Aspirin's role in epigenetic reorganization of placental mesenchymal stem cells in preeclampsia

Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality. The pathogenesis of PE is not well understood, and treatment consists of completion of pregnancy. Aspirin (ASA) has been used to for PE prevention, but the mechanism of action is not fully known. Our objectives were to explore the effect of ASA on placental mesenchymal stem cells (P-MSCs), identify which biological pathways ASA affects, and the unique molecular targets of ASA treatment. P-MSCs were derived and passaged from healthy and PE singleton, term pregnancies. Exclusion criteria included placental or fetal abnormalities, and maternal comorbidities including diabetes, chronic hypertension, autoimmune, or renal diseases. After ASA (1mM) treatment, mRNA from P-MSCs was isolated and sequenced. Data was analyzed using Ingenuity Pathway Analysis to demonstrate differentially expressed gene pathways between PE and healthy P-MSCs, with return towards normal expression in ASA treated PE compared with healthy P-MSCs. Activation z scores demonstrated which canonical pathways were most impacted. The canonical pathways with greatest differential that return towards normal expression with ASA treatment were Cell Cycle Control of Chromosomal Replication, Base Excision Repair (BER), Nucleotide Excision Repair (NER), and Sumoylation. All these pathways had differential RNA transcripts in PE vs. healthy P-MSCs, with return towards healthy RNA transcription with ASA treatment. Specific upstream regulators that were differentially expressed with ASA treatment were DNA polymerase, replication factor C, and minichromosome maintenance complex proteins. In P-MSCs, ASA affected changes in gene expression in canonical pathways related to DNA damage, repair, and cell cycle control. In addition, ASA alters the expression of upstream regulators of these pathways, which can lead to licensing the P-MSCs back towards healthy function in PE. This work suggests that ASA may prevent PE by changing the gene expression in these pathways.View Large Image Figure ViewerDownload Hi-res image Download (PPT)