Effect of EVT-Derived Small Extracellular Vesicles on Normal and Impaired Human Implantation

Uncontrolled and excessive inflammation could negatively impact embryo implantation, potentially leading to implantation failure or miscarriage. Small extracellular vesicles (sEVs) secreted by extravillous trophoblasts (EVTs) play a significant role in mediating the homeostasis at the maternal–fetal interface. In the present work we assessed the role of EVT-derived sEVs in the protection of the human blastocyst’s integrity and function in a microenvironment with excessive Th1-induced inflammation using the Sw71 blastocyst-like surrogate (Sw71 BLS) as a model of implanting a human embryo. Conditioned media from primary trophoblast-derived EVT cells were used as the source for sEVs’ isolation by precipitation. sEVs were characterized by TEM, IEM, and protein content. To simulate Th1-induced inflammation, we performed TCR stimulation and polyclonal activation of isolated T cells, which preferentially led to Th1 cytokine production. The use of the Sw71 spheroid model allowed us to monitor directly the damaging effect of high levels of Th1 cytokines on the ability of trophoblast cells to self-organize and migrate. The addition of EVT-sEVs unlocked the absolute migration capacity of the trophoblast cells in a healthy microenvironment. However, EVT-sEV treatment could not counteract the adverse effects of excessive Th1-mediated inflammation. This study provides a platform for further elucidation of the EVT-sEV dosage and potency for trophoblast functional recovery.