Placental Development

To help support and maintain the pregnancy, the placenta must rapidly develop simultaneously with the embryo. The placenta is a transient organ which develops from the trophectoderm of the implanting blastocyst. Maternal blood flows into the placental intervillous space, where solutes (nutrients, oxygen) diffuse across the transporting epithelium to the fetal circulation, while fetal metabolic waste products are removed (Figure 1). The separation of circulations helps to control solute transport, and protect the fetus from toxins. Not only this, but it also protects the fetus from the maternal immune system. The placenta also manipulates maternal physiology through the production of hormones: Human chorionic gonadotropin (hCG), human placental lactogen (hPL) as well as the steroid hormones estrogen and progesterone.

A majority of placental functions are carried out by one tissue, the specialised transporting multinucleate epithelium – the syncytiotrophoblast. Formed from the constant fusion of underlying 'stem-like' cells, cytotrophoblasts, a continous exchange surface is created. To adapt for high rates of diffusion, the placenta has a large surface area through the development of villous tree structures, surrounded by the syncytiotrophoblast (Figure 1).  



The Invasive Syncytiotrophoblast and its Changing Function

Following fertilization and the production of a viable embryo, there is the differentiation of two cell types – those which form the inner cell mass (ICM) (and will become the fetus), and the trophoblast cells that form the trophectoderm surrounding the ICM. Upon day 6 post conception, the blastocyst is released into the uterine cavity from the oviduct where it adheres to the endometrium. The blastocyst migrates to a primed region of the endometrium where it can form the necessary interactions to promote invasion. Pregnancy complications (particularly placenta praevia and accreta) can arise if this adhesion occurs at an inappropriate region of the endometrium.

It is the initial function of the syncytiotrophoblast to remodel the maternal endometrium into which it implants. The syncytiotrophoblast produces large quantities of matrix degrading enzymes, such as MMPs (matrix metalloproteinases), and growth factors, to promote the development of the syncytiotrophoblast and proliferation and fusion of the underlying cytotrophoblast layer.

The syncytiotrophoblast is a multinucleate epithelium which undergoes a constant and controlled process of renewal and apoptosis. Renewal is undertaken by the proliferation, aggregation and fusion of a type of trophoblast ‘stem cell’ located beneath the syncytiotrophoblast, known as cytotrophoblasts. At the start of the pregnancy the syncytiotrophoblast is an invasive tissue however by the end of first month it adopts a new function as a selective transporting epithelium. It is the syncytiotrophoblast which can arguably be considered the most important tissue in supporting and maintaining pregnancy and fetal growth. It has two key functions during pregnancy: it acts as an endocrine tissue and as a specialised transporting epithelium, transporting nutrients and removing waste products to promote fetal growth. To facilitate the transport of nutrients to the fetus, and waste and harmful toxins away from the fetal circulation, a huge variety of transporters are expressed in the syncytiotrophoblast including aquaporins, ion channels, ATP-binding cassette transporters as well as many others.

Disruption to syncytiotrophoblast renewal and apoptosis (or ‘turnover’) has been related to pregnancy pathology, highlighting the importance of this epithelial structure is for a healthy pregnancy. Little is known about the mechanisms underlying the turnover process and so, this is a focus of much placental research.

Villous Tree Formation

To increase diffusion efficiency, the embryo-derived placenta consists of multiple villous tree structures which come into direct contact with the maternal blood. These contain vast fetal capillary networks surrounded by a trophoblast layer of cytotrophoblasts and the multinucleate syncytiotrophoblast.

By days 4 post conception, fluid filled lacunae form within the syncytiotrophoblast, separated by trabaculae. These go on to form the basis of the villous trees. Mesenchymal cells and cytotrophoblast migrate down the trabaculae to the maternal tissue. The mesenchymal cells develop the vasculature within the villous trees. Cytotrophoblast cells, which make contact with the maternal tissue, anchor the villous trees and can differentiate into extravillous cytotrophoblasts – involved in remodelling of the maternal spiral arteries that supply blood to the placenta.

The villous branches form by budding from larger diameter villi:

  • Stem
  • Immature intermediate
  • Mature intermediate
  • Terminal

At the tips of the terminal villi are specialised regions for solute transport known as the vasculosyncytial membrane. Here, the fetal blood vessel forms a sinusoid, pushing against the syncytiotrophoblast and displacing nuclei. There is fusion of the endothelium and syncytiotrophoblast basement membranes, further reducing the diffusion distance to approximately 0.5μm.

