Search Results (58)

Gestational diabetes mellitus (GDM) occurs in approximately 9–25% of pregnancies and, if left undiagnosed or inadequately controlled, can lead to adverse outcomes for both the mother and the fetus, short and long term. GDM is characterized by glucose intolerance with onset or first recognition during pregnancy and is a multifactorial condition with a pathophysiology that remains incompletely understood. It is strongly associated with a chronic low-grade inflammatory state that contributes to insulin resistance, a hallmark of GDM pathogenesis. Among the fundamental pro-inflammatory cytokines implicated in this process, TNF-α and IL-6 play central roles. TNF-α is a cytokine primarily secreted by activated macrophages, as well as by adipocytes in the context of obesity. Many studies have shown that its levels are elevated in pregnant women with GDM compared to normoglycemic pregnant individuals. IL-6 is another pro-inflammatory cytokine secreted by immune cells, adipose tissue, and the placenta. It is found in higher concentrations in the maternal circulation during pregnancies complicated by GDM. Both TNF-α and IL-6 act synergistically to perpetuate a pro-inflammatory intrauterine environment. Their combined effects exacerbate insulin resistance and may impair pancreatic β-cell compensation during pregnancy, facilitating the onset of GDM in genetically or metabolically susceptible individuals. Recent research has identified various maternal serum biomarkers, such as TNF-α and IL-6, that may hold promise for the early detection of GDM. The aim of our study is to evaluate whether TNF-α and IL-6 can be used as diagnostic tools for the early diagnosis of GDM, allowing for timely intervention and reducing the risk of associated maternal and fetal complications. Full article

Maternal melatonin (MT) readily crosses the placental barrier to enter the fetal circulation, and it holds the potential to enhance hair follicle (HF) development, possibly augmented through nutritional interventions during pregnancy. However, the specific impact of maternal MT treatment on fetal HF development remains largely unexplored. In this study, we implanted pregnant rabbits with 10 mg of MT-containing and non-MT-containing silica gel microcapsules. We then assessed HF density and the extent of HF cell apoptosis in the neonatal rabbits. Our findings revealed that maternal MT implantation significantly reduced HF cell apoptosis and promoted an increased HF density in the neonates. Mechanistically, this process involved MT downregulating the expression of JUN/FOS and AP-1, while concurrently upregulating equol expression and reducing norepinephrine levels. Analysis of key protein expression within the MAPK pathway indicated that maternal MT activated this pathway. These results suggest that maternal MT treatment promotes beneficial HF development in offspring. Notably, the transcriptional regulation of JUN/FOS members of the AP-1 complex emerges as a pivotal factor mediating the beneficial effects of MT on neonatal hair follicle development. Full article

Preeclampsia (preE) is a severe multisystem hypertensive syndrome of pregnancy associated with ischemia/hypoxia, angiogenic imbalance, apolipoprotein E (ApoE)-mediated dyslipidemia, placental insufficiency, and inflammation at the maternal–fetal interface. Our recent data further suggest that preE is associated with impaired autophagy, vascular dysfunction, and proteinopathy/tauopathy disorder, similar to neurodegenerative diseases such as Alzheimer’s disease (AD), including the presence of the cis stereo-isoform of phosphorylated tau (cis P-tau), amyloid-β, and transthyretin in the placenta and circulation. This review provides an overview of the factors that may lead to the induction and accumulation of cis P-tau-like proteins by focusing on the inactivation of peptidyl-prolyl cis–trans isomerase (Pin1) that catalyzes the cis to trans isomerization of P-tau. We also highlighted the novel role of the Pin1-cis P-tau-ApoE axis in the development of preE, and propagation of cis P-tau-mediated abnormal protein aggregation (tauopathy) from the placenta to cerebral tissues later in life, leading to neurodegenerative conditions. In the case of preE, proteinopathy/tauopathy may interrupt trophoblast differentiation and induce cell death, similar to the events occurring in neurons. These events may eventually damage the endothelium and cause systemic features of disorders such as preE. Despite impressive research and therapeutic advances in both fields of preE and neurodegenerative diseases, further investigation of Pin1-cis P-tau and ApoE-related mechanistic underpinnings may unravel novel therapeutic options, and new transcriptional and proteomic markers. This review will also cover genetic polymorphisms in the ApoE alleles leading to dyslipidemia induction that may regulate the pathways causing preE or dementia-like features in the reproductive age or later in life, respectively. Full article

