An engineered human placental organoid microphysiological system in a vascular niche to model viral infection.

The placenta forms the maternal-fetal interface to protect the developing fetus from xenobiotics or pathogens. However, the understanding of complex placental features and responses to pathogens are hindered due to the lack of near-physiological models. Here, we present an engineered human placental organoid microphysiological system (MPS) incorporated with vascular endothelium, which allows to recapitulate early placental features in a vascular niche. The MPS comprises a customized insert-based organ chip and a rocker, enabling in situ differentiation and formation of placental organoids from human trophoblast stem cells under dynamic culture conditions. By incorporating vascular endothelium, trophoblast organoids (TOs) maintain improved cell viability, long-term trophoblast proliferation and differentiation. Moreover, trophoblast organoids cocultured with endothelium (EndTOs) show the activation of innate immune-related signaling pathways and high-level secretion of distinct immunomodulatory factors, including antiviral type I and III interferons and trophoblast-specific factors. We further demonstrate that EndTOs exhibit attenuated susceptibility to Zika virus (ZIKV) than single cultured TOs, indicating the crucial role of vascular niche in enhancing intrinsic antiviral defenses functions of trophoblasts. This bioinspired placental organoid MPS provides a useful platform for studying placental physiology and relevant diseases.