Spiral Artery Remodelling

The fluid filled lacunae formed within the syncytiotrophoblast during early pregnancy eventually become the intervillous space into which maternal blood flows at a high volume and low pressure. Maternal blood enters through the spiral arteries which branch off from uterine arteries and transverse the muscular wall of the uterus myometrium and decidua (lining of the uterus, modified for pregnancy). To facilitate the high volume, low pressure blood flow, the spiral arteries must be remodelled; reducing the resistance and increasing the lumen diameter. This process depends on extravillous cytotrophoblasts and leukocytes that promote the migration and apoptosis of the vascular smooth muscle cells.

During the initial step of vascular remodelling, aggregates of extravillous cytotrophoblast plug the vessels and recruit macrophages and another type of immune cells known as Natural Killer cells. Plugging the vessels is a vital stage in vessel remodelling, preventing maternal blood entering the intervillous space at high pressure. Insufficient plugging of the spiral arteries and premature entry of maternal blood into the intervillous space has been linked to pregnancy pathologies such as preeclampsia, possibly through induction of oxidative stress. The maternal leukocytes promote vascular smooth muscle apoptosis. A variety of proteases are also produced to break down the extracellular matrix and disrupt the cell-cell interactions of the vascular smooth muscle cells. Trophoblast cells migrate and replace the maternal vascular endothelium to become endovascular trophoblast. By 11 weeks, blood flow into the extravillous space is established however spiral artery remodelling can still be detected after 18 weeks.

Variation in Placental Development and Structure between Species

The placental structure varies widely between species both in terms of barriers between maternal and fetal circulations and the shape of the interchange region. This is mainly due to the fact that the placenta is relatively new in evolutionary terms. Humans have a discoid haemonochorial villous placenta (Figure 2A), whereby maternal circulation comes into direct contact with the zygote derived trophoblast cells. Solutes between mother and fetus must cross the syncytiotrophoblast and fetal capillary endothelium.

When studying both normal and pathological placental developments, mice models are often used. In some aspects this is a less than perfect model for comparison with human placental physiology as the murine placenta is somewhat different, however there are also many similarities, making them a useful model. Mice have a discoid haemotrichorial placenta (Figure 2B) where a three layers of trophoblast separate maternal blood from fetal vessels. The exchange region of the mouse placenta is known as the labyrinth zone and is analogous to the human villous placenta; maternal blood flows at low pressure and high volume into the blood spaces of the labyrinth, coming into direct contact with embryo-derived trophoblast. In humans, the trophoblast layer in contact with maternal blood is a single syncytiotrophoblast layer with underlying cytotrophoblasts. In the mouse, there are two syncytiotrophoblast layers with a underlying layer of single trophoblast underneath.

Despite the differences, the mouse models have been incredibly useful when looking at placental development, function and pathologies.. Much of this research has shown that that the signalling molecules and transcription factors important in murine placental development and function are conserved in the human placenta. The development of the murine placenta displays many similarities to human placental development, such as hypoxic intervillous spaces before a certain stage of the pregnancy. Correlating events of placental development between the two classes of placenta helps to support the fact that some of the same mechanisms may be involved in both. It must also be noted that mice make excellent models due to the relative ease to create genetically manipulated colonies and breed large numbers.



References

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Harris L.K. 2010, 'Review: Trophoblast-Vascular Cell Interactions In Early Pregnancy: How To Remodel A Vessel.', Placenta, 31 Suppl, , p. S93-8.

Harris L.K., Smith S.D., Keogh R.J. et al. 2010, 'Trophoblast- And Vascular Smooth Muscle Cell-Derived Mmp-12 Mediates Elastolysis During Uterine Spiral Artery Remodeling.', Am J Pathol, 177, , pp. 2103-2115.

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Jiang B., Zhao W., Yuan J. et al. 2012, 'Lack Of Cul4B, An E3 Ubiquitin Ligase Component, Leads To Embryonic Lethality And Abnormal Placental Development', PLoS One, 7, , p. e37070.

Longtine M.S., Chen B., Odibo A.O. et al. 2012, 'Caspase-Mediated Apoptosis Of Trophoblasts In Term Human Placental Villi Is Restricted To Cytotrophoblasts And Absent From The Multinucleated Syncytiotrophoblast.', Reproduction, 143, , pp. 107-121.

Senner C.E.& Hemberger M. 2010, 'Regulation Of Early Trophoblast Differentiation - Lessons From The Mouse', Placenta, 31, , pp. 944-950.

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