Immune cells at the feto-maternal interface: Comprehensive characterization and insights into term labor.

Immune cells at the feto-maternal interface play an important role in pregnancy; starting at implantation, maintenance of pregnancy, and parturition. The role of decidual immune cells in induction of labor still needs to be understood. Published reports on this topic show heterogeneity in methods of cell isolation, assay, analysis and cellular characterization making it difficult to collate available information in order to understand the contribution of immune cells at term leading to parturition. In the present study, available literature was reviewed to study the differences in immune cells between the decidua basalis and decidua parietalis, as well as between immune cells in term and preterm labor. Additionally, immune cells at the decidua parietalis were isolated from term not in labor (TNL) or term in labor (TL) samples and characterized via flow cytometry using a comprehensive, high-dimensional antibody panel. This allowed a full view of immune cell differences without combining multiple studies, which must include variation in isolation and analysis methods, for more conclusive data. The ratio of cells found in decidua parietalis in this study generally matched those reported in the literature, although we report a lower percentage of natural killer (NK) cells at term. We report that CD4 expression on CD8- NK cells decreased in term labor compared to not in labor samples, suggesting that natural killer cells may be migrating to other sites during labor. Also, we report a decrease in CD38 expression on CD8+ CD57+ T cells in labor, indicative of cytotoxic T cell senescence. Our study provides a comprehensive status of immune cells at the decidua-chorion interface at term.

Establishment and comparison of human term placenta-derived trophoblast cells†.

Research on the biology of fetal-maternal barriers has been limited by access to physiologically relevant cells, including trophoblast cells. In this study, we describe the development of a human term placenta-derived cytotrophoblast immortalized cell line (hPTCCTB) derived from the basal plate. Human-term placenta-derived cytotrophoblast immortalized cell line cells are comparable to their primary cells of origin in terms of morphology, marker expression, and functional responses. We demonstrate that these can transform into syncytiotrophoblast and extravillous trophoblasts. We also compared the hPTCCTB cells to immortalized chorionic trophoblasts (hFM-CTC), trophoblasts of the chorionic plate, and BeWo cells, choriocarcinoma cell lines of conventional use. Human-term placenta-derived cytotrophoblast immortalized cell line and hFM-CTCs displayed more similarity to each other than to BeWos, but these differ in syncytialization ability. Overall, this study (1) demonstrates that the immortalized hPTCCTB generated are cells of higher physiological relevance and (2) provides a look into the distinction between the spatially distinct placental and fetal barrier trophoblasts cells, hPTCCTB and hFM-CTC, respectively.

Endocrine-disrupting compounds and their impact on human placental function: evidence from placenta organ-on-chip studies.

The effects of endocrine-disrupting compounds (EDCs) on the placenta, a critical gestational organ for xenobiotic protection, are well reported; however, models to determine the role of EDCs in placental disruption are limited. An advanced 2nd-trimester human placenta organ-on-chip model (2TPLA-OOC) was developed and validated, with six representative cells of the maternal and the fetal interface interconnected with microchannels. Various EDCs (150 ng mL-1 each of bisphenol A, bisphenol S, and polybrominated diphenyl ethers-47 and -99) were gradually propagated across the chip for 72 hours, and their various effects were determined. Cigarette smoke extract (CSE), an environmental risk factor, was used as a positive control. EDCs produced overall oxidative stress in the placental/decidual cells, induced cell-specific endocrine effects, caused limited (<10%) apoptosis/necrosis in trophoblasts and mesenchymal cells, induced localized inflammation but an overall anti-inflammatory shift, did not change immune cell migration from stroma to decidua, and did not affect placental nutrient transport. Overall, (1) the humanized 2TPLA-OOC recreated the placental organ and generated data distinct from the trophoblast and other cells studied in isolation, and (2) at doses associated with adverse pregnancies, EDCs produced limited and localized insults, and the whole organ compensated for the exposure.

Impact of bisphenol A on cell viability and inflammatory cytokine production in human cervical epithelial cells.

PROBLEM: An intact cervix is a barrier that prevents pathogenic bacteria from invading the uterine and amniotic cavity during pregnancy. Its disruption is associated with ascending infection and adverse pregnancy outcomes. This study analyzed the effects of bisphenol A (BPA), a chemical used in plastics manufacturing, on cell death and inflammation in cervical epithelial cells. METHODS: Ectocervical epithelial (ecto) and endocervical epithelial (endo) cells were treated with 100 ng/mL and 300 ng/mL of BPA for 48 h. The cells were subjected to flow cytometry using annexin V and propidium iodide to determine apoptosis and necrosis, cell cycle analysis, and ELISA to determine the levels of inflammatory cytokines (IL-6, IL-8, and IL-10). RESULTS: Low-dose and high-dose BPA significantly increased the live ecto cell population dose-dependently. BPA did not have any noticeable effect on cell cycle progression in either cell type. BPA treatment also decreased the apoptotic ecto and endo cell population dose-dependently. Lastly, high dose BPA significantly increased IL-6 in ecto and endo cells. However, IL-8 and IL-10 were not affected by BPA treatments. CONCLUSION: Chemical exposure damage to the cervix can lead to adverse pregnancy outcomes. Our study showed that the BPA concentrations reported in pregnant subjects do not induce cervical cell toxicity . The decrease in apoptosis and increase in live cells may be a compensatory mechanism to preserve the integrity of the cervical epithelial layer.

