Placental Type Research Articles

Angiogenic factors (sFlt-1, PlGF) in twin pregnancy with placentaassociated complications

Aim : to determine reference values of angiogenic factors dynamics in pregnancy for female patients with twins and different types of placentation for early diagnostics and assessment of preeclampsia (PE) severity. Materials and Methods . There was conducted 2020–2021 prospective study enrolling 93 females with twin pregnancy to examine 68 with dichorionic diamniotic (DCDA) twins and 25 with monochorionic diamniotic (MCDA) twins. All patients were divided into 2 groups: group I consisted of 65 women with twin pregnancy without PE, group II included 28 women with twin pregnancy complicated by PE. In blood serum of pregnant women the level of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and their ratio were studied for diagnosing and predicting PE severity at 4 time points of gestation (20.0–23.6 weeks, 24.0–28.6 weeks, 29.0–33.6 weeks, 34.0–36.6 weeks). Results . No significant difference was found in angiogenic factors level and their ratio in pregnant women with uncomplicated DCDA and MCDA twins. Regardless of placentation type, sFlt-1/PlGF ratio in women with twin pregnancy and PE at 24 weeks of gestation was 103.3, by 20-fold exceeding this level than in uncomplicated twin pregnancy. Cut-off values for sFlt-1/PlGF ratio were determined allowing highly reliable to rule out diagnosis PE (sFlt-1/PlGF < 21.85; sensitivity 100 %, specificity 85 %) and to diagnose PE (sFlt-1/PlGF > 49.4; sensitivity 71.1 %, specificity 100 %). The sFlt-1/PlGF ratio was higher in pregnant women with severe PE compared with the moderate degree of the disease throughout pregnancy (р < 0.05). In pregnant women with early PE, the angiogenic factors ratio exceeded the upper threshold value from 24 weeks of gestation, with late PE – from 34.0–36.6 weeks. Significantly higher sFlt-1 level (18359 ± 8656 pg/ml vs. 5526 ± 2808 pg/ml; р < 0.001) and the sFlt-1/PlGF ratio (118,0 ± 65,2 vs. 32,8 ± 18,6; р < 0.03) as well as severe degree of PE were noted in patients with induced twin pregnancy from 24.0–28.6 weeks of gestation compared with spontaneous multiple pregnancy (42,2 and 22,2 % respectively; p < 0,05). Conclusion . The developed reference values of the sFlt-1/PlGF ratio in pregnant women with twins and different types of placentation can be used not only to diagnose PE, but also to assess the severity and timing of the disease manifestation.

Placental Cellular Composition and Umbilical Cord Metal Concentrations: A Descriptive Molecular Epidemiology Study Leveraging DNA Methylation

Background and Aim: During pregnancy, potentially toxic metals and metalloids can cross the placenta with varying degrees of efficiency. We hypothesized metal toxicokinetics may be regulated by placental cellular composition. Until recently, disentangling complex placental tissue at the population level has been challenging. Here, we leveraged DNA methylation profiles to characterize major placental cell types and described relationships with umbilical cord metal concentrations in an extremely preterm birth cohort. Methods: Among 145 infants born before 28 weeks’ gestation enrolled in the US-based ELGAN cohort (2002-2004), we quantified concentrations of 7 non-essential metals/metalloids in cord tissue, representing passage through the placental barrier. Placental DNA methylation profiles were measured by the Illumina EPIC BeadChip and deconvoluted using a novel reference-based approach (planet) to estimate proportions of six constituent cell types. To satisfy the sum-to-one constraint of proportions, we transformed the data into pivot coordinates (a special case of isometric log-ratios) before fitting linear regression models with cord tissue metal concentrations. Results: Arsenic, lead, strontium, and barium were detected in all umbilical cord tissue samples; cadmium and mercury were detected in 97.9% and antimony in 93.7%. The most relatively abundant cell type in placental tissue was syncytiotrophoblast (31.7%), followed by nucleated red blood (27.3%), endothelial (19.4%), Hofbauer (9.6%), stromal (8.8%), and trophoblast cells (3.2%). As syncytiotrophoblasts increase, arsenic levels in cord tissue decrease (Coefficient = -0.6 ng per 1-percentage point, p-value = 0.03) whereas as Hofbauer cells increase, cadmium levels increase (Coefficient = 0.3 ng per 1-percentage point, p-value = 0.03). Null associations were observed for the other metals/metalloids. Conclusions: The findings suggest the cellular composition of the placenta may influence the transport of environmental metals to the fetus. Future studies examining prenatal environmental exposures should consider methylation-based deconvolution as a powerful tool for investigating placental biology.

