The placenta, mediating maternal-fetal interaction, is the first organ to form during mammalian development. By providing an environment for maternal-fetal oxygen, nutrients and waste exchange, the placenta ensures the survival as well as long-term health of the fetus. The placenta also protects the fetus from maternal immune responses and is an important source for pregnancy dependent hormones and growth factors. Disruption of placental development causes placental insufficiency, which results in fetal growth restriction and death. In humans, placental deficiency can cause fetal and maternal abnormalities including miscarriage, intrauterine growth restriction (IUGR), gestational diabetes and pre-eclampsia. The genetic pathway of human placental development and disease is not well understood due to the limitation of human materials and the restriction for the use of human as an experimental system. However, the short gestation time and available genetic tools make the laboratory mouse an excellent model system for studying placental development. Another major benefit is the availability of mouse trophoblast stem cells. These stem cells can be derived from embryos and facilitate the investigation of molecular mechanisms underlying placental development.
The cell types and architecture of human and mouse placentas are slightly different, but functionally analogous. The trophoblasts derived from the outer cell layer of a blastocyst develop into several specialized subtypes. These different trophoblast lineages are responsible for altering maternal physiology, promoting blood flow to the implantation site and nutrient uptakes. In mice, three distinct trophoblast layers begin to be established at embryonic day (E) 10.5. The outermost trophoblast giant cell (TGC) layer forms a boundary between the maternal and fetal tissues. The intermediate layer is composed of spongiotrophoblasts that support placental structure. The innermost labyrinth layer is responsible for maternal-fetal interaction.
In mice, formation of the labyrinth layer starts at -E8.5 when the allantois attaches to the chorion. The allantoic mesoderm begins to invade the chorion and generate primary branches, which are aligned by thin and elongated trophoblast cells. The primary branches further elongate and undergo branching morphogenesis to form the mature fetal vascular system. Along with endothelial morphogenesis, the trophoblast cells differentiate and give rise to three sublayers separating the maternal blood sinus and fetal vasculature. The mononuclear cytotrophoblasts form a discontinuous layer surrounding the maternal blood cells. Two layers of multi-nucleated syncytiotrophoblasts, resulting from cell-cell fusion, reside between the mononuclear trophoblasts and fetal capillaries. The three trophoblast sublayers were thought to be derived from trophoblast precursors at different regions of the chorion. However, there is a lack of lineage tracing study to actually support this theory. The maternal vascular system is established by trophoblast-lined sinusoids, instead of endothelial cells, after maternal blood enters the trophoblast giant cell layer. The mechanism by which trophoblasts replace endothelial cells remains elusive.
The molecular mechanism underlying labyrinth trophoblast differentiation and vascular formation is not well understood. Deletion of glial cell missing 1 (Gcml) in mice revealed its requirement for proper labyrinth development. Gcml transcription factor is expressed in the chorion trophoblast cell clusters with a scattered pattern one day before chorioallantoic fusion. The Gcml-expressing cell clusters determine chorionic folding and branching sites, where allantoic mesoderm invades. Gcml ex
The spongiotrophoblast layer is a compacted cell layer providing structural support for the placenta. However, the physiological role of the spongiotrophoblast layer is not clear. Spongiotrophoblasts develop from precursor cells residing in the ectoplacental cone. Mouse genetic studies suggest that spongiotrophoblasts and TGCs are derived from a common precursor population in the ectoplacental cone. For example, mammalian achaete-scute homologue 2 (Mash2), expressed in the ectoplacental cone, is required for spongiotrophoblast development. Deletion of Mash2 results in an expansion of TGCs and loss of spongiotrophoblasts. Several other genes (such as choroideremia, Cx31 and Keratin8/19) also have opposing roles in the development of spongiotrophoblasts and TGC, further supporting this theory.
Trophoblast giant cells arise from two precursor populations in two distinct phases of development. During implantation, the primary TGCs arise directly from the mural trophectoderm of the blastocyst while the secondary TGCs arise from the polar trophectoderm-derived ectoplacental cone at later stages. Primary and secondary TGCs are morphologically indistinguishable and express several genes in common (i.e., PL-I and PLF). However, several reports showed differential gene ex