In utero priming of fetal immune activation: Myths and mechanisms.

Mechanisms of fetal immune system development in utero remain incompletely elucidated. Protective immunity, the arm of reproductive immunology concerned with the progressive education of the fetal immune system as pregnancy advances, allows for programming of the immune system and immune maturation in utero and provides a responsive system to respond to rapid microbial and other antigenic exposure ex utero. Challenges in studying fetal tissues, immune system development, and the contributions of various endogenous and exogenous factors to this process are difficult to study as a progressive sampling of fetal biological samples is impractical during pregnancy, and animal models are limited. This review provides a summary of mechanisms of protective immunity and how it has been shaped, from transplacental transfer of immunoglobulins, cytokines, metabolites, as well as antigenic microchimeric cells to perhaps more controversial notions of materno-fetal transfer of bacteria that subsequently organize into microbiomes within the fetal tissues. This review will also provide a quick overview of future direction in the area of research on fetal immune system development and discusses methods to visualize fetal immune populations and determine fetal immune functions, as well as a quick look into appropriate models for studying fetal immunity.

Spontaneous preterm birth: Involvement of multiple feto-maternal tissues and organ systems, differing mechanisms, and pathways.

Survivors of preterm birth struggle with multitudes of disabilities due to improper in utero programming of various tissues and organ systems contributing to adult-onset diseases at a very early stage of their lives. Therefore, the persistent rates of low birth weight (birth weight < 2,500 grams), as well as rates of neonatal and maternal morbidities and mortalities, need to be addressed. Active research throughout the years has provided us with multiple theories regarding the risk factors, initiators, biomarkers, and clinical manifestations of spontaneous preterm birth. Fetal organs, like the placenta and fetal membranes, and maternal tissues and organs, like the decidua, myometrium, and cervix, have all been shown to uniquely respond to specific exogenous or endogenous risk factors. These uniquely contribute to dynamic changes at the molecular and cellular levels to effect preterm labor pathways leading to delivery. Multiple intervention targets in these different tissues and organs have been successfully tested in preclinical trials to reduce the individual impacts on promoting preterm birth. However, these preclinical trial data have not been effectively translated into developing biomarkers of high-risk individuals for an early diagnosis of the disease. This becomes more evident when examining the current global rate of preterm birth, which remains staggeringly high despite years of research. We postulate that studying each tissue and organ in silos, as how the majority of research has been conducted in the past years, is unlikely to address the network interaction between various systems leading to a synchronized activity during either term or preterm labor and delivery. To address current limitations, this review proposes an integrated approach to studying various tissues and organs involved in the maintenance of normal pregnancy, promotion of normal parturition, and more importantly, contributions towards preterm birth. We also stress the need for biological models that allows for concomitant observation and analysis of interactions, rather than focusing on these tissues and organ in silos.

Environmental Toxicants and Preterm Birth: A Bibliometric Analysis of Research Trends and Output.

Preterm birth remains a problem globally, as multiple factors contribute to its etiology and pathogenesis. One such factor is the exposure to environmental toxicants, in which recent literature has described contributory roles in disease progression. This study aims to show research trends and collaborations in papers related to environmental toxicants and preterm birth through a bibliometric analysis to determine hot spots for research as well as to identify already established themes that can point to policy making and development. Using the Scopus database, we were able to identify 956 original research articles from 72 countries between 1955 and 2021; bibliographic information was exported, analyzed, and visualized using Bibliometrix and VOSviewer. There was an annual growth of research and reporting in this area, which significantly increased within the last two decades. The top countries that have published on this topic include the USA (n = 343), China (n = 103), and Australia (n = 43), with strong international collaboration in reports from China. Top journals for publication include Environmental Research (n = 53), Environmental Health Perspectives (n = 47), and Environment International (n = 46). Previous literature focused on establishing toxicants that are significantly associated with preterm birth, with current research focusing on molecular mechanisms of environmental toxicants. Overall, our bibliometric analysis gives a scoping view of the existing research landscape in terms of environmental health and preterm birth.

G-Protein Coupled Receptor Dysregulation May Play Roles in Severe Preeclampsia-A Weighted Gene Correlation Network Analysis of Placental Gene Expression Profile.

