Trophoblast Development /Second Week of Development

Trophoblast Development /Second Week of Development

Second Week of Development/Week 2 is often referred to as the week of twos. It’s the week when the embryoblast, extraembryonic mesoderm and trophoblast each separate into two distinct .

Trophoblast Development

Trophoblasts are the outer layer of cells that provide nutrients to the embryo and form part of the placenta.

Key Points

The trophoblast is subdivided into two layers, the inner cytotrophoblast, which proliferates upon implantation, and the outer syncytiotrophoblast, which supports cytotrophoblast proliferation through contact with the maternal blood.

The cytotrophoblast, at the edges of the villi in the placenta, further differentiates into extravillous trophoblasts, which penetrate into the uterus and attach to the placenta and the mother to promote placental vasculature.

Some trophoblasts replace endothelial cells in the uterine spiral arteries and remodel them into wide-bore conduits that are independent of maternal vasoconstriction. This ensures the fetus receives a steady supply of blood, and that the placenta is not sensitive to damaging fluctuations in oxygen.

Key Terms

  • decidualization: The changes in the endometrial lining after ovulation, characterized by its transformation into a secretory lining in preparation to accept an embryo.
  • extravillous trophoblast: These grow out from the placenta and penetrate into the decidualized uterus.
  • trophoblast: The membrane of cells that forms the wall of a blastocyst during early pregnancy, and also provides nutrients to the embryo and later develops into part of the placenta.

Trophoblasts

Trophoblasts (from the Greek words trephein, to feed, and blastos, germinator) are cells that form the outer layer of a blastocyst. These cells provide nutrients to the embryo and develop into a large part of the placenta.

They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg. This layer of trophoblasts is also collectively referred to as the trophoblast, or, after gastrulation, the trophectoderm, as it is then contiguous with the ectoderm of the embryo.

Trophoblast Function

Trophoblasts play an important role in embryo implantation and interaction with the endometrium of the maternal uterus following decidualization. The trophoblast is composed of two layers: an inner cytotrophoblast and an outer syncytiotrophoblast.

The syncytiotrophoblast is non-proliferative and thus relies on fusion of the underlying cytotrophoblast cells to expand. The syncytiotrophoblast are the cells in direct contact with the maternal blood that reaches the placental surface, and thus facilitates the exchange of nutrients, wastes, and gases between the maternal and fetal systems.

Cytotrophoblast in the tips of villi can differentiate into another type of trophoblast called the extravillous trophoblast. Extravillous trophoblasts grow out from the placenta and penetrate into the decidualized uterus.

This process is essential not only for physically attaching the placenta to the mother, but also for altering the vasculature in the uterus to allow it to provide an adequate blood supply to the growing fetus as pregnancy progresses.

Some of the trophoblast even replaces the endothelial cells in the uterine spiral arteries as they remodel these vessels into wide bore conduits that are independent of maternal vasoconstriction. This ensures the fetus receives a steady supply of blood, and the placenta is not sensitive to fluctuations in oxygen that could cause it damage.

This is a drawing of the extraembryonic coelom or chorionic cavitiy It depicts a blastocyst embedded in the uterine decidua. Also identified are the amniotic cavity, blood clot, body stalk, embryonic ectoderm, entoderm, mesoderm, maternal vessels, trophoblast, uterine epithelium, uterine glands, and yolk-sac.

Extraembryonic coelom or chorionic cavitiy: A blastocyst embedded in the uterine decidua. (am. Amniotic cavity, b.c. Blood clot., b.s. Body stalk., etc Embryonic ectoderm, ent. Entoderm., mes. Mesoderm, m.v. Maternal vessels., tr. Trophoblast., u.e. Uterine epithelium, u.g. Uterine glands., y.s. Yolk-sac.)

Clinical Example

Intrauterine growth restriction (IUGR) can result in an undersized fetus with poor organ development or even death. The primary factor in IUGR is placental dysfunction caused by a failure of the extravillous trophoblasts to penetrate and modify the uterine spiral arteries. The result is a poorly-oxygenated environment and reduced fetal growth.

Bilaminar Embryonic Disc Development

The floor of the amniotic cavity is formed by the embryonic disc.

Key Points

In humans, the formation of the embryonic disc occurs after implantation and prior to embryonic folding (between about day 14 to day 21 post-fertilization).

The embryonic disc is derived from the epiblast layer, which lies between the hypoblast layer and the amnion. The epiblast layer is derived from the inner cell mass.

The formation of the bilaminar embryonic disc precedes gastrulation.

Key Terms

  • optic disc: The location where ganglion cell axons exit the eye to form the optic nerve.
  • bilaminar: Formed of, or having, two laminae, or thin plates.

The floor of the amniotic cavity is formed by the embryonic disc, which is composed of a layer of prismatic cells and the embryonic ectoderm. It is derived from the inner cell mass and lies adjacent to the endoderm.

In humans, the formation of the embryonic disc occurs after implantation and prior to embryonic folding (between about day 14 to day 21 post-fertilization). The embryonic disc is derived from the epiblast layer, which lies between the hypoblast layer and the amnion. The epiblast layer is derived from the inner cell mass.