Uptake, Transport, and Toxicity of Pristine and Weathered Micro- and Nanoplastics in Human Placenta Cells.

Background:The first evidence of micro- and nanoplastic (MNP) exposure in the human placenta is emerging. However, the toxicokinetics and toxicity of MNPs in the placenta, specifically environmentally relevant particles, remain unclear.Objectives:We examined the transport, uptake, and toxicity of pristine and experimentally weathered MNPs in nonsyncytialized and syncytialized BeWo b30 choriocarcinoma cells.Methods:We performed untargeted chemical characterization of pristine and weathered MNPs using liquid chromatography high-resolution mass spectrometry to evaluate compositional differences following particle weathering. We investigated cellular internalization of pristine and weathered polystyrene (PS; ) and high-density polyethylene (HDPE; ) particles using high-resolution confocal imaging and three-dimensional rendering. We investigated the influence of particle coating with human plasma on the cellular transport of PS particles using a transwell setup and examined the influence of acute MNP exposure on cell viability, damage to the plasma membrane, and expression of genes involved in steroidogenesis.Results:Chemical characterization of MNPs showed a significantly higher number of unique features in pristine particles in comparison with weathered particles. Size-dependent placental uptake of pristine and weathered MNPs was observed in both placental cell types after 24 h exposure. Cellular transport was limited and size-dependent and was not influenced by particle coating with human plasma. None of the MNPs affected cell viability. Damage to the plasma membrane was observed only for PS particles in the nonsyncytialized cells at the highest concentration tested (). Modest down-regulation of hsd17b1 was observed in syncytialized cells exposed to pristine MNPs.Discussion:Our results suggest that pristine and weathered MNPs are internalized and translocated in placental cells in vitro. Effects on gene expression observed upon pristine PS and HDPE particle exposure warrant further examination. More in-depth investigations are needed to better understand the potential health risks of MNP and chemicals associated with them under environmentally relevant exposure scenarios. https://doi.org/10.1289/EHP10873

Effectiveness of a fetal magnetic resonance imaging scoring system for predicting the prognosis of pernicious placenta previa: A retrospective study.

Background: The value of multiple magnetic resonance imaging (MRI) signs in predicting pernicious placenta previa (PPP) with placenta accreta spectrum disorders (PAS) is still controversial. This study aimed to investigate the value of a self-made fetal magnetic resonance imaging scoring system in predicting the different types of PAS in pernicious placenta previa and its associated risk of bleeding. Methods: This retrospective study included 193 patients diagnosed with PPP based on MRI findings before delivery. Based on pathological and intraoperative findings, we divided patients into four groups: non-PAS, placental adhesion, placental implantation, and placenta percreta. Receiver operator characteristic curves of the MRI total score and placental implantation type were drawn using pROC packages in the R Studio environment, and cutoff values of each type were calculated, as well as diagnostic evaluation indexes, such as sensitivity, specificity, and the Youden index. Hemorrhage during surgery was compared between the groups. Results: The boundary value between the non-PAS and placental adhesion was 5.5, that between placental adhesion and placental implantation was 11.5, and that between placental implantation and placenta percreta was 15.5 points. The respective specificities were 0.700, 0.869, and 0.958, and the respective sensitivities were 0.994, 0.802, and 0.577. The Youden indices were 0.694, 0.671, and 0.535, respectively. The median (minimum, maximum) quantities of hemorrhage during the operation in the non-PAS, placental adhesion, placental implantation, and placenta percreta groups were 225 (100, 3700), 600 (200, 6000), 1500 (300, 7000), and 3000 (400, 6300) ml, respectively. Hemorrhage was significantly different between the four groups (p < 0.001). Conclusion: These results suggest that the proposed MRI scoring system could be an effective diagnostic tool for assessing PPP types and predicting the associated bleeding risk.