(1) Background: Fetal chromosomal examination is a critical component of modern prenatal testing. Traditionally, maternal serum biomarkers such as free β-human chorionic gonadotropin (Free β-HCG) and pregnancy-associated plasma protein A (PAPPA) have been employed for screening, achieving a detection rate of approximately 90% for fetuses with Down syndrome, albeit with a false positive rate of 5%. While amniocentesis remains the gold standard for the prenatal diagnosis of chromosomal abnormalities, including Down syndrome and Edwards syndrome, its invasive nature carries a significant risk of complications, such as infection, preterm labor, or miscarriage, occurring at a rate of 7 per 1000 procedures. Beyond Down syndrome and Edwards syndrome, other chromosomal abnormalities, such as trisomy of chromosomes 9, 16, or Barr bodies, pose additional diagnostic challenges. Non-invasive prenatal testing (NIPT) has emerged as a powerful alternative for fetal genetic screening by leveraging maternal blood sampling. However, due to the extremely low abundance of fetal cells in maternal circulation, NIPT based on fetal cells faces substantial technical challenges. (2) Methods: Fetal nucleated red blood cells (FnRBCs) were first identified in maternal circulation in a landmark study published in The Lancet in 1959. Due to their fetal origin and presence in maternal peripheral blood, FnRBCs represent an ideal target for non-invasive prenatal testing (NIPT). In this study, we introduce a novel self-assembled cell array (SACA) chip system, a microfluidic-based platform designed to efficiently settle and align cells into a monolayer at the chip’s base within five minutes using lateral flow dynamics and gravity. This system is integrated with a fully automated, multi-channel fluorescence scanning module, enabling the real-time imaging and molecular profiling of fetal cells through fluorescence-tagged antibodies. By employing a combination of Hoechst+/CD71+/HbF+/CD45− markers, the platform achieves the precise enrichment and isolation of FnRBCs at the single-cell level from maternal peripheral blood. (3) Results: The SACA chip system effectively reduces the displacement of non-target cells by 31.2%, achieving a single-cell capture accuracy of 97.85%. This isolation and enrichment system for single cells is well suited for subsequent genetic analysis. Furthermore, the platform achieves a high purity of isolated cells, overcoming the concentration detection limit of short tandem repeat (STR) analysis, demonstrating its capability for reliable non-invasive prenatal testing. (4) Conclusions: This study demonstrates that the SACA chip, combined with an automated image positioning system, can efficiently isolate single fetal nucleated red blood cells (FnRBCs) from 50 million PBMCs in 2 mL of maternal blood, completing STR analysis within 120 min. With higher purification efficiency compared to existing NIPT methods, this platform shows great promise for prenatal diagnostics and potential applications in other clinical fields. Full article

Δ⁹-Tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis which is being increasingly consumed by pregnant people. In humans, THC is sequentially metabolized in the liver to its circulating metabolites 11-hydroxy-THC (11-OH-THC, psychoactive) and 11-nor-9-carboxy-THC (THC-COOH, non-psychoactive). Human and macaque data show that fetal exposure to THC is considerably lower than the corresponding maternal exposure. Through perfused human placenta studies, we showed that this is due to the active efflux of THC (fetal-to-maternal) by a placental transporter(s) other than P-glycoprotein or breast cancer resistance protein. The identity of this placental transporter(s) as well as whether THC or its metabolites are substrates or inhibitors of hepatic solute carrier transporters is unknown. Therefore, we investigated whether 5 μM THC, 0.3 μM 11-OH-THC, and 2.5 μM THC-COOH are substrates and/or inhibitors of placental or hepatic solute carrier transporters at their pharmacologically relevant concentrations. Using HEK cells overexpressing human OATP1B1, OATP1B3, OATP2B1, OCT1, OCT3, OAT2, OAT4, or NTCP, and prototypic substrates/inhibitors of these transporters, we found that THC and THC-COOH were substrates but not inhibitors of OCT1. THC-COOH was a weak substrate of OCT3 and a weak inhibitor of OAT4. THC, 11-OH-THC, and THC-COOH were found not to be substrates/inhibitors of the remaining transporters investigated. Full article

