The placenta is an organ essential for the normal development of the fetus and maintenance of a healthy pregnancy. This organ provides a connection between the developing fetus and the uterine wall, allowing vital exchanges such as nutrient uptake, waste elimination and gas exchange to occur via the maternal blood circulation. In addition, during pregnancy, the placenta is an important source for peptide and steroid hormone secretion, and it has a significant role in preventing the rejection of the fetal allograft.
This feto-maternal organ can be separated into two divisions: the fetal placenta (Chorion frondosum) and the maternal placenta (Decidua basalis). The fetal placenta develops from the same blastocyst as the fetus, and the maternal uterine tissue gives rise to the maternal placenta. Here we will look at the various stages of placental development, and discuss the importance of placental hormone production in relation to the endocrine changes that occur during pregnancy.
Implantation and Invasion
Figure 1 | Blastocyst implantation: (a) Apposition; Adhesion of the blastocyst with the decidua (purple). (b) Cytotrophoblast proliferation during invasion (c) to form an invasive multinucleated syncytiotrophoblast (ST) (Kay et al. 2011).
Placental and fetal development begins at the time of fertilisation. The fertilized egg traverses the Fallopian tube, and undergoes numerous mitotic divisions, leading to the formation of the morula, a solid mass of blastomere cells. This ball of cells enters the uterus four days after fertilisation and on the fifth day it accumulates fluids and undergoes polarization, giving rise to a blastocyst.
The outer layer of the blastocyst consists of a layer of cells known as the trophoblast. The trophoblast cells form the placenta and fetal membranes, while the inner cell mass of the blastocyst forms the embryo. The continual division of the inner & outer cell masses and enlargement of the fluid cavity leads to the hatching of the expanded blastocyst out of the zona pellucida. Initially the uterine secretions fulfil blastocyst’s metabolic and oxygen needs, but these secretions are not adequate for supporting the long term development of the fetus and the placenta. Thus, by implanting into the uterine lining, the blastocyst gains access to vital substrates (glycogen filled stromal cells) necessary for continued development (Roberts & Myatt 2012).
During implantation, the blastocyst migrates to an optimal location within the uterus, after which it starts the process of adhesion (FIG. 1-(a)) and invasion of the uterine wall. The invading cells invade deeper into the decidua to penetrate the uterine epithelium and reside in the decidua (FIG. 1-(b)), during this process small vacuoles form. By day 13 after fertilisation, these vacuoles coalesce and go on to become lacunae (FIG. 1-(c)). Ultimately the lacunar space becomes the intervillous space in the chorioallantoic placenta, where maternal blood will circulate, and from which the fetus will receive nutrients.
Figure 2 | Anchoring of the conceptus at the level of decidua is dependent on the interstitial EVT’s invasion of the decidua and myometrium. Endovascular EVTs can either act within the vessel wall (intramural) or act to replace the endothelium (intra-arterial) in their quest to transform narrow spiral arteries (adapted from Roberts & Myatt 2012).
The progenitor cytotrophoblast cell is the stem cell that gives rise to the placenta. The cytotrophoblast cells differentiate along one of two possible ways to become either villous cytotrophoblast or extravillous cytotrophoblast. The villous cytotrophoblast later goes on to become syncytiotrophoblasts (outer epithelial covering of the vascular embryonic placental villi), whereas the extravillous cytotrophoblast (inner cellular layer) has a more diverse path of differentiation (FIG. 2). The syncytiotrophoblast carries out key functions such as gas exchange, nutrient transport, waste disposal and secretion of a variety of peptide and hormones necessary for normal regulation of placental, fetal and maternal systems.
The extravillous trophoblast (EVT) has different components: the invasive, the proliferative and the migratory. The proliferative and the invasive EVT form the base and the distal portion of columns of erupted EVT respectively; these EVT columns then go on to invade the decidua or invade and remodel the spiral arteries (Kam et al. 1999). Decidua invading EVT is called interstitial EVT, and endovascular EVT is what’s used to address the invading EVT that remodel spiral arteries.
During endovascular invasion, the vascular smooth muscle cells and endothelial cells are replaced/displaced, and the narrow spiral arteries are transformed into wide uteroplacental arteries (Roberts & Myatt 2012). The connections between the dilated spiral arteries and endometrial veins result in the formation of maternal sinusoids, which consequently allow blood to enter the low resistance vascular network of the lacunar system, consequently marking the beginning of the uteroplacental circulation.
At different stages of EVT invasion, there are specific proteins expressed by these cells, which are essential for differentiation and regulation of invasion. For example, the invasion of the decidua and myometrium by EVT requires degradation of the extracellular matrix, to allow this several members of the metalloproteinase (MMPs) family are employed; these cells themselves are regulated by their tissue inhibitors (TIMPs) such as TIMP-2 which has been detected in decidual cells and EVT; The decidua blocks any uncontrolled EVT invasion through secretion of factors such as protease inhibitors, thus modulating trophoblast invasion (Benirschke et al. 2012).
