Epithelial membrane protein 2 (EMP2) deficiency alters placental angiogenesis, mimicking features of human placental insufficiency

Abstract

Epithelial membrane protein-2 (EMP2) is a tetraspan protein predicted to regulate placental development. Highly expressed in secretory endometrium and trophectoderm cells, previous studies suggest that it may regulate implantation by orchestrating the surface expression of integrins and other membrane proteins. In order to test the role of EMP2 in pregnancy, mice lacking EMP2 (Emp2−/−) were generated. Emp2−/− females are fertile but have reduced litter sizes when carrying Emp2−/− but not Emp2+/− fetuses. Placentas of Emp2−/− fetuses exhibit dysregulation in pathways related to neoangiogenesis, coagulation, and oxidative stress, and have increased fibrin deposition and altered vasculature. Given that these findings often occur due to placental insufficiency resulting in an oxygen-poor environment, the expression of hypoxia-inducible factor-1 alpha (HIF-1α) was examined. Placentas from Emp2−/− fetuses had increased total HIF-1α expression in large part through an increase in uterine NK (uNK) cells, demonstrating a unique interplay between uNK cells and trophoblasts modulated through EMP2. To determine if these results translated to human pregnancy, placentas from normal, term deliveries or those complicated by placental insufficiency resulting in intrauterine growth restriction (IUGR) were stained for EMP2. EMP2 was significantly reduced in both villous and extravillous trophoblast populations in IUGR placentas. Experiments in vitro using human trophoblast cells lines indicate that EMP2 modulates angiogenesis by altering HIF-1α expression. Our results reveal a novel role for EMP2 in regulating trophoblast function and vascular development in mice and humans and suggest it may be a new biomarker for placental insufficiency.

Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils

“…Knockdown of EMP2 in mice impairs successful implantation [37]. In vitro investigation of human trophoblast cell lines has shown that EMP2 similarly regulates angiogenesis and trophoblast invasion, and that its deficiency is associated with intrauterine growth restriction [38]. In this same study, upregulation of EMP2 correlated with increased trophoblast cell migration.…”

Single-Cell RNA Sequencing Reveals Regulatory Mechanism for Trophoblast Cell-Fate Divergence in Human Peri-Implantation Embryo

“…For example, EMP2 was a hub gene in the early-stage network. Emp2 -deficiency in mice causes aberrant placental angiogenesis [16]. ESRRG was identified as a hub for the late-stage network, and abnormal reduction of ESRRG expression in human placenta is associated with intrauterine growth restriction and pre-eclampsia [17].…”

Towards Improving Embryo Prioritization: Parallel Next Generation Sequencing of DNA and RNA from a Single Trophectoderm Biopsy

“…Notably, previous studies on EMP2 suggest that it may regulate implantation by orchestrating the surface expression of integrins and other membrane proteins 45 . EMP2 was previously shown to be significantly reduced in both villous and extra-villous trophoblast populations in placentas of pregnancies with fetal intrauterine growth restriction 46 . When comparing our data to available data in the literature it should be noted that many factors alter the transcripts that are detected by sequencing and the level of their expression, thus making it challenging to compare different datasets.…”