Potential biological mechanisms by which placental microRNA dysfunction might contribute to spontaneous preterm birth are highlighted and putative sPTB biomarkers that may be detectable in maternal circulation are highlighted.
Abstract
Background The placenta has a unique transcriptomic profile, including microRNAs that are secreted into maternal circulation throughout pregnancy. MicroRNAs are small, non-coding RNA that post-transcriptionally regulate gene expression. Spontaneous preterm birth (sPTB) is associated with substantial differences in both placental pathophysiology and placental gene expression compared to term birth. We aimed to generate microRNA signatures of sPTB and map them to target genes using a microRNA–mRNA network. Methods This study was conducted within the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Placental samples were collected at delivery, and RNA was isolated for mRNA and microRNA sequencing. To investigate sPTB, this study excluded placental samples of participants with iatrogenic indications for PTB or induced labor. We examined differences in microRNA expression in participants who delivered before 37 weeks (N=35) compared to term participants (N=404) in a series of covariate-adjusted linear regression models. We used paired placental microRNA and mRNA expression data from this cohort to validate associations between computationally predicted microRNA–mRNA pairs and establish a microRNA–mRNA network. Results Expression of 7 microRNAs were increased in sPTB (FDR<0.05) and were inversely correlated with sPTB-associated genes involved in immune signaling. Expression of 12 microRNAs were decreased in sPTB, including 4 members of the maternally expressed chromosome 14 microRNA cluster (miR-376a-3p, miR-376c-3p, miR-377-3p, and miR-381-3p). These microRNAs were predicted to negatively regulate oxidative phosphorylation genes that were increased in sPTB. The associations between miR-376c-3p and miR-377-3p and oxidative phosphorylation were confirmed in microRNA knockdown experiments. Conclusions This study highlights potential biological mechanisms by which placental microRNA dysfunction might contribute to sPTB and highlights putative sPTB biomarkers that may be detectable in maternal circulation.
ABSTRACT Preeclampsia (PE) is a pregnancy‐specific disorder characterized by maternal hypertension and proteinuria, typically manifesting in the late second or third trimester. It affects approximately 5%–8% of pregnancies worldwide and accounts for nearly 10%–15% of maternal deaths. PE is also associated with adverse neonatal outcomes, including preterm birth, fetal growth restriction, and low birth weight, with long‐term cardiovascular and metabolic consequences for both mother and offspring. Although clinical symptoms appear in the latter half of pregnancy, substantial evidence indicates that PE originates earlier during placental development. Impaired trophoblast invasion and defective spiral artery remodeling result in placental insufficiency, compromised uteroplacental perfusion, and a hypoxic placental microenvironment, which are hallmark features of the disease. Despite extensive research, PE remains a heterogeneous disorder lacking reliable early diagnostic markers or effective targeted therapies, with placental delivery remaining the only definitive treatment. MicroRNAs (miRNAs) have emerged as critical regulators of placental development and function. Owing to their abundance, evolutionary conservation, and ability to modulate multiple gene networks, miRNAs regulate trophoblast proliferation, migration, invasion, angiogenesis, and apoptosis, processes that are profoundly disrupted in PE. Genome‐wide expression studies have revealed widespread dysregulation of placental miRNAs in PE, frequently associated with hypoxia and angiogenic imbalance. This review summarizes current advances in miRNA expression and function in the preeclamptic placenta, focusing on their roles in trophoblast dysfunction and disease pathogenesis. We highlight differentially expressed placental miRNAs, their targets, and the regulatory pathways they influence, emphasizing the central role of miRNA‐mediated gene regulation in the development and progression of PE.