Embryonic Disc Development

A drawing of a rabbit embryo that identifies the embryonic disc and the primitive streak on it.

Surface view of a rabbit embryo: A drawing of a rabbit embryo that identifies the embryonic disc and the primitive streak (arg—embryonic disc; pr—primitive streak).

The embryonic disc forms during early development. By the blastocyst stage, the embryo is a hollow ball of cells with the inner cell mass (embryoblast) off to one side, and the blastocystic cavity fills the remainder of the sphere.

As the embryo progresses in implantation, a small space appears in the embryoblast and forms the amniotic cavity. Simultaneously, morphological changes occur in the embryoblast that result in the formation of a flat, almost circular bilaminar plate of cells that include the epiblast and the hypoblast—the embryonic disk.

The epiblast forms the floor of the amniotic cavity and is continuous with the amnion. The hypoblast forms the roof of the exocoelomic cavity and is continuous with the thin exocoelomic membrane.

The formation of the bilaminar embryonic disc precedes gastrulation. As gastrulation progresses, the embryonic disc becomes trilaminar and the notochord is formed. Through the process of neurulation, the notochord induces the formation of the central nervous system in the embryonic disc.

Amnion Development

The amnion contains the fluid that cushions and protects the fetus.

Key Points

In humans, the amnion is present in the earliest observed embryonic stage, appearing as a cavity within a mass of cells.

The amniotic cavity is roofed in by a single stratum of flattened, ectodermal cells, called the amniotic ectoderm, while the floor is composed of the prismatic ectoderm of the embryonic disk.

Outside the amniotic ectoderm, a thin layer of mesoderm is connected by the body stalk with the mesodermal lining of the chorion.

By approximately the fourth to fifth week, amniotic fluid (liquor amnii) begins to accumulate in the amnion, which increases in quantity and expands to contact the chorion.

During the later stages of pregnancy, the amniotic fluid allows easier and more fluid movements of the fetus and diminishes the risk of injury.

Key Terms

  • amniotic fluid: In placental mammals, a fluid contained within the amnion membrane that surrounds a developing embryo or fetus (also called liquor amnii).
  • embryonic disk: The floor of the amniotic cavity is formed by the embryonic disk (or disc), which is composed of a layer of prismatic cells.
  • amnion: The innermost membrane of the fetal membranes of reptiles, birds, and mammals; the sac in which the embryo is suspended.
  • chorion: One of the membranes that exist during pregnancy between the developing fetus and mother.

This is a cutaway drawing showing a human fetus in a womb. The fetus is seen enclosed within the amnion.

Amnion: The human fetus is enclosed within the amnion.

The amnion is a closed sac appearing in the inner cell mass as a cavity. This cavity is roofed in by a single stratum of flattened, ectodermal cells called the amniotic ectoderm. Its floor consists of the prismatic ectoderm of the embryonic disk.

The continuity between the roof and the floor is established at the margin of the embryonic disk. Outside the amniotic ectoderm is a thin layer of mesoderm (continuous with that of the somatopleure), which is connected by the body stalk with the mesodermal lining of the chorion.

When first formed, the amnion is in contact with the body of the embryo, but by about the fourth or fifth week, amniotic fluid (liquor amnii) begins to accumulate within it. This fluid increases in quantity, causing the amnion to expand and ultimately to adhere to the inner surface of the chorion so that the extra-embryonic part of the coelom is obliterated.

This increase continues up to the sixth or seventh month of pregnancy, after which it diminishes somewhat. At the end of pregnancy, it amounts to about one liter.

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The amniotic fluid allows some free movement for the fetus during the later stages of pregnancy and also diminishes the risk of injury. It contains less than two percent solids, and consists mainly of urea and other extractives, inorganic salts, a small amount of protein, and, frequently, a trace of sugar.

Note: That some of the liquor amnii is swallowed by the fetus is proved by the fact that epidermal debris and hairs have been found among the contents of the fetal alimentary canal.

Yolk Sac Development

The yolk sac is vascularized and contributes nutrients to the embryo.

Key Points

The yolk sac is the earliest visible portion of the gestational sac and is situated on the ventral portion of the embryo, arising from extra-embryonic endoderm.

The blood to and from the yolk sac is conveyed via the primitive aorta and vitelline circulation.

At approximately the end of the fourth week, the yolk sac is connected to the primitive digestive system, which allows the yolk sac to contribute nutrients to the embryo.

Key Terms

  • yolk sac: A membranous sac attached to an embryo that provides early nourishment in the form of yolk in bony fishes, sharks, reptiles, birds, and mammals. It functions as the developmental circulatory system of the human embryo before internal circulation begins.
  • vitelline circulation: The system of blood flowing from the embryo to the yolk sac and back again.
  • gestational sac: The gestational sac (or gestation sac) is the only available intrauterine structure that can be used to determine if an intrauterine pregnancy (IUP) exists until the embryo is identified.
  • Heuser’s membrane: Also called the exocoelomic membrane, it is a short lived combination of hypoblast cells and extracellular matrix.
  • mesenchyme: A type of tissue characterized by loosely associated cells that lack polarity and are surrounded by a large extracellular matrix.

