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Nutrients Sep 2023The factors controlling linear growth and weight gain in the human fetus and newborn infant are poorly understood. We review here the changes in linear growth, weight... (Review)
Review
The factors controlling linear growth and weight gain in the human fetus and newborn infant are poorly understood. We review here the changes in linear growth, weight gain, lean body mass, and fat mass during mid- and late gestation and the early postnatal period in the context of changes in the secretion and action of maternal, placental, fetal, and neonatal hormones, growth factors, and adipocytokines. We assess the effects of hormonal determinants on placental nutrient delivery and the impact of preterm delivery on hormone expression and postnatal growth and metabolic function. We then discuss the effects of various maternal disorders and nutritional and pharmacologic interventions on fetal and perinatal hormone and growth factor production, growth, and fat deposition and consider important unresolved questions in the field.
PubMed: 37764824
DOI: 10.3390/nu15184041 -
Cell Communication and Signaling : CCS Jul 2023The production of human chorionic gonadotropin (hCG) by the placental trophoblast cells is essential for maintaining a normal pregnancy. Aberrant hCG levels are...
BACKGROUND
The production of human chorionic gonadotropin (hCG) by the placental trophoblast cells is essential for maintaining a normal pregnancy. Aberrant hCG levels are associated with reproductive disorders. The protein of hCG is a dimer consisting of an α subunit and a β subunit. The β subunit is encoded by the CGB gene and is unique to hCG. Growth differentiation factor-11 (GDF-11), a member of the transforming growth factor-β (TGF-β) superfamily, is expressed in the human placenta and can stimulate trophoblast cell invasion. However, whether the expression of CGB and the production of hCG are regulated by GDF-11 remains undetermined.
METHODS
Two human choriocarcinoma cell lines, BeWo and JEG-3, and primary cultures of human cytotrophoblast (CTB) cells were used as experimental models. The effects of GDF-11 on CGB expression and hCG production, as well as the underlying mechanisms, were explored by a series of in vitro experiments.
RESULTS
Our results show that treatment of GDF-11 downregulates the expression of CGB and the production of hCG in both BeWo and JEG-3 cells as well as in primary CTB cells. Using a pharmacological inhibitor and siRNA-mediated approach, we reveal that both ALK4 and ALK5 are required for the GDF-11-induced downregulation of CGB expression. In addition, treatment of GDF-11 activates SMAD2/3 but not SMAD1/5/8 signaling pathways. Moreover, both SMAD2 and SMAD3 are involved in the GDF-11-downregulated CGB expression. ELISA results show that the GDF-11-suppressed hCG production requires the ALK4/5-mediated activation of SMAD2/3 signaling pathways.
CONCLUSIONS
This study not only discovers the biological function of GDF-11 in the human placenta but also provides important insights into the regulation of the expression of hCG. Video Abstract.
Topics: Female; Humans; Pregnancy; Cell Line, Tumor; Chorionic Gonadotropin; Placenta; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta
PubMed: 37480123
DOI: 10.1186/s12964-023-01201-5 -
Nature Cell Biology Aug 2023SARS-CoV-2 infection causes COVID-19. Several clinical reports have linked COVID-19 during pregnancy to negative birth outcomes and placentitis. However, the...
SARS-CoV-2 infection causes COVID-19. Several clinical reports have linked COVID-19 during pregnancy to negative birth outcomes and placentitis. However, the pathophysiological mechanisms underpinning SARS-CoV-2 infection during placentation and early pregnancy are not clear. Here, to shed light on this, we used induced trophoblast stem cells to generate an in vitro early placenta infection model. We identified that syncytiotrophoblasts could be infected through angiotensin-converting enzyme 2 (ACE2). Using a co-culture model of vertical transmission, we confirmed the ability of the virus to infect syncytiotrophoblasts through a previous endometrial cell infection. We further demonstrated transcriptional changes in infected syncytiotrophoblasts that led to impairment of cellular processes, reduced secretion of HCG hormone and morphological changes vital for syncytiotrophoblast function. Furthermore, different antibody strategies and antiviral drugs restore these impairments. In summary, we have established a scalable and tractable platform to study early placental cell types and highlighted its use in studying strategies to protect the placenta.
Topics: Pregnancy; Female; Humans; COVID-19; Placenta; Trophoblasts; Angiotensin-Converting Enzyme 2; SARS-CoV-2; Cell Differentiation
PubMed: 37443288
DOI: 10.1038/s41556-023-01182-0 -
Clinical Epigenetics Aug 2023Gestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and...
