The human gestational sac as a choriovitelline placenta during early pregnancy; the secondary yolk sac and organoid models

The yolk sac is phylogenetically the oldest of the extra-embryonic membranes and plays important roles in nutrient transfer during early pregnancy in many species. In the human this function is considered largely vestigial, in part because the secondary yolk sac never makes contact with the inner surface of the chorionic sac. Instead, it is separated from the chorion by the fluid-filled extra-embryonic coelom and attached to the developing embryo by a relatively long vitelline duct. The coelomic fluid is, however, rich in nutrients and key co-factors, including folic acid and anti-oxidants, derived from maternal plasma and the endometrial glands. Bulk sequencing has recently revealed the presence of transcripts encoding numerous transporter proteins for these ligands. Mounting evidence suggests the human secondary yolk sac plays a pivotal role in the transfer of histotrophic nutrition during the critical phase of organogenesis but also of chemicals such as medical drugs and cotinine. We therefore propose that the early placental villi, coelomic cavity and yolk sac combine to function physiologically as a choriovitelline placenta during the first weeks of pregnancy. We have derived organoids from the mouse yolk sac as proof-of-principle of a model system that could be used to answer many questions concerning the functional capacity of the human yolk sac as a maternal-fetal exchange interface during the first trimester of pregnancy.