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American Journal of Reproductive... Apr 2024Preeclampsia is one of the most common disorders that poses threat to both mothers and neonates and a major contributor to perinatal morbidity and mortality worldwide.... (Review)
Review
Preeclampsia is one of the most common disorders that poses threat to both mothers and neonates and a major contributor to perinatal morbidity and mortality worldwide. Viral infection during pregnancy is not typically considered to cause preeclampsia; however, syndromic nature of preeclampsia etiology and the immunomodulatory effects of viral infections suggest that microbes could trigger a subset of preeclampsia. Notably, SARS-CoV-2 infection is associated with an increased risk of preeclampsia. Herein, we review the potential role of viral infections in this great obstetrical syndrome. According to in vitro and in vivo experimental studies, viral infections can cause preeclampsia by introducing poor placentation, syncytiotrophoblast stress, and/or maternal systemic inflammation, which are all known to play a critical role in the development of preeclampsia. Moreover, clinical and experimental investigations have suggested a link between several viruses and the onset of preeclampsia via multiple pathways. However, the results of experimental and clinical research are not always consistent. Therefore, future studies should investigate the causal link between viral infections and preeclampsia to elucidate the mechanism behind this relationship and the etiology of preeclampsia itself.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Pre-Eclampsia; Placentation; Trophoblasts; Viruses; Virus Diseases; Placenta
PubMed: 38627916
DOI: 10.1111/aji.13844 -
Reproductive Biology and Endocrinology... Oct 2023Cathepsin C (Cat C) is involved in the inflammatory-immune system and can be degraded by cathepsin D (Cat D). Preeclampsia (PE) and the inflammation-immunity...
BACKGROUND
Cathepsin C (Cat C) is involved in the inflammatory-immune system and can be degraded by cathepsin D (Cat D). Preeclampsia (PE) and the inflammation-immunity relationship is currently a hot research topic, but there are still few studies. The aim was to investigate the expression and significance of Cat C and D in the serum of nonpregnant women, patients in various stages of pregnancy and patients with PE, and in the placenta of patients with normal pregnancy and PE.
METHODS
Sixty young healthy nonpregnant women were selected: 180 normal pregnant women, including 60 each in the first, second, and third trimesters, and 100 women with PE, including 39 women with severe preeclampsia. The levels of Cat C and D in serum were detected by enzyme-linked immunosorbent assay (ELISA), and the expression levels of Cat C and D in placentas were detected by immunohistochemistry (IHC).
RESULTS
The serum of Cat C in the first trimester was significantly lower than that in the nonpregnant group (P < 0.001), whereas Cat D was significantly higher than that in the nonpregnant group (P < 0.01). The levels of Cat C and D in the second trimester and third trimester were significantly higher than those in the first trimester (P < 0.05), but there was no significant difference in Cat C and D between the second trimester and third trimester. The levels of Cat C in the serum and placentas of patients with PE were significantly higher than those in the third trimester (P < 0.001) and positively correlated with the severity of PE (P < 0.001), whereas the levels of Cat D in the serum and placentas of patients with PE were significantly lower than those in the third trimester (P < 0.001) and negatively correlated with the severity of PE (P < 0.001). Age, primigravida proportion, and body mass index were significantly higher in the PE group than in the control group (P < 0.05), which were high-risk factors for PE.
CONCLUSIONS
Cat C and D are associated with the maintenance of normal pregnancy. In patients with preeclampsia, a significant increase in Cat C and a significant decrease in Cat D levels may lead to the occurrence and development of preeclampsia.
Topics: Female; Humans; Pregnancy; Cathepsin C; Cathepsin D; Placenta; Pre-Eclampsia; Pregnancy Trimester, First
PubMed: 37794357
DOI: 10.1186/s12958-023-01138-x -
Scientific Reports Jul 2023Trophectoderm cells of the blastocyst are the precursor of the placenta that is comprised of trophoblast, endothelial and smooth muscle cells. Since trophoectoderm cells...
