Abstract
AbstractObjectiveAs an idiopathic hypertensive disorder of pregnancy, pre-eclampsia (PE) remains a major cause of maternal and neonatal morbidity and mortality, with no effective strategy for causal treatment.MethodsThis study was performed by downloading the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) based on the GSE173193 dataset, including single-cell sequencing data from placental samples of two PE patients and two normal controls. Placental cell subpopulations and their transcriptional heterogeneity were compared between PE and healthy pregnancies, and the mechanisms of PE cell dynamics in the hypoxic microenvironment were confirmed by in vitro experiments.ResultsIn this study, we constructed a large-scale single-cell transcriptome ecological landscape of 26,416 cells from healthy pregnant and PE patients placenta and further identified a PE-specific CSNK2B-positive subpopulation of chorionic villous trophoblast (EVT) cells. Specifically, this study revealed that the EVT subpopulation PTBP1 was inactivated by lactonization in the hypoxic microenvironment, resulting in low expression of the N6-methyladenosine (m6A) reading protein IGF2BP2. On the basis of this, low expression of IGF2BP2 inhibits mitochondrial autophagy, causes the accumulation of damaged mitochondria, exacerbates lactic acid accumulation while inducing EVT apoptosis on the one hand. In particular, hypoxia may initially promote oxidative stress through the production of mitochondrial reactive oxygen species. on the other hand, it inhibits EVT adherent spot signaling, decreases EVT invasive ability, leads to impaired placental spiral vessel recast, and promotes PE disease process. In addition, there are interactions between abnormal metabolic signaling of PE-specific EVT subpopulations and microenvironmental immune cells, which activate metabolic inflammation.ConclusionThe present study not only provides a new cell biological and genetic basis for elucidating the pathogenesis of PE, but also contributes to the design of an allopathic treatment strategy for PE.
Publisher
Cold Spring Harbor Laboratory