Abstract
Current intervention strategies have not been successful in reducing the risks of adverse pregnancy complications nor maternal and fetal morbidities associated with pregnancy complications. Improving pregnancy and neonatal outcomes requires a better understanding of drug transport mechanisms at the feto-maternal interfaces, specifically the placenta and fetal membrane (FM). The role of several solute carrier uptake transporter proteins (TPs), such as the organic anion transporting polypeptide 2B1 (OATP2B1) in transporting drug across the placenta, is well-established. However, the mechanistic role of FMs in this drug transport has not yet been elucidated. We hypothesize that human FMs express OATP2B1 and functions as an alternate gatekeeper for drug transport at the feto-maternal interface. We determined the expression of OATP2B1 in term, not-in-labor, FM tissues and human FM cells [amnion epithelial cell (AEC), chorion trophoblast cell (CTC), and mesenchymal cells] using western blot analyses and their localization using immunohistochemistry. Changes in OATP2B1 expression was determined for up to 48 h after stimulation with cigarette smoke extract (CSE), an inducer of oxidative stress. The functional role of OATP2B1 was determined by flow cytometry using a zombie violet dye substrate assay. After OATP2B1 gene silencing, its functional relevance in drug transport through the feto-maternal interface was tested using a recently developed feto-maternal interface organ-on-a-chip (OOC) system that contained both FM and maternal decidual cells. Propagation of a drug (Rosuvastatin, that can be transported by OATP2B1) within the feto-maternal interface OOC system was determined by mass spectrometry. FMs express OATP2B1 in the CTC and AEC layers. In FM explants, OATP2B1 expression was not impacted by oxidative stress. Uptake of the zombie violet dye within AECs and CTCs showed OATP2B1 is functionally active. Silencing OATP2B1 in CTCs reduced Rosuvastatin propagation from the decidua to the fetal AEC layer within the feto-maternal interface-OOC model. Our data suggest that TPs in FMs may function as a drug transport system at the feto-maternal interface, a function that was previously thought to be performed exclusively by the placenta. This new knowledge will help improve drug delivery testing during pregnancy and contribute to designing drug delivery strategies to treat adverse pregnancy outcomes.
Highlights
More than one in six pregnancies are affected by various pregnancy-related complications, including preterm birth, fetal growth restrictions, or preeclampsia, which are associated with substantial maternal, fetal, and neonatal morbidity and mortality (Collier and Molina, 2019)
organic anion transporting polypeptide 2B1 (OATP2B1) localization was confirmed in different layers of fetal membrane (FM) by IHC (n 3)
OATP2B1 expression was localized on the basolateral surface of amnion epithelial cell (AEC) and on both the apical and basolateral surfaces of chorion trophoblast cell (CTC) (Figure 1A)
Summary
More than one in six pregnancies are affected by various pregnancy-related complications, including preterm birth, fetal growth restrictions, or preeclampsia, which are associated with substantial maternal, fetal, and neonatal morbidity and mortality (Collier and Molina, 2019). The feto-maternal interface is comprised of the placenta-decidua basalis interface and the fetal membrane (FM) (i.e., amniochorion)-decidua parietalis interface, both acting as protective barriers throughout pregnancy while maintaining communication between the mother and the fetus (Menon et al, 2021). Disruption of these interfaces leads to various pregnancy complications, including preterm birth, which can have long-term adverse effects on maternal and fetal health (Menon et al, 2019). Understanding the role of the feto-maternal interfaces in drug transport is critical to advancing clinical treatment strategies during pregnancy
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