632 (924-2926) pg/mL vs. 630 (448-4002) pg/mL, = .026, and late preeclampsia: 1833 (1441-5534) pg/mL vs. 910 (526-6178) pg/mL, = .021]. Among women with early preeclampsia, those with MVM lesions in the placenta had the highest median (IQR) plasma MNRR1 concentration among the three groups [with MVM: 2066 (1070-3188) pg/mL vs. without MVM: 888 (812-1781) pg/mL, = .03; and with MVM vs. control: 630 (448-4002) pg/mL, = .04]. There was no significant difference in the median plasma MNRR1 concentration between women with early preeclampsia without MVM lesions and those with an uncomplicated pregnancy ( = .3). By contrast, women with late preeclampsia, regardless of MVM lesions, had a significantly higher median (IQR) plasma MNRR1 concentration than women in the control group [with MVM: 1609 (1392-3135) pg/mL vs. control: 910 (526-6178), = .045; and without MVM: 2023 (1578-8936) pg/mL vs. control, = .01].
CONCLUSIONS
MNRR1, a mitochondrial regulator protein, is elevated in the maternal plasma of women with preeclampsia (both early and late) at the time of diagnosis. These findings may reflect some degree of mitochondrial dysfunction, intravascular inflammation, or other unknown pathologic processes that characterize this obstetrical syndrome.
Topics: Female; Humans; Pregnancy; Case-Control Studies; Hypoxia; Mitochondrial Diseases; Mitochondrial Proteins; Placenta; Pre-Eclampsia; Reactive Oxygen Species; Retrospective Studies
PubMed: 38220225
DOI: 10.1080/14767058.2023.2297158 -
Proceedings of the National Academy of... Dec 2023The placenta serves as the interface between the mother and fetus, facilitating the exchange of gases and nutrients between their separate blood circulation systems....
The placenta serves as the interface between the mother and fetus, facilitating the exchange of gases and nutrients between their separate blood circulation systems. Trophoblasts in the placenta play a central role in this process. Our current understanding of mammalian trophoblast development relies largely on mouse models. However, given the diversification of mammalian placentas, findings from the mouse placenta cannot be readily extrapolated to other mammalian species, including humans. To fill this knowledge gap, we performed CRISPR knockout screening in human trophoblast stem cells (hTSCs). We targeted genes essential for mouse placental development and identified more than 100 genes as critical regulators in both human hTSCs and mouse placentas. Among them, we further characterized in detail two transcription factors, DLX3 and GCM1, and revealed their essential roles in hTSC differentiation. Moreover, a gene function-based comparison between human and mouse trophoblast subtypes suggests that their relationship may differ significantly from previous assumptions based on tissue localization or cellular function. Notably, our data reveal that hTSCs may not be analogous to mouse TSCs or the extraembryonic ectoderm (ExE) in which in vivo TSCs reside. Instead, hTSCs may be analogous to progenitor cells in the mouse ectoplacental cone and chorion. This finding is consistent with the absence of ExE-like structures during human placental development. Our data not only deepen our understanding of human trophoblast development but also facilitate cross-species comparison of mammalian placentas.
Topics: Humans; Pregnancy; Mice; Female; Animals; Placentation; Placenta; Clustered Regularly Interspaced Short Palindromic Repeats; Trophoblasts; Cell Differentiation; Stem Cells; Mammals
PubMed: 38085778
DOI: 10.1073/pnas.2311372120 -
Ultrasound in Obstetrics & Gynecology :... Dec 2023To use superb microvascular imaging (SMI) to evaluate longitudinally spiral artery (SA) and uterine artery (UtA) vascular adaptation in normal human pregnancy, and to...
OBJECTIVES
To use superb microvascular imaging (SMI) to evaluate longitudinally spiral artery (SA) and uterine artery (UtA) vascular adaptation in normal human pregnancy, and to develop reference ranges for use at various gestational ages throughout pregnancy.
METHODS
The data for this study were obtained from the National Institutes of Health (NIH)-funded Human Placenta Project. Women aged 18-35 years, with a body mass index < 30 kg/m , without comorbidities, with a singleton gestation conceived spontaneously, and gestational age at or less than 13 + 6 weeks were eligible for inclusion. The current analysis was restricted to uncomplicated pregnancies carried to term. Exclusion criteria included maternal or neonatal complications, fetal or umbilical cord anomalies, abnormal placental implantation or delivery < 37 weeks. Women who fulfilled the inclusion criteria formed the reference population of the Human Placenta Project study. Each participant underwent eight ultrasound examinations during pregnancy. The pulsatility index (PI) of both the left and right UtA were obtained twice for each artery and the presence or absence of a notch was noted. Using SMI technology, the total number of SA imaged was recorded in a sagittal placental section at the level of cord insertion. The PI and peak systolic velocity (PSV) were also measured in a total of six SA, including two in the central portion of the placenta, two peripherally towards the uterine fundal portion, and two peripherally towards the lower uterine segment.