In the early stages of gestation the trophoblast shell plugs the terminal points of the uteroplacental vessels. This results in the placental tissue to develop in a low oxygen environment; where it’s supported by histiotrophic nutrition (Hustin & Schaaps 1987; Burton et al. 2001). Histotroph is the nutrient secreted by the decidual endometrial glands, which occupy the void between the maternal and fetal tissues. The environment created by the histotroph is thought to actively protect the developing embryo from potential harms of oxygen free radicals, including teratogenesis (Burton et al. 2003).
The formerly mentioned trophoblast plugs are displaced at around 10 – 14 weeks of gestation allowing blood to flow into the intervillous space, thus allowing hemotrophic nutrition to take place; in other words, it allows gas and nutrient exchange between the maternal and the fetal circulations. However, this transition results in a higher blood flow which also leads to elevated intraplacental oxygen concentration; this increase in oxygen concentration leads to an oxidative stress, and depending on its severity it may even lead to miscarriages in some pregnancies (Jauniaux et al. 2000) (Burton & Jauniaux 2004) .
Oxygen is also found to influence trophoblast invasion, such that factors involved in inhibition of invasion such as TGF-β3 and hypoxia-inducible factor 1 are both present at high levels during the first trimester of pregnancy, when there is low placental oxygen tension and trophoblast invasion happening. But consequently the expression of these transcription factors fall during 10-12 weeks of gestation, when the blood flow to the intervillous space is established and oxygen tension rises, thus reducing trophoblast invasion. This observation is also replicated in in vitro studies where hypoxic conditions promote trophoblast differentiation to follow the EVT pathway (Caniggia et al. 2000).
Villous Development
Figure 3 | Early villous development: formation of primary (a), Secondary (b) and tertiary (c) villi (adapted from Benirschke et al. 2012).
Early villous development involves the invasion of cytotrophoblasts into columns of syncytiotrophoblast trabeculae. During the second week of placental development, a primary villus is formed by the evagination of a layer of syncytiotrophoblast with a core of cytotrophoblast into the lacunar spaces (FIG 3 (a)). As development proceeds, the inner cores of the primary villi are occupied by embryonic mesoderm; this transformation leads to the formation of secondary villi (FIG 3 (b)). A tertiary villus (mesenchymal villi) is formed through the differentiation of embryonic mesoderm into blood vessels, which consequently connect to the developing vessels of the umbilical cord and the embryo (FIG 3 (c)). By the end of the 4th week post-conception, all of the placental villi have differentiated into tertiary villi. The villi can take on different positions, such that some remain anchored to the maternal decidua, whilst others roam freely in the lacuna. Moreover, owing to the placental barrier (layer of trophoblast), the maternal and the embryonic circulation are always kept separate from each other.
The placental villi of the first trimester are enveloped by a continuous layer of cytotrophoblast cells (the Langhans layer), which actively contribute daughter cells to the overlying syncytiotrophoblast. Later in gestation, the numbers of villous cytotrophoblasts decline, whereas the syncytiotrophoblast reaches a surface area of around 13 m2. The turnover of this continuous syncytium (syncytiotrophoblast) is maintained by the fusion of the underlying villous cytotrophoblasts and programmed cell death (apoptosis). In humans, syncytin (human derived retrovirus HERV-W-derived protein) is expressed in high levels in the syncytiotrophoblast and has been shown to regulate the rate of cytotrophoblast fusion as well as syncytialisation of the trophoblast (Mi et al. 2000). It has been shown that reduced levels of syncytin are associated with abnormal protein localisation during cell fusion and disturbed placental function in hypertensive disorders of pregnancy (Mi et al. 2000) (Lee et al. 2001).
Vascular Development
Figure 4 | Schematic representation of the villous tree and the branching villi. Also displaying the rise of the terminal villi from the intermediate villi (Kay et al. 2011).
As gestation continues, the numbers of blood vessels occupying the placenta escalate to allow adequate transport of nutrients for optimal development of the fetus. Human placental vascular development can be divided into three phases of: vasculogenesis, branching angiogenesis and non-branching angiogenesis. The two umbilical arteries and the vein undergo various rounds of divisions, primarily resulting in networks of secondary and consequently tertiary vessels prior to their entrance into the main stem villi, which itself originates from the chorionic plate.
Further division of these vessels results in the formation of the intermediate villi (rami chordii) and more division result in even finer vascular branches (ramuli chorii). Amongst the ramuli chorri, some find their way towards the terminal villi and terminate there. The terminal villi are the “functional units of exchange” (Burton et al. 2001), and form the final branches of the villous tree (FIG. 4). The terminal villi are most noticeable in the last trimester, where there close proximity to the maternal blood and high ratio of surface to cross-section area allows for optimal nutrient and gas exchange. In addition the capillaries of terminal villi often form capillary loops and sometime sinusoids, which are though to be for reducing resistance and slowing down the flow, so that there is more time for vital exchanges to occur.