Trophectoderm cells of the blastocyst are the precursor of the placenta that is comprised of trophoblast, endothelial and smooth muscle cells. Since trophoectoderm cells are epithelial in nature, epithelial mesenchymal transition (EMT) of trophoblast stem (TS) cells might play pivotal role in placental morphogenesis. However, the molecular regulation of EMT during placental development and trophoblast differentiation still remained elusive. In this report, we sought to identify the molecular signature that regulates EMT during placental development and TS cell differentiation in mice. On E7.5 onwards the TS cells, located in the ectoplacental cone (EPC), rapidly divide and differentiate leading to formation of placenta proper. Using a real time PCR based array of functional EMT transcriptome with RNA from mouse implantation sites (IS) on E7.5 and E9.5, it was observed that there was an overall reduction of EMT gene expression in the IS as gestation progressed from E7.5 to E9.5 albeit the levels of EMT gene expression were substantial on both days. Further validation of array results using real time PCR and western blot analysis showed significant decrease in EMT-associated genes that included (a) transcription factors (Snai2, Zeb1, Stat3 and Foxc2), (b) extracellular matrix and cell adhesion related genes (Bmp1, Itga5, Vcan and Col3A1), (c) migration and motility- associated genes (Vim, Msn and FN1) and (d) differentiation and development related genes (Wnt5b, Jag1 and Cleaved Notch-1) on E9.5. To understand whether EMT is an ongoing process during placentation, the EMT-associated signatures genes, prevalent on E 7.5 and 9.5, were analysed on E12.5, E14.5 and E17.5 of mouse placenta. Interestingly, expression of these EMT-signature proteins were significantly higher at E12.5 though substantial expressions was observed in placenta with progression of gestation from mid- to late. To evaluate whether TS cells have the potential to undergo EMT ex vivo, TS cells were subjected to EMT induction, which was confirmed using morphological analysis and marker gene expression. Induction of EMT in TS cells showed similar gene expression profile of placental EMT. These results have broad biological implications, as inadequate mesenchymal transition leading to improper trophoblast-vasculogenic mimicry leads to placental pathophysiology and pregnancy failure.
Topics: Pregnancy; Female; Animals; Mice; Trophoblasts; Placenta; Epithelial-Mesenchymal Transition; Placentation; Cell Differentiation; Stem Cells
PubMed: 37414855
DOI: 10.1038/s41598-023-37977-2 -
Toxicology and Applied Pharmacology Sep 2023The placenta is a critical organ for fetal development and a healthy pregnancy, and has multifaceted functions (e.g., substance exchange and hormone secretion)....
The placenta is a critical organ for fetal development and a healthy pregnancy, and has multifaceted functions (e.g., substance exchange and hormone secretion). Syncytialization of trophoblasts is important for maintaining placental functions. Epilepsy is one of the most common neurological conditions worldwide. Therefore, this study aimed to reveal the influence of antiepileptic drugs, including valproic acid (VPA), carbamazepine, lamotrigine, gabapentin, levetiracetam, topiramate, lacosamide, and clobazam, at clinically relevant concentrations on syncytialization using in vitro models of trophoblasts. To induce differentiation into syncytiotrophoblast-like cells, BeWo cells were treated with forskolin. Exposure to VPA was found to dose-dependently influence syncytialization-associated genes (ERVW-1, ERVFRD-1, GJA1, CGB, CSH, SLC1A5, and ABCC4) in differentiated BeWo cells. Herein, the biomarkers between differentiated BeWo cells and the human trophoblast stem model (TS) were compared. In particular, MFSD2A levels were low in BeWo cells but abundant in TS cells. VPA exposure affected the expression of ERVW-1, ERVFRD-1, GJA1, CSH, MFSD2A, and ABCC4 in differentiated cells (ST-TS). Furthermore, VPA exposure attenuated BeWo and TS cell fusion. Finally, the relationships between neonatal/placental parameters and the expression of syncytialization markers in human term placentas were analyzed. MFSD2A expression was positively correlated with neonatal body weight, head circumference, chest circumference, and placental weight. Our findings have important implications for better understanding the mechanisms of toxicity of antiepileptic drugs and predicting the risks to placental and fetal development.