BACKGROUND
Gestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and cardiometabolic disorders later in life. This process has been attributed partly to DNA methylation modifications in growth and stress-related pathways. Nutrients involved with one-carbon metabolism (OCM), such as folate, choline, betaine, and vitamin B, provide methyl groups for DNA methylation of these pathways. Therefore, this study aimed to determine whether maternal OCM nutrient intakes and levels modified fetal DNA methylation and in turn altered fetal growth patterns in pregnancies with and without GDM.
RESULTS
In this prospective study at a single academic institution from September 2016 to June 2019, we recruited 76 pregnant women with and without GDM at 25-33 weeks gestational age and assessed their OCM nutrient intake by diet recalls and measured maternal blood OCM nutrient levels. We also collected placenta and cord blood samples at delivery to examine fetal tissue DNA methylation of the genes that modify fetal growth and stress response such as insulin-like growth factor 2 (IGF2) and corticotropin-releasing hormone (CRH). We analyzed the association between maternal OCM nutrients and fetal DNA methylation using a generalized linear mixed model. Our results demonstrated that maternal choline intake was positively correlated with cord blood CRH methylation levels in both GDM and non-GDM pregnancies (r = 0.13, p = 0.007). Further, the downstream stress hormone cortisol regulated by CRH was inversely associated with maternal choline intake (r = - 0.36, p = 0.021). Higher maternal betaine intake and serum folate levels were associated with lower cord blood and placental IGF2 DNA methylation (r = - 0.13, p = 0.049 and r = - 0.065, p = 0.034, respectively) in both GDM and non-GDM pregnancies. Further, there was an inverse association between maternal betaine intake and birthweight of infants (r = - 0.28, p = 0.015).
CONCLUSIONS
In conclusion, we observed a complex interrelationship between maternal OCM nutrients and fetal DNA methylation levels regardless of GDM status, which may, epigenetically, program molecular pathways related to fetal growth and stress response.
Topics: DNA Methylation; Humans; Female; Diabetes, Gestational; Pregnancy; Fetus; Folic Acid; Promoter Regions, Genetic; Prospective Studies
PubMed: 37633918
DOI: 10.1186/s13148-023-01554-1 -
BioRxiv : the Preprint Server For... Aug 2023Maternal prenatal stress is associated with adverse pregnancy outcomes and predisposition to long-term adverse health outcomes in children. While the molecular...
INTRODUCTION
Maternal prenatal stress is associated with adverse pregnancy outcomes and predisposition to long-term adverse health outcomes in children. While the molecular mechanisms that govern these associations has not been fully teased apart, stress-induced changes in placental function can drive sex-specific phenotypes in offspring. We sought to identify and examine molecular pathways in the placenta that are altered in response to maternal prenatal stress.
METHODS
Using a mouse model of maternal prenatal stress, we conducted RNA-seq analysis of whole placenta at E18.5. We used qRT-PCR to validate gene expression changes in the placenta and in a trophoblast cell line. ELISAs were used to measure the abundance of thyroid hormones in maternal and fetal serum and in the placenta.
RESULTS
was amongst the top differentially expressed genes in response to elevated maternal stress hormone. expression was more downregulated in female placenta from stressed dams than both female control and male placenta. Consistent with Dio2's role in production of bioactive thyroid hormone (T3), we found that there was a reduction of T3 in placenta and serum of female embryos from stressed dams at E18.5. Both T3 and T4 were reduced in the fetal compartment of the female placenta from stressed dams at E16.5. Stress hormone induced reduction in thyroid hormone in females was independent of circulating levels of TH in the dams.
DISCUSSION
The placental thyroid hormone synthesis pathway may be a target of maternal stress and modulate fetal programming of health and disease of offspring in a sex-specific fashion.
PubMed: 37461599
DOI: 10.1101/2023.07.05.547278 -
Frontiers in Physiology 2023Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer from a singular etiology. Most experience cumulative...
Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer from a singular etiology. Most experience cumulative insults from prenatal inflammation, genetic and epigenetic vulnerability, toxins (opioids, other drug exposures, environmental exposure), hypoxia-ischemia, and postnatal stressors such as sepsis and seizures. Accordingly, tailoring of emerging therapeutic regimens with endogenous repair or neuro-immunomodulatory agents for individuals requires a more precise understanding of ligand, receptor-, and non-receptor-mediated regulation of essential developmental hormones. Given the recent clinical focus on neurorepair for PBI, we hypothesized that there would be injury-induced changes in erythropoietin (EPO), erythropoietin receptor (EPOR), melatonin receptor (MLTR), NAD-dependent deacetylase sirtuin-1 (SIRT1) signaling, and hypoxia inducible factors (HIF1α, HIF2α). Specifically, we predicted that EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α alterations after chorioamnionitis (CHORIO) would reflect relative changes observed in human preterm infants. Similarly, we expected unique developmental regulation after injury that would reveal potential clues to mechanisms and timing of inflammatory and oxidative injury after CHORIO that could inform future therapeutic development to treat PBI. To induce CHORIO, a laparotomy was performed on embryonic day 18 (E18) in rats with transient uterine artery occlusion plus intra-amniotic injection of lipopolysaccharide (LPS). Placentae and fetal brains were collected at 24 h. Brains were also collected on postnatal day 2 (P2), P7, and P21. EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α levels were quantified using a clinical electrochemiluminescent biomarker platform, qPCR, and/or RNAscope. MLT levels were quantified with liquid chromatography mass spectrometry. Examination of EPO, EPOR, and MLTR1 at 24 h showed that while placental levels of EPO and MLTR1 mRNA were decreased acutely after CHORIO, cerebral levels of EPO, EPOR and MLTR1 mRNA were increased compared to control. Notably, CHORIO brains at P2 were SIRT1 mRNA deficient with increased HIF1α and HIF2α despite normalized levels of EPO, EPOR and MLTR1, and in the presence of elevated serum EPO levels. Uniquely, brain levels of EPO, EPOR and MLTR1 shifted at P7 and P21, with prominent CHORIO-induced changes in mRNA expression. Reductions at P21 were concomitant with increased serum EPO levels in CHORIO rats compared to controls and variable MLT levels. These data reveal that commensurate with robust inflammation through the maternal placental-fetal axis, CHORIO impacts EPO, MLT, SIRT1, and HIF signal transduction defined by dynamic changes in EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α mRNA, and EPO protein. Notably, ligand-receptor mismatch, tissue compartment differential regulation, and non-receptor-mediated signaling highlight the importance, complexity and nuance of neural and immune cell development and provide essential clues to mechanisms of injury in PBI. As the placenta, immune cells, and neural cells share many common, developmentally regulated signal transduction pathways, further studies are needed to clarify the perinatal dynamics of EPO and MLT signaling and to capitalize on therapies that target endogenous neurorepair mechanisms.
PubMed: 37546540
DOI: 10.3389/fphys.2023.1201699 -
Chembiochem : a European Journal of... Dec 2023During placental formation, cytotrophoblasts (CTBs) fuse into multinucleate, microvilli-coated syncytiotrophoblasts (STBs), which contact maternal blood, mediating...
During placental formation, cytotrophoblasts (CTBs) fuse into multinucleate, microvilli-coated syncytiotrophoblasts (STBs), which contact maternal blood, mediating nutrient, metabolite, and gas exchange between mother and fetus, and providing a barrier against fetal infection. Trophoblasts remodel the surrounding extracellular matrix through the secretion of matrix metalloproteinases (MMPs). Maternal obesity and diabetes mellitus can negatively impact fetal development and may impair trophoblast function. We sought to model the impact of metabolic stress on STB function by examining MMP and hormone secretion. The BeWo CTB cell line was syncytialized to STB-like cells with forskolin. Cell morphology was examined by electron microscopy and immunofluorescence; phenotype was further assessed by ELISA and RT-qPCR. STBs were exposed to a metabolic stress cocktail (MetaC: 30 mM glucose, 10 nM insulin, and 0.1 mM palmitic acid). BeWo syncytialization was demonstrated by increased secretion of HCGβ and progesterone, elevated syncytin gene expression (ERVW-1 and ERVFRD-1), loss of tight junctions, and increased surface microvilli. MetaC strongly suppressed syncytin gene expression (ERVW-1 and ERVFRD-1), suppressed HCGβ and progesterone secretion, and altered both MMP-9 and MMP-2 production. Metabolic stress modeling diabetes and obesity altered BeWo STB hormone and MMP production in vitro.
Topics: Female; Pregnancy; Humans; Placenta; Progesterone; Trophoblasts; Cell Line
PubMed: 37800606
DOI: 10.1002/cbic.202300410 -
Placenta Oct 2023Maternal prenatal psychological stress is associated with adverse pregnancy outcomes and increased risk of adverse health outcomes in children. While the molecular...
INTRODUCTION
Maternal prenatal psychological stress is associated with adverse pregnancy outcomes and increased risk of adverse health outcomes in children. While the molecular mechanisms that govern these associations has not been fully teased apart, stress-induced changes in placental function can drive sex-specific phenotypes in offspring. We sought to identify and examine molecular pathways in the placenta that are altered in response to maternal prenatal stress.
METHODS
We previously employed a mouse model of maternal prenatal stress where pregnant dams were treated with stress hormone (CORT) beginning in mid-gestation. Using this model, we conducted RNAseq analysis of whole placenta at E18.5. We used qRT-PCR to validate gene expression changes in the placenta and in a trophoblast cell line. ELISAs were used to measure the abundance of thyroid hormones in maternal and fetal serum and in the placenta.
