3.1.4. Cord Blood Cells

In 2014, Nomura and coworkers analyzed the global methylation profile of cord blood cells using the LUMA technique [161] and failed to observe an actual difference but with a limited number of controls samples (5) [216]. Genome-Wide Methylation analysis using the 450K microarray tool on neonatal cord blood DNA showed a significant genome-scale hypomethylation in neonatal cord blood DNA associated with EOPE, with 51,486 hypomethylated and 12,563 hypermethylated CpGs [187]. In this study the most differential methylated genes were associated with inflammatory pathways, cholesterol and lipid metabolism, including IL12B, FAS, PIK31 and IGF1. Deregulation of both metabolic pathways may increase the risk of cardiovascular diseases in the fetus [187]. The same microarray approach allowed to identify 5001 mostly hypermethylated regions in umbilical cord white blood cells and 869 mostly hypomethylated regions in the placenta [217]. In the cord blood cells, the gene networks enriched were involved in cardiovascular system development, cell cycle, cancer, cell morphology, infectious diseases, suggesting specific alterations that could have long-term consequences on the fetal health.

Some studies focused on mitochondrial DNA, showing hypomethylation in PE cord blood cells. The most affected loci are keys in mitochondria functionality: D-loop (control of mitochondrial DNA replication), Cytochrome C oxidase subunit 1 gene (respiratory chain) and TF/RNR1 locus (necessary for protein synthesis) [218]. Increased copy of mitochondria is observed in the placenta and maternal blood during PE suggesting an adaptive response to stress [219,220]. This is also observed in mouse models of PE [221]. Hypomethylation in the D-loop may lead to increased mitochondrial replication explaining the pathological increase of mitochondrial DNA. Methylation assay in endothelial colony-forming cells present in cord blood from PE presents differential methylation level in genes related to RNA metabolic processes, cellular protein modification processes and in positive regulation transcription, as assessed with the EPIC Illumina array, interrogating over 850,000 CpG [222]. However, at later passages, an increased number of genes are abnormally methylated. This suggests that preeclampsia may drive an altered epigenetic program in endothelial cell precursors that will be the building bricks of the newborn vascular system and program later complications.