Mitochondria Targeted Antioxidant Significantly Alleviates Preeclampsia Caused by 11β-HSD2 Dysfunction via OPA1 and MtDNA Maintenance.

We have previously demonstrated that placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) dysfunction contributes to PE pathogenesis. We sought to elucidate molecular mechanisms underlying 11β-HSD2 dysfunction-induced PE and to seek potential therapeutic targets using a 11β-HSD2 dysfunction-induced PE-like rat model as well as cultured extravillous trophoblasts (EVTs) since PE begins with impaired function of EVTs. In 11β-HSD2 dysfunction-induced PE-like rat model, we revealed that placental mitochondrial dysfunction occurred, which was associated with mitDNA instability and impaired mitochondrial dynamics, such as decreased optic atrophy 1 (OPA1) expression. MitoTEMPO treatment significantly alleviated the hallmark of PE-like features and improved mitDNA stability and mitochondrial dynamics in the placentas of rat PE-like model. In cultured human EVTs, we found that 11β-HSD2 dysfunction led to mitochondrial dysfunction and disrupted mtDNA stability. MitoTEMPO treatment improved impaired invasion and migration induced by 11β-HSD2 dysfunction in cultured EVTs. Further, we revealed that OPA1 was one of the key factors that mediated 11β-HSD2 dysfunction-induced excess ROS production, mitochondrial dysfunction and mtDNA reduction. Our data indicates that 11β-HSD2 dysfunction causes mitochondrial dysfunctions, which impairs trophoblast function and subsequently results in PE development. Our study immediately highlights that excess ROS is a potential therapeutic target for PE.

Early steps of embryo implantation are regulated by exchange of extracellular vesicles between the embryo and the endometrium.

In early pregnancy, as the embryo arrives in the uterus, intensive communication between the embryo and uterus begins. Hundreds of molecules are known to be involved, but despite numerous findings, full understanding of the complexity of the embryo-maternal dialog remains elusive. Recently, extracellular vesicles, nanoparticles able to transfer functionally active cargo between cells, have emerged as important players in cell-cell communication, and as such, they have gained great attention over the past decade also in reproductive biology. Here, we use a domestic animal model (Sus scrofa) with an epitheliochorial, superficial type of placentation because of its advantage in studding uterine luminal fluid extracellular vesicles. We show that during early pregnancy, the uterine lumen is abundant with extracellular vesicles that carry a plethora of miRNAs able to target genes involved in embryonic and organismal development. These extracellular vesicles, upon the delivery to primary trophoblast cells, affect genes governing development as well as cell-to-cell signaling and interactions, consequently having an impact on trophoblast cell proliferation, migration, and invasion. We conclude that the exchange of a unique population of extracellular vesicles and their molecular cargo at the maternal-embryo interface is the key to the success of embryo implantation and pregnancy.

Deconvolution of a Large Cohort of Placental Microarray Data Reveals Clinically Distinct Subtypes of Preeclampsia.

It has been well established that the dysfunctional placenta plays an important role in the pathogenesis of preeclampsia (PE), a hypertensive disorder in pregnancy. However, it is not well understood how individual cell types in the placenta are involved in placenta dysfunction because of limited single-cell studies of placenta with PE. Given that a high-resolution single-cell atlas in the placenta is now available, deconvolution of publicly available bulk PE transcriptome data may provide us with the opportunity to investigate the contribution of individual placental cell types to PE. Recent benchmark studies on deconvolution have provided suggestions on the strategy of marker gene selection and the choice of methodologies. In this study, we experimented with these suggestions by using real bulk data with known cell-type proportions and established a deconvolution pipeline using CIBERSORT. Applying the deconvolution pipeline to a large cohort of PE placental microarray data, we found that the proportions of trophoblast cells in the placenta were significantly different between PE and normal controls. We then predicted cell-type-level expression profiles for each sample using CIBERSORTx and found that the activities of several canonical PE-related pathways were significantly altered in specific subtypes of trophoblasts in PE. Finally, we constructed an integrated expression profile for each PE sample by combining the predicted cell-type-level expression profiles of several clinically relevant placental cell types and identified four clusters likely representing four PE subtypes with clinically distinct features. As such, our study showed that deconvolution of a large cohort of placental microarray provided new insights about the molecular mechanism of PE that would not be obtained by analyzing bulk expression profiles.