The development of fetal organs can be impacted by systemic changes in maternal circulation, with the placenta playing a pivotal role in maintaining pregnancy homeostasis and nutrient exchange. In clinical obstetrics, oxytocin (OXT) is commonly used to induce labor. To explore the potential role of OXT in the placental homeostasis of OXT, we compared OXT levels in neonatal cord blood among neonates (23–42 weeks gestation) whose mothers either received prenatal OXT or experienced spontaneous labor. Our previous research revealed that the oxytocin receptor (OXTR), essential in forming the blood–retina barrier, is expressed in the retinal pigment epithelium (RPE). We hypothesized that perinatal OXT administration might influence the development of the neural retina and its vasculature, offering therapeutic potential for retinal diseases such as retinopathy of prematurity (ROP). Plasma OXT levels were measured using a commercial OXT ELISA kit. Human fetal RPE (hfRPE) cells treated with OXT (10 µM) were assessed for gene expression via RNA sequencing, revealing 14 downregulated and 32 upregulated genes. To validate these differentially expressed genes (DEGs), hfRPE cells were exposed to OXT (0.01, 0.1, 1, or 10 µM) for 12 h, followed by RNA analysis via real-time PCR. Functional, enrichment, and network analyses (Gene Ontology term, FunRich, Cytoscape) were performed to predict the affected pathways. This translational study suggests that OXT likely crosses the placenta, altering fetal OXT concentrations. RNA sequencing identified 46 DEGs involved in vital metabolic and signaling pathways and critical cellular components. Our results indicate that the perinatal administration of OXT may affect neural retina and retinal vessel development, making OXT a potential therapeutic option for developmental eye diseases, including ROP. Full article

During pregnancy, the adipokines leptin and adiponectin can affect placental nutrient transport and inflammatory pathways, potentially leading to altered fetal growth and pregnancy complications including gestational diabetes mellitus (GDM) and preeclampsia (PE). The aim of this systematic review is to gather and analyze research on maternal circulating leptin and adiponectin levels and their relationship to adverse pregnancy and birth outcomes. Additionally, it seeks to determine whether these hormones are linked to alterations in placental transporters and cell signaling pathways. PubMed and MEDLINE were systematically searched to include studies published between 2012 and 2022. All primary data studies reporting serum adiponectin and/or leptin, placental mRNA and protein levels of related transporters, and adverse birth outcomes were eligible. The current systematic review encompasses a total of 14 articles. Abnormal serum maternal leptin and adiponectin levels were associated with changes in fetal growth and placental cellular signaling and nutrient transporters. A majority of studies associated elevated maternal leptin and reduced adiponectin with fetal overgrowth, although this relationship was not consistent and may be complicated when other pathologies are present. The effects of maternal leptin and adiponectin on fetal growth may be driven by placental adaptation in nutrient transporters and mitochondria. Future studies should determine if the placental effects of leptin and adiponectin that have been found in models have mechanistic roles in human pregnancy. Full article

