Related Experiment Video
Updated: Jul 1, 2025
Author Spotlight: Modeling an Aspect of Preeclampsia in Female Mice Using Hypoxic Human Placenta-Derived Small Extracellular Vesicles
Published on: January 26, 2024
Exosomal small RNA profiling in first-trimester maternal blood explores early molecular pathways of preterm
Luca Gál1,2, Ábel Fóthi1, Gergő Orosz3
1Gene Regulation Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.
Insights
Researchers identified specific small RNAs in exosomes from early pregnancy blood that could help diagnose preeclampsia with intrauterine growth restriction (IUGR) early. These biomarkers are linked to immune pathway disruptions in this severe pregnancy condition.
Area of Science:
- Obstetrics and Gynecology
- Molecular Biology
- Genomics
Background:
- Preeclampsia (PE) with intrauterine growth restriction (IUGR) is a severe pregnancy complication with significant long-term health risks.
- Early diagnosis of PE is crucial for timely intervention and prevention of adverse outcomes.
- The heterogeneity of PE has hindered early and accurate diagnosis, necessitating novel biomarkers.
Purpose of the Study:
- To investigate the role of exosomal regulatory small RNAs in the early detection of preterm preeclampsia with intrauterine growth restriction (IUGR).
- To identify potential non-invasive biomarkers for the most severe subtype of preeclampsia.
Main Methods:
- Isolation of exosomal extracellular vesicles (EVs) from first-trimester plasma of women who later developed preterm PE with IUGR and healthy controls.
- Next-generation sequencing and quantitative real-time PCR to analyze small RNA content and differential expression.
- Bioinformatics analysis (exceRpt pipeline) for small RNA identification, target prediction, and Gene Ontology analysis.
Main Results:
- Over 2700 small RNAs identified, predominantly from RNA interference (RNAi) pathways.
- 16 differentially expressed microRNAs and six Piwi-associated RNAs (piRNAs) identified in PE cases.
- Gene Ontology analysis revealed enrichment of immune-related pathways, suggesting a link between small RNA dysregulation and impaired immune function in PE.
- The piRNA hsa_piR_016658 was validated as a promising biomarker candidate for preterm PE with IUGR.
Conclusions:
- Circulating maternal exosomal small RNAs are dysregulated in preterm PE with IUGR, impacting key physiological pathways.
- Identified small RNAs serve as potential biomarker candidates for early diagnosis of severe PE.
- The study provides insights into the complex pathology of preeclampsia by revealing dysregulated immune pathways.
Introduction:
Preeclampsia (PE) is a severe obstetrical syndrome characterized by new-onset hypertension and proteinuria and it is often associated with fetal intrauterine growth restriction (IUGR). PE leads to long-term health complications, so early diagnosis would be crucial for timely prevention. There are multiple etiologies and subtypes of PE, and this heterogeneity has hindered accurate identification in the presymptomatic phase. Recent investigations have pointed to the potential role of small regulatory RNAs in PE, and these species, which travel in extracellular vesicles (EVs) in the circulation, have raised the possibility of non-invasive diagnostics. The aim of this study was to investigate the behavior of exosomal regulatory small RNAs in the most severe subtype of PE with IUGR.
Methods:
We isolated exosomal EVs from first-trimester peripheral blood plasma samples of women who later developed preterm PE with IUGR (n=6) and gestational age-matched healthy controls (n=14). The small RNA content of EVs and their differential expression were determined by next-generation sequencing and further validated by quantitative real-time PCR. We also applied the rigorous exceRpt bioinformatics pipeline for small RNA identification, followed by target verification and Gene Ontology analysis.
Results:
Overall, >2700 small RNAs were identified in all samples and, of interest, the majority belonged to the RNA interference (RNAi) pathways. Among the RNAi species, 16 differentially expressed microRNAs were up-regulated in PE, whereas up-regulated and down-regulated members were equally found among the six identified Piwi-associated RNAs. Gene ontology analysis of the predicted small RNA targets showed enrichment of genes in pathways related to immune processes involved in decidualization, placentation and embryonic development, indicating that dysregulation of the induced small RNAs is connected to the impairment of immune pathways in preeclampsia development. Finally, the subsequent validation experiments revealed that the hsa_piR_016658 piRNA is a promising biomarker candidate for preterm PE associated with IUGR.
Discussion:
Our rigorously designed study in a homogeneous group of patients unraveled small RNAs in circulating maternal exosomes that act on physiological pathways dysregulated in preterm PE with IUGR. Therefore, our small RNA hits are not only suitable biomarker candidates, but the revealed biological pathways may further inform us about the complex pathology of this severe PE subtype.
