Roles of Trophoblast Differentiation, Cell Fusion, and Microvilli Formation in Placentation and Prospects for a Model for Their Assessment

The placenta, which acts as an interface between fetal and maternal circulations, is an indispensable organ for fetal growth in mammalian pregnancy. It mediates the transportation of nutrients, the exchange of gases such as oxygen and carbon dioxide, and the excretion of waste products between the fetus and mother. The surface of placental villi is covered by two layers of mononuclear undifferentiated cytotrophoblasts (CT) and multinucleated syncytiotrophoblasts (ST). The formation of the multinucleated ST layer via fusion of CT is referred to as syncytialization, which is a well-characterized morphological sign of terminal differentiation. STs function not only as the placental barrier to separate maternal blood from fetal tissue but also as the main source of human chorionic gonadotropin (hCG) and progesterone (P4) during pregnancy. The significance of appropriate differentiation and fusion of CTs to form STs is demonstrated by the finding that disturbance of these processes is linked to the pathogenesis of pregnancy-associated complications such as hypertensive disorders of pregnancy (HDP) and fetal growth restriction (FGR). In this review, we focused on trophoblast differentiation, cell fusion and microvilli formation, and showed the role of short-chain fatty acid butyrate and progesterone receptor membrane component 1 (PGRMC1) in these processes. Furthermore, we described the evaluation of placental function and its prospects utilizing a quantitative trophoblast cell fusion system and microfluidic device.