Sarbani Saha, R. Ain· FASEB bioAdvances· 0 citations
Prenatal environmental exposures may influence fetal growth by disrupting the maternal metabolome and placental function. This exploratory study integrates untargeted maternal serum metabolomics and placental transcriptomics to identify shared molecular pathways through which the maternal environment affects fetal development. Data were drawn from the SAWASDEE birth cohort in northern Thailand, comprising pregnant farmworkers living in an agricultural region with known environmental exposure concerns. Weighted gene coexpression network analysis (WGCNA) of placental transcriptomic data (n = 254) identified gene expression modules, which were analyzed for associations with neonatal outcomes in a subset with paired maternal metabolomics and birth data (n = 40). A placental gene module enriched for myogenesis-related genes was inversely associated with birth weight (β = −0.11, p = 0.03). Seventeen maternal serum metabolic features were associated with both this module and birth weight, including phospholipids related to membrane remodeling and putatively annotated quinoline-containing xenobiotic-like features with structural similarity to combustion-related or industrial compounds. Mediation analysis did not identify statistically significant indirect effects, although one putative xenobiotic-like feature showed a directionally consistent estimate. In this exploratory analysis, these findings identify maternal metabolomic patterns and placental gene networks that are associated with fetal growth and generate hypotheses regarding biologically relevant pathways linking maternal metabolism, placental function, and neonatal growth. Multiomics integration provides a useful exploratory framework for identifying candidate molecular pathways that warrant validation in larger studies.
Ye-Wei Wang, Dong-Hai Liang, Duan Wang et al.· Environment & Health· 0 citations
Spontaneous preterm birth (sPTB) affects ~9.9% of pregnancies worldwide and is driven in part by placental dysfunction, yet the signalling events linking placental dysregulation to spontaneous prematurity remain incompletely defined. Using a cross-sectional design, we profiled 70 placentae from spontaneous term and preterm birth delivery to construct protein co-expression networks and identified 13 hub proteins associated with sPTB. Quantification of placental circulatory proteins in an independent nested case-control set of 53 maternal plasma samples highlighted elevated levels of the transcription factor ladybird homeobox protein 1 (LBX1) in maternal circulation from sPTB cases. Elevated LBX1 in trophoblast cells undergo KPNB1 mediated nuclear import, where it deregulates ribosomal biogenesis and perturbs subsequent ribosomal protein homeostasis, contributing to the accumulation of newly synthesised proteins. Accumulation of these nascent proteins triggers unfolded protein response which may lead to adverse pregnancy outcome. These findings implicate LBX1-mediated ribosomal disruption and activation of unfolded protein response in trophoblasts as a placental mechanism contributing to sPTB.
A. Biswas, N. Kharbanda, K. Bisht et al.· medRxiv· 0 citations
This study aimed to identify microRNA (miRNA) expression profiles associated with recurrent spontaneous abortion (RSA) and to explore whether their dysregulation is linked to relevant clinical characteristics.
A total of 51 villous specimens were collected from spontaneous abortion (SA) patients, including 31 RSA cases. Three RSA and three control specimens were randomly chosen for miRNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to annotate target gene functions and related signaling pathways. Low-depth whole-genome sequencing was performed on all specimens to eliminate confounding effects induced by chromosomal karyotypic abnormalities. RT-qPCR was used to validate the expression of candidate miRNAs.
Thirty-six significantly differentially expressed microRNAs were identified, consisting of 16 upregulated and 20 downregulated miRNAs. The proportion of abnormal chromosomal karyotypes was significantly higher in women with a single spontaneous abortion than in those with two or more spontaneous abortions (
p
< 0.001). The relative expression levels of miR-182-5p, miR-2110, and miR-320a-3p was not significantly different between samples with normal and abnormal karyotype. The expression levels of miR-182-5p and miR-2110 in the villi of the RSA group were significantly lower than those in the control group (0.736 ± 0.139 vs. 1.830 ± 0.480,
p
< 0.01; 1.874 ± 0.476 vs. 2.493 ± 0.582,
p
< 0.05, respectively). No significant difference was observed for miR-320a-3p expression between the RSA and control groups. Similarly, when the primary RSA subgroup was compared with the control group, comparable results were obtained for miR-182-5p, miR-2110, and miR-320a-3p. Notably, the expression level of miR-320a-3p was significantly upregulated in the high BMI group compared with the normal BMI group (
p
< 0.05).