Neutralizing Antibodies to Human Cytomegalovirus Recombinant Proteins Reduce Infection in an Ex Vivo Model of Developing Human Placentas.

Human cytomegalovirus (HCMV) is the leading viral cause of congenital disease and permanent birth defects worldwide. Although the development of an effective vaccine is a public health priority, no vaccines are approved. Among the major antigenic targets are glycoproteins in the virion envelope, including gB, which facilitates cellular entry, and the pentameric complex (gH/gL/pUL128-131), required for the infection of specialized cell types. In this study, sera from rabbits immunized with the recombinant pentameric complex were tested for their ability to neutralize infection of epithelial cells, fibroblasts, and primary placental cell types. Sera from rhesus macaques immunized with recombinant gB or gB plus pentameric complex were tested for HCMV neutralizing activity on both cultured cells and cell column cytotrophoblasts in first-trimester chorionic villus explants. Sera from rabbits immunized with the pentameric complex potently blocked infection by pathogenic viral strains in amniotic epithelial cells and cytotrophoblasts but were less effective in fibroblasts and trophoblast progenitor cells. Sera from rhesus macaques immunized with the pentameric complex and gB more strongly reduced infection in fibroblasts, epithelial cells, and chorionic villus explants than sera from immunization with gB alone. These results suggest that the pentameric complex and gB together elicit antibodies that could have potential as prophylactic vaccine antigens.

A comprehensive analysis of the association between placental pathology and recurrent preterm birth

Histologic examination of the placenta is often performed after preterm birth. Although placental examination cannot change the index pregnancy outcome, it may inform the risk of adverse outcomes in a subsequent pregnancy. Previous research has examined the association between individual histologic lesions and pregnancy outcomes without consistent results. This study aimed to determine the independent contributions of the major placental pathology histologic types to recurrent preterm birth. This was a retrospective cohort study of deliveries at a tertiary care center from January 2009 to March 2018. Individuals with ≥2 births, an index birth of <37 weeks of gestation, and a placental pathology report from the index pregnancy were included. The presence of maternal vascular malperfusion, fetal vascular malperfusion, acute inflammation, and chronic inflammation was extracted from the pathology reports for each index placenta and classified as none, low grade, or high grade. A log-binomial model incorporating all 4 placental pathology histologic types, index gestational age, race, and maternal age was used to estimate the associations between each placental histologic type and risk of recurrent preterm birth. Moreover, 2-way interaction terms were studied among placental histologic types. In addition, 2 stratified analyses were completed on the basis of characteristics of the index preterm birth: (1) by late preterm (gestational age of 34-36 weeks) vs early-to-moderate preterm birth (<34 weeks) and (2) a subgroup analysis of those with spontaneous preterm birth. A total of 924 pregnancy pairs met the inclusion criteria. Only high-grade chronic inflammation was independently associated with an increased risk of recurrent preterm birth (adjusted risk ratio, 1.37; 95% confidence interval, 1.03-1.81). Stratified analysis by gestational age group demonstrated maternal vascular malperfusion was associated with recurrent preterm birth only among those with early preterm birth (adjusted risk ratio, 1.40; 95% confidence interval, 1.01-1.93). Among participants with spontaneous preterm labor, no association was found between pathology histologic types and risk of preterm birth. Among index preterm pregnancies, high-grade chronic placental inflammation was associated with recurrent preterm birth. Low-grade maternal vascular malperfusion was associated with recurrent preterm birth only among those with an early or moderate index preterm birth (<34 weeks of gestation). These findings may be useful in determining the risk profile for individual patients and may generate hypotheses as to the pathogenesis of recurrent preterm birth.