Placental Hormone Secretion
Due to placenta’s lack of innervation, any communications between this organ, the mother and the fetus must be relayed via humoral agents. This means that the placenta secretes signaling molecules, which act locally via autocrine and paracrine regulation. Most importantly, the placenta acts as an endocrine organ, secreting hormones into maternal and fetal circulation. These secretions can be divided into two categories of peptide and steroid hormones.
The peptide hormone category of placental secretions are mainly produced by the trophoblast of the chorionic villi and include: human chorionic gonadotrophin (hCG), human placental lactogen (hPL), growth hormone (GH), corticotropin releasing hormone (CRH), cytokines, insulin-like growth factors (IGFs), Vascular endothelial growth factor (VEGF) and placental growth factor (PGF).
HCG is a glycoprotein with close structural resemblance (shared the same alpha subunit) to LH, FSH and TSH. HCG is secreted by the syncytiotrophoblast and plays a key role in preventing the involution of the corpus luteum, so that it continues to produce progesterone. HCG levels escalate throughout the first 8 weeks of gestation, and after reaching its peak level during this period, it dramatically falls to a low steady state, this usually occurs around week 13, since at this stage the placenta itself is capable of producing adequate amounts of progesterone for supporting pregnancy.
HPL is a trophoblast synthesized peptide hormone. Its principal role includes the up-regulation of glucose supply to the fetus by breaking down the maternal stores of fatty acid by altering the levels of insulin secretion in the mother. Interestingly, it has been shown that hPL deficient women who have successful pregnancies have higher levels of “compensatory prolactin” (Freemark 2006).
In addition to secreting hCG, the syncytiotrophoblast also synthesizes CRH. CRH is a 162 amino acid peptide, which is thought to be involved in stimulating adrenocorticotropin (ACTH) release, which results in the release of prostaglandins and cortisol. Placental CRH expression is stimulated by glucocorticoids, but interestingly the same glucocorticoids have inhibitory effects on hypothalamic CRH. Both estrogen and progesterone also inhibit CRH expression. Throughout gestation CRH levels increase, but they are bound by CRH binding protein (CRHBP) produced by the liver, such that they cannot affect maternal pituitary, however, near term CRHBP levels fall, making unbound CRH more available; Given the effects of CRH on prostaglandin secretion, this is thought to be important for the onset of labor.
CRH has been previously dubbed as the “placental clock”. This title stems from the observation that women with idiopathic pre term labor often have very rapid surge in CRH levels. CRH in the fetal circulation is thought to drive increased cortisol production, aid fetal lung maturation and may also act as a vasodilator of the fetal-placental circulation (Clifton et al. 1994; Wadhwa et al. 2004).
Since placenta is a highly vascular organ, it produces many angiogenic factors to allow vasculogenesis. One such angiogenic factor is VEGF. VEGF is synthesized in villous trophoblast and macrophages. VEGF acts via two receptors: VEGF-R1 and VEGF-R2. These receptors are found in the villous vascular endothelium (Charnock-Jones et al. 1994), and VEGF is thought to act via these receptors in the placenta to facilitate branching angiogenesis.
In addition, PGF, a member of the VEGF subfamily, is primarily produced in villous syncytiotrophoblasts (Khalil et al. 2008) during pregnancy, and acts via the VEGF receptors R1 & R2 to possibly take part in late gestation non-branching angiogenesis. Furthermore, oxygen tension seems to be a regulator of VEGF and PGF levels, such that hypoxic conditions in the trophoblast result in increased VEGF and decreased PGF levels (Shore et al. 1997).
Furthermore, the placenta is an important source of progesterone production. This hormone is initially produced by the corpus luteum to prepare the endometrium for conceptus implantation; however, usually after the 8th week of gestation, the luteo-placental shift takes place, after which the placenta takes over progesterone production from the ovary. Progesterone is essential for maintenance of uterine quiescence (Kallen 2004); also owing to the anti-inflammatory and immunosuppressive functions of progesterone, it has been postulated to be important in preventing immunological rejection of the conceptus by the mother’s immune system (Kallen 2004).
The placenta also produces estrogen, however this is dependent on the production of the precursor dehydroepiandrosterone-sulfate (DHEA-S) by the fetal and maternal adrenal glands. Estrogen has been associated with up regulation of proteins needed for continued progesterone production as well as steroid metabolism. It has also been shown to affect uterine blood flow and more importantly it is involved in preparing the breast for lactation (Kallen 2004).
Conclusion
The placenta is a multifaceted organ that is essential for maintaining and protecting the developing fetus. In addition to placenta’s role as an exchange medium between the mother and the fetus, it also acts as an important endocrine organ for regulating various aspects of hormonal regulation during pregnancy.
After fertilization, the development of the placenta involves the differentiation and transformation of a variety of cells, of which the trophoblast cells are of key importance. Various phenotypes of trophoblast exist, with each performing specific functions in the placenta. These functions range from the invasion of the decidua by the interstitial trophoblast to the transformation of the spiral arteries by the actions of the endovascular trophoblast.
Further investigations into the developmental and structural features of the placenta will not only extend our understanding of placental functions, but will also allow us to better interpret the observations from abnormal pregnancies where there is compromised placental function.
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