The placenta: epigenetic insights into trophoblast developmental models of a generation-bridging organ with long-lasting impact on lifelong health

The placenta is a unique organ system that functionally combines both maternal and fetal cell types with distinct lineage origins. Normal placentation is critical for developmental progression and reproductive success. Although the placenta is best known for its nutrient supply function to the fetus, genetic experiments in mice highlight that the placenta is also pivotal for directing the proper formation of specific fetal organs. These roles underscore the importance of the placenta for pregnancy outcome and lifelong health span, which makes it essential to better understand the molecular processes governing placental development and function and to find adequate models to study it. In this review, we provide an overview of placental development and highlight the instructional role of the epigenome in dictating cell fate decisions specifically in the placental trophoblast cell lineage. We then focus on recent advances in exploring stem cell and organoid models reflecting the feto-maternal interface in mice and humans that provide much-improved tools to study events in early development. We discuss stem cells derived from the placenta as well as those artificially induced to resemble the placenta, and how they can be combined with embryonic stem cells and with endometrial cell types of the uterus to reconstitute the early implantation site. We then allude to the exciting prospects of how these models can be harnessed in biomedicine to enhance our understanding of the pathological underpinnings of pregnancy complications in a patient-specific manner, and ultimately to facilitate therapeutic approaches of tissue- and organ-based regenerative medicine.