Background/Objectives: Intra-amniotic infection (IAI) is a rare but serious condition with potential complications such as preterm labor and intrauterine fetal death. Diagnosing IAI is challenging due to varied clinical signs. Oxidative stress and mitochondrial dysfunction have been hypothesized to evolve around IAI. This study focused on measuring circulating mtDNA levels, a proposed biomarker for mitochondrial dysfunction, in maternal serum and placenta of women with confirmed IAI and healthy controls. Methods: 12 women with confirmed IAI (IAI group) were enrolled following premature preterm rupture of the membranes (PPROM) and compared to 21 healthy women (control group). Maternal blood was obtained two weeks pre-partum and peripartum; furthermore, postpartum placental blood was taken. In the IAI group, maternal blood was taken once weekly until delivery as well as peripartum, as was placental blood. Circulating cell-free mtDNA was quantified by real-time quantitative PCR. Results: Upon admission, in the IAI group, mean plasma mtDNA levels were 735.8 fg/μL compared to 134.0 fg/μL in the control group (p < 0.05). After delivery, in the IAI group, mean mtDNA levels in the placenta were 3010 fg/μL versus 652.4 fg/μL (p < 0.05). Conclusions: Circulating cell-free mtDNA could serve as a valuable biomarker for IAI prediction and diagnosis. Future research should establish reference values for sensitivity in predicting IAI. Full article

Background: The aim of the study was to investigate if feto-maternal transfusion was related to the size of the fetal-maternal interface, and, therefore, was larger in twin pregnancy in comparison with singleton pregnancy. Methods: Blood samples from women with singleton (n = 11), and monochorionic (n = 11) and dichorionic (n = 13) twin gestations were tested. Flow cytometry tests with hemoglobin F, glycophorin A, and hemoglobin F and carbonic anhydrase simultaneous staining were used to detect fetal red blood cells and maternal F cells. Results: In all cases, the volume of feto-maternal transfusion was estimated to be low. The highest rate of fetal red blood cells in the maternal circulation was observed in the blood of women with dichorionic twin gestations both before and after delivery. An increase in fetal red blood cells was observed after cesarean section in singletons and twins. The median rate of maternal F cells was 2.23% in singleton, 2.1% in monochorionic and 3.95% in dichorionic pregnancy. Conclusions: Feto-maternal transfusion during pregnancy may be related to the multiplicity and chorionicity of pregnancy. Full article

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. In clinical practice, up to 50% of pregnancies with PAS remain undiagnosed until delivery, and it is associated with increased risk of morbidity/mortality. Although many studies have evaluated the potential of fetal biomarkers circulating in maternal blood, very few studies have evaluated the potential of circulating placental extracellular vesicles (EVs) and their miRNA contents for molecular detection of PAS. Thus, to purify placental EVs from maternal blood, we customized our robust ultra-sensitive immuno-purification assay, termed EV-CATCHER, with a monoclonal antibody targeting the membrane Placental Alkaline Phosphatase (PLAP) protein, which is unique to the placenta and present on the surface of placental EVs. Then, as a pilot evaluation, we compared the miRNA expression profiles of placental EVs purified from the maternal plasma of women diagnosed with placenta previa (controls, n = 16); placenta lying low in uterus but not invasive) to those of placental EVs purified from the plasma of women with placenta percreta (cases, n = 16), PAS with the highest level of invasiveness. Our analyses reveal that miRNA profiling of PLAP⁺ EVs purified from maternal plasma identified 40 differentially expressed miRNAs when comparing these two placental pathologies. Preliminary miRNA pathway enrichment and gene ontology analysis of the top 14 upregulated and top nine downregulated miRNAs in PLAP⁺ EVs, purified from the plasma of women diagnosed with placenta percreta versus those diagnosed with placenta previa, suggests a potential role in control of cellular invasion and motility that will require further investigation. Full article