Topics: Infant, Newborn; Humans; Pregnancy; Female; Placenta; Trophoblasts; Valproic Acid; Anticonvulsants; Cell Line; ATP-Binding Cassette Transporters; Minor Histocompatibility Antigens; Amino Acid Transport System ASC
PubMed: 37385477
DOI: 10.1016/j.taap.2023.116611 -
Hypertension (Dallas, Tex. : 1979) Nov 2023Preeclampsia is a hypertensive disorder of pregnancy characterized by chronic placental ischemia and suppression of proangiogenic proteins, causing oxidative stress,...
BACKGROUND
Preeclampsia is a hypertensive disorder of pregnancy characterized by chronic placental ischemia and suppression of proangiogenic proteins, causing oxidative stress, hypertension, and maternal systemic organ damage. The transcription factor, PPARγ (peroxisome proliferator-activated receptor-γ) promotes healthy trophoblast differentiation but is dysregulated in the preeclampsia placenta. Our study identifies the beneficial impact of Rosiglitazone-mediated PPARγ-activation in the stressed preeclampsia placenta.
METHODS
We used first trimester placentas, preeclamptic and preterm control placentas, and human trophoblast cell lines to study PPARγ activation.
RESULTS
Induction of PPARγ activates cell growth and antioxidative stress pathways, including the gene, heme oxygenase 1 (). Protein expression of both PPARγ and HO1 (heme oxygenase 1) are reduced in preeclamptic placentas, but Rosiglitazone restores HO1 signaling in a PPARγ-dependent manner.
CONCLUSIONS
Restoring disrupted pathways by PPARγ in preeclampsia offers a potential therapeutic pathway to reverse placental damage, extending pregnancy duration, and reduce maternal sequelae. Future research should aim to understand the full scope of impaired PPARγ signaling in the human placenta and focus on compounds for safe use during pregnancy to prevent severe perinatal morbidity and mortality.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Heme Oxygenase-1; Placenta; PPAR gamma; Pre-Eclampsia; Rosiglitazone; Trophoblasts
PubMed: 37702083
DOI: 10.1161/HYPERTENSIONAHA.123.21645 -
Zeitschrift Fur Geburtshilfe Und... Feb 2024COVID-19 pregnancies are associated with increased rates of premature delivery and stillbirths. It is still a matter of debate whether there is a COVID-19-associated... (Meta-Analysis)
Meta-Analysis
COVID-19 pregnancies are associated with increased rates of premature delivery and stillbirths. It is still a matter of debate whether there is a COVID-19-associated pattern of placenta pathology. We updated our previously published results on a systematic literature review and meta-analysis of COVID-19 pregnancies. In total, 38 reports on 3677 placentas were evaluated regarding histopathological changes. Maternal vascular malperfusion (32%), fetal vascular malperfusion (19%), acute and chronic inflammation (20% and 22%) were frequent pathologies. In non-COVID-19 pregnancies, placentas show similar histologic patterns and mainly similar frequencies of manifestation. It has to be taken into account that there might be an observation bias, because some findings are diagnosed as a "pathology" that might have been classified as minor or unspecific findings in non-COVID-19 placentas. COVID-19 placentitis occurs in 1-2% of cases at the most. In conclusion, this updated meta-analysis indicates that COVID-19 infection during pregnancy does not result in an increased rate of a specific placenta pathology and COVID-19 placentitis is rare.
Topics: Pregnancy; Female; Humans; Placenta; COVID-19; Placenta Diseases; Premature Birth; Chorioamnionitis; Stillbirth
PubMed: 38330958
DOI: 10.1055/a-2220-7469 -
International Journal of Molecular... Nov 2023Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental... (Review)
Review
Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions.