RESULTS
A total of 90 women fulfilled the study criteria. Maternal UtA-PI decreased throughout the first half of pregnancy from a mean ± SD of 1.39 ± 0.50 at 12-13 weeks' gestation to 0.88 ± 0.24 at 20-21 weeks' gestation. The mean number of SA visualized in a sagittal plane of the placenta increased from 8.83 ± 2.37 in the first trimester to 16.99 ± 3.31 in the late-third trimester. The mean SA-PI was 0.57 ± 0.12 in the first trimester and decreased progressively during the second trimester, reaching a nadir of 0.40 ± 0.10 at 24-25 weeks, and remaining constant until the end of pregnancy. SA-PSV was highest in early pregnancy with a mean of 57.16 ± 14.84 cm/s at 12-13 weeks' gestation, declined to a mean of 49.38 ± 17.88 cm/s at 20-21 weeks' gestation and continued to trend downward for the remainder of pregnancy, reaching a nadir of 34.50 ± 15.08 cm/s at 36-37 weeks' gestation. A statistically significant correlation was noted between SA-PI and UtA-PI (r = 0.5633; P < 0.001). Multilevel regression models with natural cubic splines were used to create reference ranges of SA-PSV and SA-PI for given gestational ages.
CONCLUSION
From early gestation, we have demonstrated the ability to image and quantify SA blood flow in normal pregnancy, and have developed reference ranges for use at various gestational ages throughout pregnancy. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Uterine Artery; Placenta; Ultrasonography, Prenatal; Ultrasonography; Pregnancy Trimester, Third; Gestational Age; Pulsatile Flow; Pre-Eclampsia
PubMed: 37470712
DOI: 10.1002/uog.26312 -
Placenta Aug 2023Expression of nutrient transporters in the placenta affects fetal growth. This study reports the protein expression of nutrient transporters in the syncytial membranes...
INTRODUCTION
Expression of nutrient transporters in the placenta affects fetal growth. This study reports the protein expression of nutrient transporters in the syncytial membranes [microvillous membrane (MVM) and basal membrane (BM)] of normotensive control and preeclampsia placentae.
METHODS
Placentae were collected from fourteen normotensive control women and fourteen women with preeclampsia. The syncytiotrophoblast MVM and BM membranes were isolated. The protein expression of glucose transporter (GLUT1), vitamin B transporter (CD320) and fatty acid transporters (FATP2, FATP4) was assessed in both the membranes.
RESULTS
Comparison between membranes demonstrates similar CD320 protein expression in normotensive group whereas, in preeclampsia placentae it was higher in the BM as compared to MVM (p < 0.05). FATP2&4 protein expression was higher in the BM as compared to their respective MVM fraction in both the groups (p < 0.01 for both). Comparison between groups demonstrates higher GLUT1 expression in the MVM (p < 0.05) and BM (p < 0.05) whereas lower CD320 expression in the MVM (p < 0.05) of preeclampsia placentae as compared to their respective membranes in normotensive control. Furthermore, GLUT1 protein expression was positively associated and CD320 protein expression was negatively associated with maternal body mass index (BMI) (p < 0.05 for both). No difference was observed in the FATP2&4 protein expression. However, FATP4 protein expression was negatively associated with maternal blood pressure (p < 0.05 for MVM; p = 0.060 for BM) and birth weight (p < 0.05 for both membranes).
DISCUSSION
The current study for the first time demonstrates differential expression of various transporters in the syncytiotrophoblast membranes of the preeclampsia placentae which may influence fetal growth.
Topics: Pregnancy; Female; Humans; Trophoblasts; Pre-Eclampsia; Glucose Transporter Type 1; Placenta; Membrane Transport Proteins; Nutrients
PubMed: 37421872
DOI: 10.1016/j.placenta.2023.07.001 -
Placenta Aug 2023The development of placenta and fetal brain are intricately linked. Placental insufficiency is related to poor neonatal outcomes with impacts on neurodevelopment. This...
INTRODUCTION
The development of placenta and fetal brain are intricately linked. Placental insufficiency is related to poor neonatal outcomes with impacts on neurodevelopment. This study sought to investigate whether simultaneous fast assessment of placental and fetal brain oxygenation using MRI T2* relaxometry can play a complementary role to US and Doppler US.
