Elsevier

Placenta

Volume 26, Supplement, April 2005, Pages S3-S9
Placenta

IFPA 2004 Award in Placentology Lecture
How to make a placenta: Mechanisms of trophoblast cell differentiation in mice – A Review

https://doi.org/10.1016/j.placenta.2005.01.015Get rights and content

The word placenta is derived from the Latin term meaning ‘flat cake’. Despite the rather humble name, the placenta is an amazing organ that forms both the interface for selective delivery of nutrients from the mother to the fetus and also re-directs maternal metabolic, endocrine, cardiovascular and immune functions to promote fetal survival and growth. These two functions are fulfilled by different specialized trophoblast cell subtypes, and my laboratory has been studying how their formation and functions are regulated during placental development. Through molecular studies in cultured cells and tissues, genetic studies in mice, and comparative analysis of placentas from humans, rodents and farm animals, it is now possible to describe molecular pathways that control the development of all major trophoblast cell subtypes and structures of the placenta. The work has revealed an intricate complexity of cell–cell interactions, environmental factors, and molecular networks that control normal development.

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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