New insights on folliculogenesis and follicular placentation in marine viviparous fish black rockfish (Sebastes schlegelii).

In viviparous fish, a considerable degree of variation in placental structures have been described. However, no distinct structures are reported in Scorpaenidae. In this study, we demonstrate a new type of folliculogenesis and follicular placentation in Sebastes schlegelii. Before copulation, the germinal epithelium gradually surrounds the oocytes and develops into individually follicles with a stalk-like structure hanging on the ovigerous lamella, which ensures each follicle have access to spermatozoa after copulation. From V to early gestation stage, the cyp17-I highly expressesaccompanied by cyp19a1a signals disappearance, and 11-ketotestosterone level keeps rising and peaks at blastula stage, while 17β-estradiol declines to the bottom. Meanwhile, the theca cells rapidly proliferate and invade outwards forming a highly hypertrophied and folded microvillous placenta. This unbalance of hormone might be an important factor driving the theca cells proliferation and invasion. Additionally, some conserved genes related to mammalian placentation are significantly high expression in follicular placenta suggesting the high convergence in vertebrate placenta evolution.

Genome-Wide Placental Gene Methylations in Gestational Diabetes Mellitus, Fetal Growth and Metabolic Health Biomarkers in Cord Blood.

Gestational diabetes mellitus (GDM) “program” an elevated risk of metabolic syndrome in the offspring. Epigenetic alterations are a suspected mechanism. GDM has been associated with placental DNA methylation changes in some epigenome-wide association studies. It remains unclear which genes or pathways are affected, and whether any placental differential gene methylations are correlated to fetal growth or circulating metabolic health biomarkers. In an epigenome-wide association study using the Infinium MethylationEPIC Beadchip, we sought to identify genome-wide placental differentially methylated genes and enriched pathways in GDM, and to assess the correlations with fetal growth and metabolic health biomarkers in cord blood. The study samples were 30 pairs of term placentas in GDM vs. euglycemic pregnancies (controls) matched by infant sex and gestational age at delivery in the Shanghai Birth Cohort. Cord blood metabolic health biomarkers included insulin, C-peptide, proinsulin, IGF-I, IGF-II, leptin and adiponectin. Adjusting for maternal age, pre-pregnancy BMI, parity, mode of delivery and placental cell type heterogeneity, 256 differentially methylated positions (DMPs,130 hypermethylated and 126 hypomethylated) were detected between GDM and control groups accounting for multiple tests with false discovery rate <0.05 and beta-value difference >0.05. WSCD2 was identified as a differentially methylated gene in both site- and region-level analyses. We validated 7 hypermethylated (CYP1A2, GFRA1, HDAC4, LIMS2, NAV3, PAX6, UPK1B) and 10 hypomethylated (DPP10, CPLX1, CSMD2, GPR133, NRXN1, PCSK9, PENK, PRDM16, PTPRN2, TNXB) genes reported in previous epigenome-wide association studies. We did not find any enriched pathway accounting for multiple tests. DMPs in 11 genes (CYP2D7P1, PCDHB15, ERG, SIRPB1, DKK2, RAPGEF5, CACNA2D4, PCSK9, TSNARE1, CADM2, KCNAB2) were correlated with birth weight (z score) accounting for multiple tests. There were no significant correlations between placental gene methylations and cord blood biomarkers. In conclusions, GDM was associated with DNA methylation changes in a number of placental genes, but these placental gene methylations were uncorrelated to the observed metabolic health biomarkers (fetal growth factors, leptin and adiponectin) in cord blood. We validated 17 differentially methylated placental genes in GDM, and identified 11 differentially methylated genes relevant to fetal growth.

A Novel Role for Plasminogen Activator Inhibitor Type-2 as a Hypochlorite-Resistant Serine Protease Inhibitor and Holdase Chaperone.