METHODS
This study is a retrospective case-control study with uncomplicated pregnancies (n = 99) and cases with placental insufficiency (PI) (n = 49). Participants underwent placental and fetal brain MRI and contemporaneous ultrasound imaging, resulting in quantitative assessment including a combined MRI score called Cerebro-placental-T2*-Ratio (CPTR). This was assessed in comparison with US-derived Cerebro-Placental-Ratio (CPR), placental histopathology, assessed using the Amsterdam criteria [1], and delivery details.
RESULTS
Pplacental and fetal brain T2* decreased with increasing gestational age in both low and high risk pregnancies and were corrected for gestational-age alsosignificantly decreased in PI. Both CPR and CPTR score were significantly correlated with gestational age at delivery for the entire cohort. CPTR was, however, also correlated independently with gestational age at delivery in the PI cohort. It furthermore showed a correlation to birth-weight-centile in healthy controls.
DISCUSSION
This study indicates that MR analysis of the placenta and brain may play a complementary role in the investigation of fetal development. The additional correlation to birth-weight-centile in controls may suggest a role in the determination of placental health even in healthy controls. To our knowledge, this is the first study assessing quantitatively both placental and fetal brain development over gestation in a large cohort of low and high risk pregnancies. Future larger prospective studies will include additional cohorts.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Placenta; Placental Insufficiency; Fetal Growth Retardation; Prospective Studies; Retrospective Studies; Case-Control Studies; Gestational Age; Magnetic Resonance Imaging; Pregnancy, High-Risk; Brain; Ultrasonography, Prenatal
PubMed: 37295055
DOI: 10.1016/j.placenta.2023.05.014 -
Placenta Sep 2023Many structures necessary for placental function can only be visualised at the ultrastructural scale. Recent technological advances have made Volume electron microscopy... (Review)
Review
Many structures necessary for placental function can only be visualised at the ultrastructural scale. Recent technological advances have made Volume electron microscopy (volume EM) approaches much more accessible. Volume EM allows the ultrastructure of tissues, cells and organelles to be visualised in 3D. It also allows the 3D spatial relationships between these structures to be determined. This review will highlight the potential for volume EM to advance our understanding of placental ultrastructure. It will focus on the human term placenta highlighting key findings spanning the placental barrier from trans-syncytial nanopores in the syncytiotrophoblast to tunnelling nanotubes in the fetal capillary endothelium. Volume EM is advancing our understanding of placental ultrastructure, but to fully exploit its potential, it will be necessary to use it as part of multimodal and correlative workflows. The complementary strengths of these different approaches can complement volume EM and reveal the biological significance of its novel observations. The use of volume EM also highlighted how ultrastructural features might underpin pregnancy pathologies and demonstrates the need for more research in this underrepresented area.
Topics: Pregnancy; Female; Humans; Placenta; Volume Electron Microscopy; Trophoblasts; Prenatal Care
PubMed: 37487796
DOI: 10.1016/j.placenta.2023.07.015 -
Fetal and Pediatric Pathology Oct 2023We evaluated what placental pathologies were associated with adverse preterm births.
OBJECTIVE
We evaluated what placental pathologies were associated with adverse preterm births.
MATERIALS AND METHODS
Placental findings, classified according to the Amsterdam criteria, were correlated with infant outcomes. The fetal vascular lesions, inflammatory responses other than histological chorioamnionitis (HCA), and placentas with combined maternal vascular malperfusion (MVM) and HCA were excluded.
RESULTS
A total of 772 placentas were evaluated. MVM was present in 394 placentas, HCA in 378. Early neonatal sepsis, retinopathy of prematurity, necrotizing enterocolitis, and neonatal death occurred more often in the MVM-only group than HCA-only group. The frequency of bronchopulmonary dysplasia (BPD) was 38.6% in the HCA-only group, and it was 20.3% in the MVM-only group ( < 0.001). HCA was the most important independent risk factor for BPD (OR 3.877, 95% CI 2.831-5.312).
CONCLUSION
Inflammation in the placenta influences fetal and neonatal outcomes. HCA is an independent risk factor for BPD.
Topics: Infant; Infant, Newborn; Pregnancy; Female; Humans; Infant, Premature; Placenta; Inflammation; Fetal Diseases; Perinatal Death; Infant, Newborn, Diseases; Chorioamnionitis; Gestational Age
PubMed: 37341537
DOI: 10.1080/15513815.2023.2223297