RESULTS
Dio2 was amongst the top differentially expressed genes in response to exogenous stress hormone. Dio2 expression was more downregulated in placenta of female fetuses from CORT-treated dams than both control placenta from females and placenta from male fetuses. Consistent with Dio2's role in production of bioactive thyroid hormone (T3), we found that there was a reduction of T3 in placenta and serum of female embryos from CORT-treated dams at E18.5. Both T3 and T4 were reduced in the fetal compartment of the placenta of female fetuses from CORT-treated dams at E16.5. Exogenous stress hormone induced reduction in thyroid hormone in females was independent of circulating levels of TH in the dams.
DISCUSSION
The placental thyroid hormone synthesis pathway may be a target of elevated maternal stress hormone and modulate fetal programming of health and disease of offspring in a sex-specific fashion.
Topics: Humans; Child; Pregnancy; Female; Male; Mice; Animals; Placenta; Corticosterone; Thyroid Hormones; Fetus; Thyroid Gland
PubMed: 37579594
DOI: 10.1016/j.placenta.2023.08.005 -
Frontiers in Molecular Biosciences 2023Preeclampsia (PE) is a serious condition in pregnant women and hence an important topic in obstetrics. The current research aimed to recognize the potential and...
Preeclampsia (PE) is a serious condition in pregnant women and hence an important topic in obstetrics. The current research aimed to recognize the potential and significant immune-related diagnostic biomarkers for PE. From the Gene Expression Omnibus (GEO) data sets, three public gene expression profiles (GSE24129, GSE54618, and GSE60438) from the placental samples of PE and normotensive pregnancy were downloaded. Differentially expressed genes (DEGs) were selected and determined among 73 PE and 85 normotensive control pregnancy samples. The DEGs were used for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA). The candidate biomarkers were identified by the least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) analysis. The receiver operating characteristic curve (ROC) was applied to evaluate diagnostic ability. For further confirmation, the expression levels and diagnostic value of biomarkers in PE were verified in the GSE75010 data set (80 PE and 77 controls) and validated by qRT-RCR, Western blot, and immunohistochemistry (IHC). The CIBERSORT algorithm was used to calculate the compositional patterns of 22 types of immune cells in PE. In total, 15 DEGs were recognized. The GO and KEGG analyses revealed that the DEGs were enriched in the steroid metabolic process, receptor ligand activity, GnRH secretion, and neuroactive ligand-receptor interaction. The recognized DEGs were primarily implicated in cell-type benign neoplasm, kidney failure, infertility, and PE. Gene sets related to hormone activity, glycosylation, multicellular organism process, and response to BMP were activated in PE. The gene was distinguished as a diagnostic biomarker of PE (AUC = 0.712) and further certified in the GSE75010 data set (AUC = 0.850). The high expression of was associated with PE in clinical samples. In addition, the analysis of the immune microenvironment showed that gamma delta T cells, memory B cells, M0 macrophages, and regulatory T cells were positively correlated with expression ( < 0.05). expression can be considered to be a diagnostic biomarker of PE and can offer a novel perspective for future studies regarding the occurrence and molecular mechanisms of PE.
PubMed: 37635936
DOI: 10.3389/fmolb.2023.1209144 -
Cell Death Discovery Oct 2023As an essential component of the maternal-fetal interface, the placental syncytiotrophoblast layer contributes to a successful pregnancy by secreting hormones necessary... (Review)
Review
As an essential component of the maternal-fetal interface, the placental syncytiotrophoblast layer contributes to a successful pregnancy by secreting hormones necessary for pregnancy, transporting nutrients, mediating gas exchange, balancing immune tolerance, and resisting pathogen infection. Notably, the deficiency in mononuclear trophoblast cells fusing into multinucleated syncytiotrophoblast has been linked to adverse pregnancy outcomes, such as preeclampsia, fetal growth restriction, preterm birth, and stillbirth. Despite the availability of many models for the study of trophoblast fusion, there exists a notable disparity from the ideal model, limiting the deeper exploration into the placental development. Here, we reviewed the existing models employed for the investigation of human trophoblast fusion from several aspects, including the development history, latest progress, advantages, disadvantages, scope of application, and challenges. The literature searched covers the monolayer cell lines, primary human trophoblast, placental explants, human trophoblast stem cells, human pluripotent stem cells, three-dimensional cell spheres, organoids, and placenta-on-a-chip from 1938 to 2023. These diverse models have significantly enhanced our comprehension of placental development regulation and the underlying mechanisms of placental-related disorders. Through this review, our objective is to provide readers with a thorough understanding of the existing trophoblast fusion models, making it easier to select most suitable models to address specific experimental requirements or scientific inquiries. Establishment and application of the existing human placental trophoblast fusion models.
PubMed: 37816723
DOI: 10.1038/s41420-023-01670-0