P‐Glycoprotein (P‐gp)/ABCB1 plays a functional role in extravillous trophoblast (EVT) invasion and is decreased in the pre‐eclamptic placenta

Abstract

Dysregulation of trophoblast differentiation is implicated in the placental pathologies of intrauterine growth restriction and pre‐eclampsia. P‐glycoprotein (P‐gp encoded by ABCB1) is an ATP‐binding cassette transporter present in the syncytiotrophoblast layer of the placenta where it acts as a molecular sieve. In this study, we show that P‐gp is also expressed in the proliferating cytotrophoblast (CT), the syncytiotrophoblast (ST) and the extravillous trophoblast (EVT), suggesting our hypothesis of a functional role for P‐gp in placental development. Silencing of ABCB1, via siRNA duplex, results in dramatically reduced invasion and migration, and increased tube formation and fusion in the EVT‐like HTR8/SV neo cell line. In both EVT and CT explant differentiation experiments, silencing of ABCB1 leads to induction of the fusion markers human hCG, ERVW‐1 and GJA1 and terminal differentiation of both trophoblast subtypes. Moreover, P‐gp protein levels are decreased in both the villous and the EVT of severe early‐onset pre‐eclamptic placentas. We conclude that, in addition to its role as a syncytial transporter, P‐gp is a key factor in the maintenance of both CT and EVT lineages and that its decrease in severe pre‐eclampsia may contribute to the syncytial and EVT placental pathologies associated with this disease.

Gestational age‐dependent gene expression profiling ofATP‐binding cassette transporters in the healthy human placenta

“…P‐gp is highly expressed in the human placenta and is primarily localized to the apical membrane of the syncytiotrophoblast. P‐gp functions as a major efflux transporter that protects the fetus from accumulation of several obstetric‐relevant drugs and environmental toxins and is an important transporter that modulates extravillous trophoblast invasion in early pregnancy . In our previous studies, syncytiotrophoblast P‐gp staining and placental ABCB1 expression decreased towards term, suggesting a higher protection of the fetus from exposure to P‐gp substrates in the first trimester, a period in which the developing conceptus is most vulnerable to teratogenicity .…”

Role of Elevated SFLT‐1 on the Regulation of Placental Transporters in Women With Pre‐Eclampsia

“…As immuno-detectable levels of proteins are measured in membrane fractions rather than whole cell lysates, it is also possible that increased trafficking of OCT3 to the membrane occurs in response to reduced transcript levels. 18 The ABC transporters, PGP, BCRP, and the MRPs along with the SLC transporters, OCT3, OATP2B1, and OATP4A1 are together responsible for the transport of numerous endogenous substrates, including steroid hormones, metabolites, and neurotransmitters, as well as exogenous substrates, including statins, glycosides, and antivirals, among others. These transporters are found at both the apical and basolateral membranes, supporting the bidirectional flow of substrates across the placenta.…”

SARS-CoV-2 cell entry gene ACE2 expression in immune cells that infiltrate the placenta in infection-associated preterm birth

“…The copyright holder for this this version posted September 29, 2020. ; https://doi.org/10.1101/2020.09.27.20201590 doi: medRxiv preprint were performed as described previously (Salio et al, 2005;Dunk et al, 2018;Choudhury et al, 2019). In brief, ChA placental slides were deparaffinized, rehydrated, and subjected to antigen retrieval with 1mM EDTA Ph9.0.…”