IFPA 2004 Award in Placentology LectureHow to make a placenta: Mechanisms of trophoblast cell differentiation in mice – A Review
Introduction
The last 10 years have seen a rapid evolution in our understanding of placental development. This has been driven in part by experimental embryology and the development of new culture systems that facilitate a cellular level of understanding, but also by the use of molecular biology and genetic approaches for the discovery of individual molecular pathways that are essential for development. The application of transgenic and gene knockout techniques in mice in particular has changed the face of our knowledge. Whereas we knew of less than five genes that were essential for placental development in 1994 [1], there are now over 100 (Table 1). While the functions of individual genes are interesting in their own ways, this article will review some of the remaining fundamental questions about placental development that my laboratory has been interested in trying to answer using the mouse as a model system:
- (1)
What are the cell types that make up the placenta and what is the cell lineage that underlies their formation? Anatomical descriptions have in large part described many of the cell types that make up the placenta and it is clear that there are a number of differentiated trophoblast cell subtypes that make up the placenta. In addition, though, molecular biology and studies that have localized gene expression patterns in the placenta have sometimes demonstrated that the repertoire of trophoblast cell subtypes is more complex than originally thought. Addressing how these diverse cell subtypes arise during development is difficult and often our understanding of how the single layered trophectoderm in the blastocyst diversifies into range of cell trophoblast subtypes in the mature placenta is incomplete or based on indirect evidence.
- (2)
How is the identity of different trophoblast cell subtypes determined during development, and are the molecular pathways conserved evolutionarily? Based largely on the analysis of knockout mice as well as gene mis-expression studies in trophoblast stem cells, it is now possible to describe most of the cell differentiation steps underlying mouse placental development in molecular terms. Unfortunately, there are only a limited number of studies that address whether the genes that are important for placental development in mice are likely to have a similar function in other species. However, human homologues for many of the genes are expressed in a pattern at least consistent with a conserved role [2]. Such studies have also helped to make comparisons between cell types across species, which has been a significant advance over comparative anatomy alone.
Section snippets
Trophoblast cell subtypes and their developmental origins in mice
After implantation, the simple trophectoderm surrounding the blastocyst goes on to differentiate into a variety of trophoblast cell subtypes each with specific functions (Figure 1). Much of our knowledge about the cell lineage – going from multi-potent trophoblast stem cells to the various differentiated trophoblast subtypes – is based on indirect studies. Trophoblast stem cells emerge from the polar trophectoderm that overlies the inner cell mass in the blastocyst. They proliferate in response
Molecular mechanisms regulating differentiation of alternative trophoblast cell subtypes in mice
Through gene knockout and transgenic studies in mice, as well as in vitro experiments in which genes have been mis-expressed, we now have a fairly long list of the genes/proteins that are important for development of the placenta. One of the important conclusions to emerge from these studies is that differentiation of alternative trophoblast cell subtypes is regulated by distinct molecular mechanisms (Table 1). In most cases, however, the individual genes have not been put into complete
Conclusions
Our understanding of placental development and of the molecules that regulate it has improved dramatically in the last decade. These studies have revealed several general conclusions. First, it is clear that development of the placenta occurs by progression through stereotypical steps. Second, we now know of several key molecular regulators underlying each step. This allows us to piece together the more complete picture through subsequent studies of identifying the upstream and downstream
Acknowledgments
I want to sincerely thank a long line of talented people who have worked in my lab as well as key collaborators who have contributed to my work on placental development over the last 10 years including Lee Adamson, Fran Allen, Lynn Anson-Cartwright, Tyler Davies, Kerri Dawson, Susan Fisher, Amanda Fortier, Colleen Geary, Naka Hattori, Myriam Hemberger, Martha Hughes, Patricia Hunter, Yong Lu, John Kingdom, Haruo Nakano, Hiroki Nakayama, David Natale, Paul Riley, Ian Scott, David Simmons, Maja
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2022, Seminars in Cancer BiologyCitation Excerpt :The resulting polyploid cells exist as multinucleated blastomeres in the developing embryo [10–13]. Polyploidization is also inherent to the developing placenta, as villous trophoblasts fuse to form multinucleated syncytiotrophoblasts and as trophoblast stem cells differentiate by endoreplication into trophoblast giant cells, which are vital for placenta growth, implantation of the conceptus into the uterus, lactogenesis, regulation of maternal blood flow, and synthesis of cytokines and hormones like progesterone [14–16]. Polyploidization is also seen in megakaryopoiesis, where megakaryoblasts perform endomitosis to mature into megakaryocytes.
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2022, Seminars in Cancer BiologyCitation Excerpt :The epiblasts then undergo epithelial to mesenchymal transition to generate ectoderm, mesoderm, and endoderm, which develop into various fetal and adult organs. The extraembryonic trophectoderm invades into the uterus and develops into the placenta, which supports the growth of embryonic and fetal life [44,45]. The trophectoderm is composed of giant cells with multiple copies of the genome.