Trophoblast Syncytialization: A Metabolic Crossroads

During placentation, villous cytotrophoblast (CTB) stem cells proliferate and fuse, giving rise to the multinucleated syncytiotrophoblast (STB), which represents the terminally differentiated villous layer as well as the maternal-fetal interface. The syncytiotrophoblast is at the forefront of nutrient, gas, and waste exchange while also harboring essential endocrine functions to support pregnancy and fetal development. Considering that mitochondrial dynamics and respiration have been implicated in stem cell fate decisions of several cell types and that the placenta is a mitochondria-rich organ, we will highlight the role of mitochondria in facilitating trophoblast differentiation and maintaining trophoblast function. We discuss both the process of syncytialization and the distinct metabolic characteristics associated with CTB and STB sub-lineages prior to and during syncytialization. As mitochondrial respiration is tightly coupled to redox homeostasis, we emphasize the adaptations of mitochondrial respiration to the hypoxic placental environment. Furthermore, we highlight the critical role of mitochondria in conferring the steroidogenic potential of the STB following differentiation. Ultimately, mitochondrial function and morphological changes centrally regulate respiration and influence trophoblast fate decisions through the production of reactive oxygen species (ROS), whose levels modulate the transcriptional activation or suppression of pluripotency or commitment genes.