Pregnancy at advanced maternal age (AMA) is a condition of potential risk for the development of maternal–fetal complications with possible repercussions even in the long term. Here, we analyzed the changes in plasma redox balance and the effects of plasma on human umbilical cord mesenchymal cells (hUMSCs) in AMA pregnant women (patients) at various timings of pregnancy. One hundred patients and twenty pregnant women younger than 40 years (controls) were recruited and evaluated at various timings during pregnancy until after delivery. Plasma samples were used to measure the thiobarbituric acid reactive substances (TBARS), glutathione and nitric oxide (NO). In addition, plasma was used to stimulate the hUMSCs, which were tested for cell viability, reactive oxygen species (ROS) and NO release. The obtained results showed that, throughout pregnancy until after delivery in patients, the levels of plasma glutathione and NO were lower than those of controls, while those of TBARS were higher. Moreover, plasma of patients reduced cell viability and NO release, and increased ROS release in hUMSCs. Our results highlighted alterations in the redox balance and the presence of potentially harmful circulating factors in plasma of patients. They could have clinical relevance for the prevention of complications related to AMA pregnancy. Full article

Glucose, the primary energy substrate for fetal oxidative processes and growth, is transferred from maternal to fetal circulation down a concentration gradient by placental facilitative glucose transporters. In sheep, SLC2A1 and SLC2A3 are the primary transporters available in the placental epithelium, with SLC2A3 located on the maternal-facing apical trophoblast membrane and SLC2A1 located on the fetal-facing basolateral trophoblast membrane. We have previously reported that impaired placental SLC2A3 glucose transport resulted in smaller, hypoglycemic fetuses with reduced umbilical artery insulin and glucagon concentrations, in addition to diminished pancreas weights. These findings led us to subject RNA derived from SLC2A3-RNAi (RNA interference) and NTS-RNAi (non-targeting sequence) fetal pancreases to qPCR followed by transcriptomic analysis. We identified a total of 771 differentially expressed genes (DEGs). Upregulated pathways were associated with fat digestion and absorption, particularly fatty acid transport, lipid metabolism, and cholesterol biosynthesis, suggesting a potential switch in energetic substrates due to hypoglycemia. Pathways related to molecular transport and cell signaling in addition to pathways influencing growth and metabolism of the developing pancreas were also impacted. A few genes directly related to gluconeogenesis were also differentially expressed. Our results suggest that fetal hypoglycemia during the first half of gestation impacts fetal pancreas development and function that is not limited to β cell activity. Full article

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal–fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia’s genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women. Full article

Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in circulation have been linked to human cardiovascular disorders. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, the present literature suggests that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system as they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare—through the assessment of their quantity, differentiation potency, angiogenic activity, and senescence—the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems (preeclampsia, gestational diabetes mellitus, and fetal growth restriction). This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development. Full article

The etiopathogenesis of preeclampsia, a leading hypertensive disorder of pregnancy, has been proposed to involve an abnormal circulating sex hormone profile and misexpression of placental estrogen and progesterone receptors (ER and PR, respectively). However, existing research is vastly confined to third trimester preeclamptic placentas. Consequently, the placental–uterine molecular crosstalk and the dynamic ER and PR expression pattern in the peri-conception period remain overlooked. Herein, our goal was to use the BPH/5 mouse to elucidate pre-pregnancy and early gestation Er and Pr dynamics in a preeclamptic-like uterus. BPH/5 females display low circulating estrogen concentration during proestrus, followed by early gestation hypoestrogenemia, hyperprogesteronemia, and a spontaneous preeclamptic-like phenotype. Preceding pregnancy, the gene encoding Er alpha (Erα, Esr1) is upregulated in the diestrual BPH/5 uterus. At the peak of decidualization, Esr1, Er beta (Erβ, Esr2), and Pr isoform B (Pr-B) were upregulated in the BPH/5 maternal–fetal interface. At the protein level, BPH/5 females display higher percentage of decidual cells with nuclear Erα expression, as well as Pr downregulation in the decidua, luminal and glandular epithelium. In conclusion, we provide evidence of disrupted sex hormone signaling in the peri-conception period of preeclamptic-like pregnancies, potentially shedding some light onto the intricate role of sex hormone signaling at unexplored timepoints of human preeclampsia. Full article