Abstract
Although recently developed placenta-on-chip systems opened promising perspectives for placental barrier modeling, they still lack physiologically relevant trophoblasts and are poorly amenable to high-throughput studies. We aimed to implement human-induced pluripotent stem cells (hiPSC)-derived trophoblasts into a multi-well microfluidic device to develop a physiologically relevant and scalable placental barrier model. When cultured in a perfused micro-channel against a collagen-based matrix, hiPSC-derived trophoblasts self-arranged into a 3D structure showing invasive behavior, fusogenic and endocrine activities, structural integrity, and expressing placental transporters. RNA-seq analysis revealed that the microfluidic 3D environment boosted expression of genes related to early placental structural development, mainly involved in mechanosensing and cell surface receptor signaling. These results demonstrated the feasibility of generating a differentiated primitive syncytium from hiPSC in a microfluidic platform. Besides expanding hiPSC-derived trophoblast scope of applications, this study constitutes an important resource to improve placental barrier models and boost research and therapeutics evaluation in pregnancy.