Abstract
Extravillous trophoblasts (EVT) migration into the decidua is critical for establishing placental perfusion and when dysregulated, may lead to pre-eclampsia (PE) and intrauterine growth restriction (IUGR). The breast cancer resistance protein (BCRP; encoded by ABCG2) regulates the fusion of cytotrophoblasts into syncytiotrophoblasts and protects the fetus from maternally derived xenobiotics. Information about BCRP function in EVTs is limited, however placental exposure to bacterial/viral infection leads to BCRP downregulation in syncitiotrophoblasts. We hypothesized that BCRP is involved in the regulation of EVT function and is modulated by infection/inflammation. We report that besides syncitiotrophoblasts and cytotrophoblasts, BCRP is also expressed in EVTs. BCRP inhibits EVT cell migration in HTR8/SVneo (human EVT-like) cells and in human EVT explant cultures, while not affecting cell proliferation. We have also shown that bacterial—lipopolysaccharide (LPS)—and viral antigens—single stranded RNA (ssRNA)—have a profound effect in downregulating ABCG2 and BCRP levels, whilst simultaneously increasing the migration potential of EVT-like cells. Our study reports a novel function of BCRP in early placentation and suggests that exposure of EVTs to maternal infection/inflammation could disrupt their migration potential via the downregulation of BCRP. This could negatively influence placental development/function, contribute to existing obstetric pathologies, and negatively impact pregnancy outcomes and maternal/neonatal health.
Highlights
The placenta supports the growth and development of the fetus and is paramount to a successful pregnancy [1]
Expression of breast cancer resistance protein (BCRP) Is Enriched in Column Cytotrophoblasts (CCT) and Extravillous Trophoblasts (EVTs) in Placental Explants
BCRP immunostaining in ST, CT, column cytotrophoblasts (CCT), as well as, extravillous trophoblasts (EVT) invading into the matrigel and at the tips of CCT
Summary
The placenta supports the growth and development of the fetus and is paramount to a successful pregnancy [1]. A critical stage of early placental development is the proliferation and differentiation of. Cells 2019, 8, 1150 cytotrophoblasts (CT) into extravillous trophoblasts (EVTs). Insufficient invasion can result in poor placentation and can lead to preeclampsia (PE), intrauterine growth restriction (IUGR), and other serious obstetric complications [5]. Uncontrolled EVT migration/invasion can lead to the deeper penetration of trophoblasts into the myometrium rather than decidua basalis (placenta acreta) [6] or even through the uterus, affecting the surrounding organs (placenta percreta) [7], resulting in maternal/fetal morbidity and mortality. In certain circumstances, uncontrolled trophoblast proliferation and invasion can lead to choriocarcinoma [8]
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