The pro-inflammatory cytokines IFN-α and TNF-α inhibit organoid-derived extravillous trophoblast invasion

Proper placental development requires differentiation and invasion of extravillous trophoblasts (EVTs) into the maternal decidua to ensure adequate remodeling of spiral arteries and support fetal growth. Perturbations in these processes are associated with pregnancy complications such as preeclampsia and fetal growth restriction. The incidence of these pregnancy complications is increased in women with immune-mediated inflammatory diseases, which are characterized by elevated levels of pro-inflammatory cytokines, such as interferon alpha (IFN-) and tumor necrosis factor alpha (TNF-). However, the direct effects of these cytokines on trophoblast differentiation and invasion remain unclear. Using human trophoblast organoid models, we demonstrate that IFN- and TNF- impair EVT invasion while preserving their differentiation capacity. High-resolution imaging of untreated organoid-decidua co-cultures revealed extensive invasion of organoid-derived trophoblasts into the decidual stroma and spiral arteries. In contrast, organoids treated with IFN-, in particular, exhibited markedly reduced invasion within this system. Transcriptome profiling indicated altered expression of several pathways involved in invasion upon cytokine treatment. These findings support the notion that elevated levels of IFN- and TNF- can directly impair trophoblast invasive capacity, potentially contributing to suboptimal placental development and adverse pregnancy outcomes in the context of inflammatory disorders.