Trophoblasts, the specialized cells of the placenta, play a major role in implantation and formation of the maternal-fetal interface. Through an unusual differentiation process examined in this review, these fetal cells acquire properties of leukocytes and endothelial cells that enable many of their specialized functions. In recent years a great deal has been learned about the regulatory mechanisms, from transcriptional networks to oxygen tension, which control trophoblast differentiation. The challenge is to turn this information into clinically useful tests for monitoring placental function and, hence, pregnancy outcome.

In some societies the critical importance of the placenta in determining pregnancy outcome is acknowledged by its special treatment after birth. For example, the Malay people bury placentas in prominent locations near their homes, a symbolic act in recognition of the fact that the placenta is an essential in utero companion of the baby. We now know that this prescient ritual reflects an important reality. During the last decade and a half, numerous studies in transgenic mice have shown that placentation is a critical regulator of embryonic and fetal development. For example, inactivation of the retinoblastoma (Rb) tumor suppressor gene in mice resulted in unscheduled cell proliferation, apoptosis, and widespread developmental defects that eventually led to embryonic death. Careful analysis of the placenta showed numerous abnormalities, including disruption of the transport region where nutrient, waste, and gas exchange occurs and a decrease in vascularization. When conditional knockout and tetraploid rescue strategies were used to supply Rb-null embryos with wild-type placentas, the animals survived to term; the neurological and erythroid abnormalities that were thought to lead to the intrauterine demise of the pups were abrogated (1). Thus, Rb function in the murine extraembryonic lineages is required for normal differentiation of cells within the embryo. The principle that embryonic and placental development are tightly linked has been strongly reinforced by studies in the burgeoning field of life-course epidemiology and has led to the proposal of the “developmental origins hypothesis”: adult medical conditions such as cardiovascular disease and type 2 diabetes originate in response to undernutrition either in utero or during infancy and early childhood (2). Given that the placenta is an important regulator of fetal growth before birth, it is likely that a subset of the initiating events that eventually lead to the aforementioned diseases will be traced to faulty placentation at structural and/or functional levels (S1).