To evaluate the role of placental human papilloma virus (HPV) infection as a risk factor for spontaneous preterm birth: a prospective case control study

Objectives i) To compare the placental human papilloma virus (HPV) deoxynucleic acid (DNA) status of preterm deliveries with full term deliveries and to identify high risk (HR) genotypes (HPV 16 and 18); and ii) To compare the perinatal outcomes of HPV positive with HPV negative pregnant women. Methods A case control study was carried out on 100 antenatal women with singleton live pregnancies admitted in labor ward of a tertiary care teaching hospital from April 2017 to March 2018. The two study groups were i) spontaneous preterm deliveries between 24 and 36 + 6 weeks (n=50) and ii) full term deliveries ≥37 weeks (n=50). The placental tissue was analysed for HPV DNA and HR HPV genotypes were detected by type specific primers. A comparative analysis of perinatal outcomes between HPV positive and negative women was done. Results An overall placental tissue HPV prevalence of 12% (12/100) was observed in study cohort which was not significantly different between preterm and full term deliveries (16 vs. 8%, p=0.218). HPV 16 was significantly associated with preterm births (p=0.04). Both HPV affected and non-affected women were comparable in terms of mode of delivery and neonatal outcomes. However, a statistically significant association of preterm neonatal intensive care admissions with HR HPV 16 genotype was observed (p=0.04). Conclusions Spontaneous preterm births can be attributed to placental HPV infection, specifically HR HPV 16 genotype. This association identifies a potentially preventable cause of prematurity and its associated complications, in wake of availability of an effective vaccine.

Human Amniotic Epithelial Cells Secretome: Components, Bioactivity, and Challenges

Human amniotic epithelial cells (hAECs) derived from placental tissue have received significant attention as a promising tool in regenerative medicine. Several studies demonstrated their anti-inflammatory, anti-fibrotic, and tissue repair potentials. These effects were further shown to be retained in the conditioned medium of hAECs, suggesting their paracrine nature. The concept of utilizing the hAEC-secretome has thus evolved as a therapeutic cell-free option. In this article, we review the different components and constituents of hAEC-secretome and their influence as demonstrated through experimental studies in the current literature. Studies examining the effects of conditioned medium, exosomes, and micro-RNA (miRNA) derived from hAECs are included in this review. The challenges facing the application of this cell-free approach will also be discussed based on the current evidence.

Co-expression analysis of placental genes in the search for key signaling pathways and biomarkers of the great obstetrical syndromes

Objective. To study the molecular mechanisms responsible for the development of diseases grouped within the great obstetrical syndromes (GOS) at the level of the transcriptome of human maternal placenta.Material and Methods. We gathered the results of genome-wide transcriptome studies of the human placental tissue using Gene Expression Omnibus (GEO) data repository for the following phenotypes: physiological pregnancy, preeclampsia (PE), premature birth, and intrauterine growth restriction (IUGR). Eleven data sets were selected and supplemented with our experimental data; a total of 481 samples of human placental tissue were included in the integrative analysis. Bioinformatic data processing and statistical analyses were performed in the R v3.6.1 software environment using the Bioconductor packages. The pooled dataset was used to search for common molecular targets for GOS via weighted gene co-expression network analysis (WGCNA). The functional annotation of genes and the resulting clusters was carried out with the DAVID database; protein-protein interaction network was built using the STRING software; and the hub genes for the network were identified using the MCC analysis with plugin cytoHubba in Cytoscape software 3.7.2.Results. We obtained a table of expression levels for 15,167 genes in 246 samples. Hierarchical clustering of this network allowed to find 55 modules of co-expressed genes in the group with PE, 109 modules in the group with PB, 75 modules in patients with IUGR, and 56 modules in the control group. The preservation analysis of co-expressed modules for the studied phenotypes suggested the presence of a common cluster comprising eight genes specific only for patients with PE and IUGR, as well as the module of 23 co-expressed genes typical only for patients with PB and IUGR. Protein-protein interaction network was built for these gene sets, and the SOD1, TXNRD1, and UBB genes were the central nodes in the network. Based on network topology evaluation with cytoHubba, six hub genes (rank ˂ 5) were identified as follows: SOD1, TKT, TXNRD1, GCLM, GOT1, and ACO1.Conclusion. The obtained results allowed to identify promising genetic markers for preeclampsia, intrauterine growth restriction, and miscarriage. Moreover, the study also made it possible to identify the most important overlapping molecular mechanisms of these diseases occurring in the placental tissue.

The Impact of Oxidative Stress of Environmental Origin on the Onset of Placental Diseases

Oxidative stress (OS) plays a pivotal role in placental development; however, abnormal loads in oxidative stress molecules may overwhelm the placental defense mechanisms and cause pathological situations. The environment in which the mother evolves triggers an exposure of the placental tissue to chemical, physical, and biological agents of OS, with potential pathological consequences. Here we shortly review the physiological and developmental functions of OS in the placenta, and present a series of environmental pollutants inducing placental oxidative stress, for which some insights regarding the underlying mechanisms have been proposed, leading to a recapitulation of the noxious effects of OS of environmental origin upon the human placenta.

Circulating Placental Alkaline Phosphatase Expressing Exosomes in Maternal Blood Showed Temporal Regulation of Placental Genes

Background: Analysis of placental genes could unravel maternal-fetal complications. However, inaccessibility to placental tissue during early pregnancy has limited this effort. We tested if exosomes (Exo) released by human placenta in the maternal circulation harbor crucial placental genes.Methods: Placental alkaline phosphate positive exosomes (ExoPLAP) were enriched from maternal blood collected at the following gestational weeks; 6–8th (T1), 12–14th (T2), 20–24th (T3), and 28th−32nd (T4). Nanotracking analysis, electron microscopy, dynamic light scattering, and immunoblotting were used for characterization. We used microarray for transcriptome and quantitative PCR (qPCR) for gene analysis in ExoPLAP.Results: Physical characterization and presence of CD63 and CD9 proteins confirmed the successful ExoPLAP enrichment. Four of the selected 36 placental genes did not amplify in ExoPLAP, while 32 showed regulations (n = 3–8/time point). Most genes in ExoPLAP showed significantly lower expression at T2–T4, relative to T1 (p < 0.05), such as NOS3, TNFSF10, OR5H6, APOL3, and NEDD4L. In contrast, genes, such as ATF6, NEDD1, and IGF2, had significantly higher expression at T2–T4 relative to T1. Unbiased gene profiling by microarray also confirmed expression of above genes in ExoPLAP-transcriptome. In addition, repeated measure ANOVA showed a significant change in the ExoPLAP transcriptome from T2 to T4 (n = 5/time point).Conclusion: Placental alkaline phosphate positive exosomes transcriptome changed with gestational age advancement in healthy women. The transcriptome expressed crucial placental genes involved in early embryonic development, such as actin cytoskeleton organization, appropriate cell positioning, DNA replication, and B-cell regulation for protecting mammalian fetuses from rejection. Thus, ExoPLAP in maternal blood could be a promising source to study the placental genes regulation for non-invasive monitoring of placental health.