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

Proper placental development requires extravillous trophoblast (EVT) differentiation and invasion into the maternal decidua to remodel spiral arteries and support fetal growth. Disruptions in these processes contribute to preeclampsia and fetal growth restriction. These pregnancy complications are common in women with immune-mediated inflammatory diseases, which are characterized by elevated levels of pro-inflammatory cytokines such as interferon-α (IFN-α) and tumor necrosis factor-α (TNF-α). However, the direct effects of these cytokines on EVTs remain unclear. Using human trophoblast organoid models, we demonstrate that IFN-α and TNF-α impair EVT invasion while preserving differentiation capacity. High-resolution imaging of untreated organoid-decidua co-cultures revealed extensive trophoblast invasion into decidual stroma and arteries, but invasion was substantially reduced particularly upon IFN-α treatment. Transcriptome profiling identified changes in several invasion-related pathways after cytokine exposure. These findings suggest that elevated IFN-α and TNF-α can directly impair trophoblast invasive capacity, potentially contributing to suboptimal placental development in inflammatory disorders.