Plasminogen activator inhibitor type-2 (PAI-2), a member of the serpin family, is dramatically upregulated during pregnancy and in response to inflammation. Although PAI-2 exists in glycosylated and non-glycosylated forms in vivo, the majority of in vitro studies of PAI-2 have exclusively involved the intracellular non-glycosylated form. This study shows that exposure to inflammation-associated hypochlorite induces the oligomerisation of PAI-2 via a mechanism involving dityrosine formation. Compared to plasminogen activator inhibitor type-1 (PAI-1), both forms of PAI-2 are more resistant to hypochlorite-induced inactivation of its protease inhibitory activity. Holdase-type extracellular chaperone activity plays a putative non-canonical role for PAI-2. Our data demonstrate that glycosylated PAI-2 more efficiently inhibits the aggregation of Alzheimer’s disease and preeclampsia-associated amyloid beta peptide (Aβ), compared to non-glycosylated PAI-2 in vitro. However, hypochlorite-induced modification of non-glycosylated PAI-2 dramatically enhances its holdase activity by promoting the formation of very high-molecular-mass chaperone-active PAI-2 oligomers. Both PAI-2 forms protect against Aβ-induced cytotoxicity in the SH-SY5Y neuroblastoma cell line in vitro. In the villous placenta, PAI-2 is localised primarily to syncytiotrophoblast with wide interpersonal variation in women with preeclampsia and in gestational-age-matched controls. Although intracellular PAI-2 and Aβ staining localised to different placental cell types, some PAI-2 co-localised with Aβ in the extracellular plaque-like aggregated deposits abundant in preeclamptic placenta. Thus, PAI-2 potentially contributes to controlling aberrant fibrinolysis and the accumulation of misfolded proteins in states characterised by oxidative and proteostasis stress, such as in Alzheimer’s disease and preeclampsia.

ZIKV replication is differential in explants and cells of human placental which is suppressed by HSV-2 coinfection

During the Zika fever outbreak in Brazil in 2015–2016, only some babies from infected mothers had teratogenic effects, suggesting that cofactors may influence congenital transmission. We investigated the ZIKV infection profile in explants and isolated cells from full-term human placenta to infection with the Brazilian Zika virus strain (ZIKVBR) and the effect of coinfection with the Brazilian Human alphaherpesvirus 2 strain (HSV-2BR) on ZIKV replication. We found that the ZIKVBR infect the explants of amniotic and chorionic membranes, as well as chorionic villi core, but not the trophoblasts layer. It was also observed that ZIKV replication was higher in amniotic cells than chorionic and trophoblasts cells. Upon coinfection, the replication of ZIKVBR was reduced according to exposed HSV-2BR load in trophoblasts cells and the levels of TNF-α and IL-6 cytokines were also reduced. These findings suggest that the placental cell types and HSV-2BR coinfection may impact on ZIKV replication.

Maternal history of childhood maltreatment is associated with diurnal cortisol and DNA methylation of placental 11-beta-hydroxysteroid dehydrogenase type 2.

Accumulating evidence indicates that maternal hypothalamic-pituitary-adrenal (HPA) axis activity over pregnancy differs according to maternal history of childhood maltreatment. DNA methylation of the placental 11-beta-hydroxysteroid dehydrogenase (BHSD) type 2 enzyme regulates fetal exposure to maternal cortisol, yet the association between maternal history of childhood maltreatment and methylation of placental 11BHSD type 2 has not been previously studied. We examined if maternal cortisol production at 11 and 32 weeks' gestation (n = 89) and placental methylation of the 11BHSD type 2 gene (n = 19) differed among pregnant women with and without histories of childhood maltreatment. Twenty-nine percent of participants reported a history of childhood maltreatment (physical/sexual abuse). Women with histories of childhood maltreatment displayed lower cortisol in early gestation, hypo-methylation of placental 11BHSD type 2, and lower levels of cord blood cortisol. Preliminary results suggest alterations in cortisol regulation over pregnancy according to maternal history of childhood maltreatment.