Preeclampsia is one of the major hypertensive diseases of pregnancy. Genetic factors contribute to abnormal placentation. The inadequate transformation of cytotrophoblasts causes failure of maternal spiral arteries' remodeling and results in narrow, atherotic-prone vessels, leading to relative placental ischemia. This study aims to explore the possibility of identifying dysregulated gene networks that may offer a potential target in the possible prevention of preeclampsia. We performed a weighted gene correlated network analysis (WGCNA) on a subset of gene expression profiles of placental tissues from severe preeclamptic pregnancies. We identified a gene module (number of genes = 402, GS = 0.35, p = 0.02) enriched for several G-protein-coupled receptor (GPCR)-related genes with significant protein-protein molecular interaction (number of genes = 38, FDR = 0.0007) that may play key roles in preeclampsia. Some genes are noted to play key roles in preeclampsia, including LPAR4/5, CRLR, NPY, TACR1/2, and SFRP4/5, whose functions generally relate to angiogenesis and vasodilation or vasoconstriction. Other upregulated genes, including olfactory and orexigenic genes, serve limited functions in the disease pathogenesis. Altogether, this study shows the utility of WGCNA in exploring possible new gene targets, and additionally reinforces the feasibility of targeting GPCRs that may offer intervention against development and disease progression among severe preeclampsia patients.

Actions of Bisphenol A on Different Feto-Maternal Compartments Contributing to Preterm Birth.

Preterm birth remains to be one of the most prevalent obstetric complications worldwide. Since there are multiple etiological factors associated with this disease process, an integrative literature search in PubMed and Scopus databases on possible mechanism of action and effect of bisphenols on exposure on human or animal placental samples in preterm birth was conducted. From 2332 articles on initial literature search, 63 studies were included for full data extraction. Altogether, several pathways were shown to be possibly affected by bisphenols, leading to dysregulations in structural and endocrine foundation in the placenta, potential induction of senescence and failure of decidualization in the decidua, and possible propagation of inflammation in the fetal membranes. Combined, these actions may eventually counteract bisphenol-induced relaxation of the myometrium and promote contractility alongside fetal membrane weakening. In totality, these individual impairments in gestation-critical processes may lead to failure of maintenance of pregnancy, and thus effecting preterm birth.

Molar pregnancy in the last 50 years: A bibliometric analysis of global research output.

Molar pregnancy is a gestational trophoblastic disease characterized by an abnormal growth of placental tissues because of a nonviable pregnancy. The understanding of the pathophysiology and management of molar pregnancy has significantly increased in the recent years. This study aims to determine the characteristics and trends of published articles in the field of molar pregnancy through a bibliometric analysis. Using the Scopus database, we identified all original research articles on molar pregnancy from 1970 to 2020. Bibliographic and citation information were obtained, and visualization of collaboration networks of countries and keywords related to molar pregnancy was conducted using VOSviewer software. We obtained a total of 2009 relevant papers published between 1970 and 2020 from 80 different countries. The number of publications continued to increase through the years. However, the number of publications in molar pregnancy is still low compared to the other research fields in obstetrics and gynecology. The USA (n = 421, 32.1%), Japan (n = 199, 15.2%), and the UK (n = 191, 14.6%) contributed the greatest number of publications in this field. The top journals which contributed to the field of molar pregnancy include AJOG (n = 91), Obstetrics and Gynecology (n = 81), and the Gynecologic Oncology (n = 57). The most cited articles in molar pregnancy include papers on the genetics and chromosomal abnormalities in molar pregnancies. The focus of current research in this field was on elucidating the molecular mechanism of hydatidiform moles. Our bibliometric analysis showed the global research landscape, trends and development, scientific impact, and collaboration among researchers in the field of molar pregnancy.

Hyperammonemia syndrome associated with Ureaplasma spp. Infections in immunocompromised patients and transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Hyperammonemia syndrome (HS) is reported to occur in patients with Ureaplasma spp. infections. We performed a systematic review and meta-analysis of studies reporting HS in patients with Ureaplasma spp. infection. METHODS: We searched several databases (CINAHL, OVID, ProQuest, and Scopus) from inception to January 2021. We described case reports and series, and performed a meta-analysis for all cohort studies. The pooled risk ratio (RR) for the association between HS and Ureaplasma spp. infections was derived using a random-effects model. RESULTS: The systematic review yielded 18 studies. HS was reported in 53 patients with Ureaplasma spp. infections. The most common clinical manifestations were neurologic. Meta-analysis showed a higher incidence of HS (41.67%) and peak ammonia concentration among Ureaplasma spp.-infected lung transplant recipients compared with Ureaplasma spp.-negative recipients (2.84%). The risk of HS was significantly increased in Ureaplasma spp.-infected recipients compared with Ureaplasma spp.-negative recipients (RR: 14.64; CI: 2.85-75.24). Mortality from Ureaplasma-associated HS was 27.27% compared with 5.24% in those with HS from other causes. CONCLUSIONS: The risk of developing HS is higher among Ureaplasma-infected patients compared with uninfected patients. Lung transplant recipients appear to be disproportionally affected, and HS should be suspected in those who present with neurologic symptoms.