Novel quasi-mesenchymal state of extravillous trophoblasts and its regulation during pregnancy

Abstract An appropriately functional placenta is the key to a successful and healthy pregnancy. During human placentation, the cytotrophoblast cells (CTBs) differentiate into the extravillous trophoblast cells (EVTs) that invade the maternal endometrium. The invaded EVTs take part in maternal-fetal crosstalk, modulate the local immune response, and remodel the spiral arteries. Shallow invasion is often associated with preeclampsia (PE) or other placenta-related pathologies. Earlier studies have indicated that CTB to EVT differentiation has features of epithelial to mesenchymal transition (EMT). However, the pathways that control this metastable transition are not fully clear yet. We screened publicly available database GEO for microarray expression datasets containing transcriptomic profile of CTBs and EVTs isolated from first trimester placenta. Three independent datasets were chosen for the study and the dataset having the highest number of differentially expressed genes (DEGs) was chosen as the primary dataset. The DEGs of the primary dataset were used for molecular signature hallmark analysis which showed that EMT hallmark was positively enriched. Further, the series matrix files of all datasets were used to compute the relative signal intensity of EMT associated genes. The results identified a unique pattern of EMT-associated gene expression in EVTs. Further, protein-protein interaction (PPI) network analysis of DEGs identified HIF1A, NOTCH1, ERBB2, and CTNNB1 as hub genes which may be the key regulators of the EMT process during EVT differentiation. Thus, this study documented the existence of a novel quasi-mesenchymal state of EVTs and identified possible upstream regulators involved in placenta-specific EMT.