The Evolution of Placentation in Flowering Plants: A Possible Role for Kin Selection

Placentation refers to the mode of ovule attachment on the wall of the ovary. In multiovulate ovaries, placentation influences interactions among developing seeds with varying degrees of kinships. Placentation is a taxonomically informative character in flowering plants, yet little has been written about the origin and evolutionary trends of various placentation types in flowering plants since Puri’s and Stebbins’ work, over six decades and almost four decades ago, respectively. More recently, some authors have written about the evolution of placentation in certain groups, but an overall perspective for angiosperms is lacking. For 421 families of angiosperms, we collected data on placentation types and ovule number, and analyzed the data in the phylogenetic context using recent comprehensive phylogeny of angiosperms to test the hypotheses on the evolution of various placentation types and their association with ovule number. The distribution of placentation types across flowering plants suggests that axile placentation, followed by parietal and basal placentation, occurs more frequently than laminar and free central placentation that are very rare. Our results are more consistent with evolutionary trends proposed by Puri than by Stebbins and suggest that marginal placentation is the ancestral and most primitive placentation type, while axile is the most advanced. Placentation types show strong association with ovule number. Finally, our results on ovule number and placentation types indicate that most angiosperms may fall into two categories: one with one or few ovule(s) and basal placentation, and another with many ovules and parietal and axile placentation. Kin selection within ovaries may play a role in explaining the observed patterns. Overall, our results provide new insights into the evolution of placentation, particularly into the drivers underlying the diversification of various placentation types.

257 Primary cilia in placental mesenchymal stem/stromal cells: Implication in placental development and preeclampsia

Introduction and aims of the study: The development of the human placenta is tightly coordinated by a multitude of placental cell types, including placental mesenchymal stem/stromal cells (pMSCs). Defective pMSCs have been reported in preeclampsia (PE), a gestational hypertensive disease, characterized by maternal endothelial dysfunction and systemic inflammation. We were interested if pMSCs are ciliated and if altered ciliation is responsible for defective pMSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, important for various cellular activities.

Human placental mesenchymal stromal cells are ciliated and their ciliation is compromised in preeclampsia

BackgroundThe development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells (hCV-MSCs). Defective hCV-MSCs have been reported in preeclampsia (PE), a gestational hypertensive disease characterized by maternal endothelial dysfunction and systemic inflammation. Our goal was to determine whether hCV-MSCs are ciliated and whether altered ciliation is responsible for defective hCV-MSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, which is important for various cellular activities.MethodsIn the present work, we collected placental tissues from different gestational stages and we isolated hCV-MSCs from 1st trimester, term control, and preeclamptic placentas. We studied their ciliation, functionality, and impact on trophoblastic cell lines and organoids formed from human trophoblast stem cells (hTSCs) and from the trophoblastic cell line JEG-3 with various cellular and molecular methods, including immunofluorescence staining, gene analysis, spheroid/organoid formation, motility, and cellular network formation assay. The statistical evaluation was performed using a Student’s t test (two-tailed and paired or homoscedastic) or an unpaired Mann–Whitney U test (two-tailed).ResultsThe results show that primary cilia appeared abundantly in normal hCV-MSCs, especially in the early development of the placenta. Compared to control hCV-MSCs, the primary cilia were truncated, and there were fewer ciliated hCV-MSCs derived from preeclamptic placentas with impaired hedgehog signaling. Primary cilia are necessary for hCV-MSCs’ proper signal transduction, motility, homing, and differentiation, which are impaired in preeclamptic hCV-MSCs. Moreover, hCV-MSCs derived from preeclamptic placentas are significantly less capable of promoting growth and differentiation of placental organoids, as well as cellular network formation.ConclusionsThese data suggest that the primary cilium is required for the functionality of hCV-MSCs and primary cilia are impaired in hCV-MSCs from preeclamptic placentas.

