Placental cytotrophoblast microvillar stabilization is required for cell-cell fusion

The placenta is an essential organ of pregnancy required for maternal-fetal transport and communication. The surface of the placenta facing the maternal blood is formed by a single giant multinucleate cell: the syncytiotrophoblast. The syncytiotrophoblast is formed and maintained via fusion of progenitor cytotrophoblasts. Cell-cell fusion is a tightly regulated process, and in non-trophoblastic cells is accompanied by stereotypical alterations in cell shape by cells that have attained fusion-competence. The most prominent feature is the formation of actin-based membrane protrusions, but whether stereotypic morphological changes occur in fusion-competent cytotrophoblasts has not been characterized. Using a human placental explant model and trophoblast organoids, we identify apical microvilliation as an obligate morphological feature of fusion-competent cytotrophoblasts. Disruption of microvilli using an inhibitor of the actin-membrane cross linker protein ezrin prevented cytotrophoblast fusion and differentiation. We provide evidence that these polarized apical microvillar domains function to regulate polarized endocytosis and to spatially localize and accumulate a key glycoprotein for fusion, CD98. Thus, we propose that the polarized assembly of microvillar domains is critical for mediating efficient syncytiotrophoblast development.