Human trophoblast organoids for improved prediction of placental ABC transporter-mediated drug transport

Abstract

ATP-binding cassette (ABC) transporters, the important transmembrane efflux transporters, play an irreplaceable role in the placenta barrier. The disposition and drug-drug interaction of clinical drugs are also closely related to the functions of ABC transporters. The trophoblast is a unique feature of the placenta, which is crucial for normal placentation and maintenance during pregnancy. ABC transporters are abundantly expressed in placental syncytiotrophoblast, especially P-gp, BCRP, and MRPs. However, due to the lack of appropriate modeling systems, the molecular mechanisms of regulation between ABC transporters and trophoblast remains unclear. In this report, trophoblast organoids were cultured from human placental villi and developed into three-dimension structures with cavities. Trophoblast organoids exhibited transporter expression and localization comparable to that in villous tissue, indicating their physiological relevance for modeling drug transport. Moreover, fluorescent substrates can accumulate in organoids and be selectively inhibited by inhibitors, indicating the efflux function of ABC transporters (P-gp, BCRP, MRP1, and MRP2) in organoids. Two commonly used hypertension drugs and three antipsychotics were chosen to further validate this drug transport model and demonstrate varying degrees of inhibitory effects on ABC transporters. Overall, a new drug transport model mediated by ABC transporter has been successfully established based on human trophoblast organoids, which can be used to study drug transport in the placenta.