Resolving placental immune microenvironments with spatial transcriptomics

The placenta separates maternal-fetal antigens and restricts (or permits) microbe residency and vertical transmission. Mechanisms responsible for tolerizing constant antigen challenges remain poorly understood. Single-cell technologies are defining heterogeneity of placental cell types; however, current analyses lack placenta architecture spatial resolution. Thus, we employed spatial transcriptomics paired with H&E to investigate and map placental immune microenvironments.

Experience with different techniques of laser coagulation of placental anastomoses to relieve feto-fetal transfusion syndrome in monochorionic diamniotic twins

Introduction. In recent years, the problem of multiple fetuses has become particularly important, which is associated with a steady increase in the frequency of multiple pregnancies worldwide. The feto-fetal transfusion syndrome (FFTS) is a classic example of unbalanced functioning of placental anastomoses, which leads to transfusion between fetuses. The incidence of this syndrome in a group of monochorionic diamniotic twins ranges from 8% to 15% and, in the absence of timely diagnosis and intrauterine correction, leads to death of one or both fetuses in 70-100% of cases. The effect of different methods of intrauterine surgical correction of FFTS in monochorionic diamniotic multiple fetuses on perinatal outcomes is of scientific interest. Purpose of the study — to investigate the effect of different types of laser coagulation of placental anastomosis (LCPA) on perinatal outcomes in intrauterine surgical correction of FFTS. Materials and methods. Depending on the surgical technique used, women were divided into three groups: the total placental anastomosis coagulation method, Group 1 (58 pregnant women); the selective placental anastomosis coagulation method, Group 2 (67 pregnant women); the sequential selective laser coagulation of placental anastomoses, Group 3 (62 pregnant women). Results. We analyzed the results of intrauterine surgical correction of FFTS by different methods of laser coagulation of placental anastomoses in 187 women with monochorionic diamniotic type of placentation of II-IV degrees according to Quintero. We obtained statistically significant differences in many perinatal period indices depending on the LCPA method used. Discussion. Sequential selective LCPA has proven to be the most effective, safe, and promising technique for correction of FFTS. The data obtained indicate possible ways to improve pregnancy prolongation and fetal survival rates after the use of intrauterine surgical correction of placental vascular anastomoses. Conclusion. Sequential selective LCPA has proven to be the best technique to correct FFTS with the least perinatal losses and postoperative complications, as well as the highest efficacy.

Maternal 11-Ketoandrostenedione Rises Through Normal Pregnancy and Is the Dominant 11-Oxygenated Androgen in Cord Blood.

Adrenal-derived 11-oxygenated androgens (11oAs) are known important contributors to human physiology and disease but have not been studied in pregnancy. We characterize 11oAs in normal human pregnancy and neonatal period and assess the ratios between 11oAs and compare with ratios of other steroids that undergo placental metabolism. Prospective cohort study, 2010-2018. Academic institution. Pairs of pregnant women and newborns (n = 120) were studied. Inclusion criteria were maternal age between 18 and 42 years old, spontaneous singleton pregnancies, and intention to deliver at University of Michigan. Maternal venous blood was collected during first trimester and at term. Neonatal cord blood was collected following delivery. Steroids were measured via liquid chromatography-tandem mass spectrometry. Levels of 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone, and 11-ketotestoterone (11KT) in maternal first trimester, maternal term, and neonatal cord blood were compared. 11OHA4-to-11KA4 ratios were correlated with cortisol-to-cortisone ratios. Dominant 11oAs in pregnancy and the cord blood are 11OHA4 and 11KA4, compared to 11OHA4 and 11KT in adult men and nonpregnant women. We found a rise in 11oA concentrations, particularly 11KA4, from first to third trimester. In cord blood, the concentration of 11KA4 exceeded those of both 11OHA4 and 11KT, reflecting placental 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and 17β-hydroxysteroid dehydrogenase (17βHSD2) activities, respectively. 11OHA4-to-11KA4 ratios are concordant with cortisol-to-cortisone ratios across all maternal and fetal compartments, reflecting placental 11βHSD2 activity. Placental 17βHSD2 activity defends the fetus against the androgen 11KT. Our normative values may be used in future studies of 11oAs in complicated pregnancies.