Two major findings emerged from this study. First, miR-182-5p and miR-2110 are associated with RSA, particularly primary RSA. Second, miR-320a-3p appears to indirectly affect reproductive outcomes by participating in obesity-related metabolic pathways, rather than acting as a direct disease-specific marker for RSA. Collectively, these findings suggest that These findings suggest that miR-182-5p and miR-2110 may serve as potential biomarkers for RSA, while miR-320a-3p may reflect obesity-related metabolic status.
Wei Bai, Zhihai Miao, Wan-Zhong Kong et al.· BMC Pregnancy and Childbirth· 0 citations
Deciphering the cellular dynamics that sustain tolerance and placental function in health and disease is essential for better therapies. We built a maternal—fetal placental atlas to characterize common immune-mediated pregnancy complications.
We collected 69 placenta samples from patients with pregnancy complications including spontaneous preterm birth (n = 10), fetal growth restriction (n = 9), pre-term preeclampsia (n = 10), term preeclampsia (n = 8), type 1 diabetes (n = 10) and healthy controls (n = 21). We profiled samples via multi-modal10x Genomics single cell sequencing: gene expression, CITE-seq and paired T cell receptor, with spatial transcriptomics (Visium HD) in a subset for validation.
We profiled over 1.2 million placental cells, the largest atlas to date. We identified 114 cell populations, among them 15 T cell subsets. Using genetic demultiplexing we determined fetal or maternal origin of each cell. We found that the majority of the placental T cells are maternal and that the fetal T cells are only naïve or unconventional T cells (γδT cell subsets and MAIT cells). Using paired TCR-seq data we identified T cell clones and associated clonal expansions to specific T cell subsets.
This comprehensive atlas redefines the placental cellular landscape. Uncovering the different roles that the maternal and fetal T cells have in the cellular micro-environment is key for understanding mechanisms of placental dysregulation.
NIH/NIAID 1U19AI167899
Immune Mechanisms of Human Disease (HUM)
R. Normand, P. L. Lopez Zapana, Daehee Han et al.· Journal of Immunology· 0 citations
Preeclampsia (PE) is a hypertensive pregnancy-specific disorder and a leading cause of maternal and fetal mortality. A common feature of PE placentas and maternal plasma is dyslipidemia, or abnormal lipid levels, which can increase oxidative stress and endothelial dysfunction. However, the precise transcriptional, post-transcriptional, and epigenetic mechanisms underlying these abnormalities remain poorly characterized. Identifying such changes may clarify disease mechanisms and identify lipid-related PE biomarkers. We conducted a large-scale meta-analysis integrating public placental datasets from NCBI GEO, comprising four DNA methylation (DNAm) datasets (n = 172), three RNA-sequencing datasets (n = 92), and an independent RNA microarray validation cohort (n =146). We evaluated differential DNAm (limma), gene expression (DESeq2), transcript-level shifts (Swish), and alternative splicing (rMATS) in PE versus control placentas, with all analyses stratified by fetal sex via an interaction term model. We also performed placental cell-type deconvolution to quantify PE-associated cell-type proportion changes. Our results demonstrated that lipid-related regulation changes in PE placentas occur primarily at the gene and transcript level, with DNAm showing no changes. We also identified significant isoform switching in PE that were undetected by differential gene expression analysis, and primarily driven by alternative transcription initiation and termination sites rather than alternative splicing. A subset of these isoform switches mapped to pathways dysregulated in PE and were predicted to cause functional protein changes. An interaction term model identified several sex-specific differentially expressed genes (DEGs) in PE, including a subset of male-specific downregulated genes involved in oxidative metabolism. However, many of the remaining sex-specific DEGs across both sexes were previously uncharacterized in the literature. These findings suggest that transcriptional and isoform-level regulation play a role in PE-associated dyslipidemia, with certain regulatory pathways displaying fetal sex-specific patterns. Highlights - Preeclampsia-associated dyslipidemia manifests at the gene and transcript level - Reciprocal isoform switches were missed by standard gene-level analyses - Alternative transcript initiation and termination drove isoform switching - Sex-interaction modeling identified sex-specific transcriptional shifts in PE
Kriesha S Eyer, Melanie Lemaire, Xin-Yu Fan et al.· bioRxiv· 0 citations
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