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Basic Science

Poster Session 2

(626) Extracellular Vesicles Carrying Efflux Protein P-glycoprotein Alter Drug Transport Functions in Decidua

Tuesday, February 13, 2024
3:30 PM – 5:00 PM  
Location: Prince George's Exhibit Hall CDE, Lower Atrium Level
Objective: P-glycoprotein (P-gp) is primarily reported in chorion trophoblast cells (CTC) for efflux drug transport. Its presence is reported in the neighboring amnion mesenchymal cells (AMC) and decidual cells (DEC), suggesting limited efflux capabilities of these cells. To test the hypothesis that CTC-derived extracellular vesicles (EVs) containing P-gp as cargo could induce P-gp expression in AMC and DEC, we examined CTC-EVs' impact on transitioning cells to perform efflux functions.

Study Design: Gene expression levels of P-gp were analyzed in fetal membrane cells through quantitative real-time polymerase chain reaction (qRT-PCR), and protein levels were assessed using western blot analysis. CTC-derived EVs were isolated and characterized for size, shape, and quantity using nanoparticle tracking analysis, and the presence of P-gp was confirmed. Flow cytometry was utilized to evaluate CTC-EVs' effect on inducing P-gp expression in cells lacking it. The functional activity of P-gp in AMC and DEC was assessed through a multidrug resistance assay after exposure to CTC-derived P-gp-containing EVs. To validate our findings, decidual cells with P-gp knockdown (KD) using the CRISPR/Cas9 approach were treated with CTC-derived EVs containing P-gp and tested for restoration.

Results: The gene and protein expression levels of P-gp in the amniochorion layers and their derived EVs were determined (Fig. 1A and 1B). Although the expression levels of EVs within the cells were low, both amniotic epithelial cells (AEC) and CTC-derived EVs carried P-gp. Treatment with CTC-derived EVs containing P-gp led to increased P-gp expression in AMC and DEC, resulting in enhanced drug efflux and a decrease in drug resistance (Fig. 1C). Furthermore, P-gp expression was reduced in trophoblast cells with P-gp KD but was restored upon treatment with chorion-derived EVs.

Conclusion: This study demonstrates that EV-mediated delivery of P-gp can induce drug efflux functions in cells in a paracrine fashion. The modulation of P-gp by EVs highlights the interplay between EVs and the cells of the feto-maternal interface drug transport mechanisms.