Topics: Pregnancy; Female; Humans; Placenta; Glycosylation; Immunoglobulin G; Trophoblasts; Immunomodulation; Maternal-Fetal Exchange
PubMed: 38069094
DOI: 10.3390/ijms242316772 -
Frontiers in Endocrinology 2023Gestational diabetes mellitus (GDM) is the most frequent pathophysiological state of pregnancy, which in many cases produces fetuses with macrosomia, requiring increased... (Review)
Review
Gestational diabetes mellitus (GDM) is the most frequent pathophysiological state of pregnancy, which in many cases produces fetuses with macrosomia, requiring increased nutrient transport in the placenta. Recent studies by our group have demonstrated that leptin is a key hormone in placental physiology, and its expression is increased in placentas affected by GDM. However, the effect of leptin on placental nutrient transport, such as transport of glucose, amino acids, and lipids, is not fully understood. Thus, we aimed to review literature on the leptin effect involved in placental nutrient transport as well as activated leptin signaling pathways involved in the expression of placental transporters, which may contribute to an increase in placental nutrient transport in human pregnancies complicated by GDM. Leptin appears to be a relevant key hormone that regulates placental transport, and this regulation is altered in pathophysiological conditions such as gestational diabetes. Adaptations in the placental capacity to transport glucose, amino acids, and lipids may underlie both under- or overgrowth of the fetus when maternal nutrient and hormone levels are altered due to changes in maternal nutrition or metabolic disease. Implementing new strategies to modulate placental transport may improve maternal health and prove effective in normalizing fetal growth in cases of intrauterine growth restriction and fetal overgrowth. However, further studies are needed to confirm this hypothesis.
Topics: Female; Humans; Pregnancy; Amino Acids; Diabetes, Gestational; Fetal Macrosomia; Glucose; Leptin; Lipids; Membrane Transport Proteins; Nutrients; Placenta
PubMed: 37497352
DOI: 10.3389/fendo.2023.1172831 -
Journal of Cell Science Mar 2024Human trophoblast organoids (TOs) are a three-dimensional ex vivo culture model that can be used to study various aspects of placental development, physiology and...
Human trophoblast organoids (TOs) are a three-dimensional ex vivo culture model that can be used to study various aspects of placental development, physiology and pathology. However, standard culturing of TOs does not recapitulate the cellular orientation of chorionic villi in vivo given that the multi-nucleated syncytiotrophoblast (STB) develops largely within the inner facing surfaces of these organoids (STBin). Here, we developed a method to culture TOs under conditions that recapitulate the cellular orientation of chorionic villi in vivo. We show that culturing STBin TOs in suspension with gentle agitation leads to the development of TOs containing the STB on the outer surface (STBout). Using membrane capacitance measurements, we determined that the outermost surface of STBout organoids contain large syncytia comprising >50 nuclei, whereas STBin organoids contain small syncytia (<10 nuclei) and mononuclear cells. The growth of TOs under conditions that mimic the cellular orientation of chorionic villi in vivo thus allows for the study of a variety of aspects of placental biology under physiological conditions.
Topics: Female; Pregnancy; Humans; Placenta; Trophoblasts; Organoids; Cell Nucleus; Giant Cells
PubMed: 37676312
DOI: 10.1242/jcs.261528 -
Placenta Jun 2024Caspases, a family of cysteine proteases, are pivotal regulators of apoptosis, the tightly controlled cell death process crucial for eliminating excessive or unnecessary... (Review)
Review
Caspases, a family of cysteine proteases, are pivotal regulators of apoptosis, the tightly controlled cell death process crucial for eliminating excessive or unnecessary cells during development, including placental development. Collecting research has unveiled the multifaceted roles of caspases in the placenta, extending beyond apoptosis. Apart from their involvement in placental tissue remodeling via apoptosis, caspases actively participate in essential regulatory processes, such as trophoblast fusion and differentiation, significantly influencing placental growth and functionality. In addition, growing evidence indicates an elevation in caspase activity under pathological conditions like pre-eclampsia (PE) and intrauterine growth restriction (IUGR), leading to excessive cell death as well as inflammation. Drawing from advancements in caspase research and placental development under both normal and abnormal conditions, we examine the significance of caspases in both cell death (apoptosis) and non-cell death-related processes within the placenta. We also discuss potential therapeutics targeting caspase-related pathways for placenta disorders.
Topics: Humans; Pregnancy; Female; Caspases; Placenta; Apoptosis; Placentation; Animals; Placenta Diseases; Pre-Eclampsia; Trophoblasts
PubMed: 38703713
DOI: 10.1016/j.placenta.2024.03.013