The yolk sac is the first element seen in the gestational sac during pregnancy. In humans, it is usually visible at five weeks of gestation. Identifying a true gestation sac is a critical landmark, and is reliably seen in early pregnancy through ultrasound. The yolk sac, situated on the ventral aspect of the embryo, is lined by extra-embryonic endoderm, outside of which is a layer of extra-embryonic mesenchyme derived from the mesoderm.

Blood is conveyed to the wall of the sac by the primitive aorta. After circulating through a wide-meshed capillary plexus, it is returned by the vitelline veins to the tubular heart of the embryo. This vitelline circulation absorbs nutritive material from the yolk sac that is conveyed to the embryo.

The yolk sac is a membranous sac attached to the embryo that provides nourishment in the form of yolk. In this drawing the yolk sac is off to the right side of the amnion, heart, and body stalk.

Yolk sac: The yolk sac is a membranous sac attached to the embryo that provides nourishment in the form of yolk.

At the end of the fourth week, the yolk sac has the appearance of a small, pear-shaped vesicle (umbilical vesicle) opening into the digestive tube by a long, narrow tube, the vitelline duct. The vesicle can be seen in the afterbirth as a small, somewhat oval-shaped body whose diameter varies from 1 mm to 5 mm. It is situated between the amnion and the chorion and may lie on or at a varying distance from the placenta.

As a rule, the vitelline duct undergoes complete obliteration during the seventh week. In about 2% of the cases, its proximal portion persists as a diverticulum from the small intestine (Meckel’s diverticulum), which is situated about 60 cm proximal to the ileocecal valve. It may be attached by a fibrous cord to the abdominal wall at the umbilicus. Sometimes, a narrowing of the lumen of the ileum is seen opposite the site of attachment of the duct.

The yolk sac starts forming during the second week of embryonic development, at the same time of the shaping of the amniotic sac. The hypoblast starts proliferating laterally and descending. In the meantime Heuser’s membrane, located on the opposite pole of the developing vesicle, starts its upward proliferation and meets the hypoblast.

Sinusoid Development

The sinusoids are capillaries that develop after implantation to allow the exchange of gas and nutrients with the mother.

Key Points

The vitelline veins drain blood from the yolk sac. Portions of the veins above the upper ring become interrupted by the developing liver and broken up by it into a plexus of small capillary -like vessels termed sinusoids.

Sinusoids are found in the liver, lymphoid tissue, endocrine organs, and hematopoietic organs such as the bone marrow and the spleen. Sinusoids found within the terminal villi of the placenta are not comparable to these because they possess a continuous endothelium and complete basal lamina.

The invasion of endometrial sinusoids by the trophoblast
allows maternal blood flow into the trophoblastic lacunae; this forms
uteroplacental blood circulation.

Key Terms

  • sinusoid: Any of several channels through which venous blood passes in various organs.
  • trophoblastic lacunae: Spaces in the early syncytiotrophoblastic layer of the chorion present prior to the development of the villi.
  • vitelline veins: Veins that drain blood from the yolk sac.

The vitelline veins drain blood from the yolk sac. At first, they run upward in front on either side of the intestinal canal and, subsequently, unite on the ventral aspect of the canal. Beyond this, they are connected to one another by two anastomotic branches, one on the dorsal and the other on the ventral aspect of the duodenal portion of the intestine.

Thus, it is encircled by two venous rings. The superior mesenteric vein opens into the middle or dorsal anastomosis. The portions of the veins above the upper ring become interrupted by the developing liver and broken up by it into a plexus of small, capillary-like vessels termed sinusoids.

This is a drawing of the liver and veins of a human embryo, 24 or 25 days old, as seen from the ventral surface. The drawing shows the vitelline veins surrounding the stomach and the connection points of the vitelline veins to the left and right umbilical veins.

Vitelline veins: The liver and veins of a human embryo, 24 or 25 days old, as seen from the ventral surface. (The vitelline veins are visible at the center bottom.)

A sinusoid is a small blood vessel that is a type of capillary similar to a fenestrated endothelium. Sinusoids are actually classified as a type of open pore capillary (that is, discontinuous) as opposed to fenestrated.

Fenestrated capillaries have diaphragms that cover the pores, whereas open pore capillaries lack a diaphragm, having just an open pore. The open pore endothelial cells greatly increase their permeability.

Permeability is also increased by large intercellular clefts and fewer tight junctions. The level of permeability can allow small and medium-sized proteins, such as albumin, to readily enter and leave the blood stream.

Sinusoids are found in the liver, lymphoid tissue, endocrine organs, and hematopoietic organs, such as the bone marrow and the spleen. Sinusoids found within the terminal villi of the placenta are not comparable to these because they possess a continuous endothelium and complete basal lamina.

The invasion of endometrial sinusoids by the trophoblast allows maternal blood flow into the trophoblastic lacunae; this forms the uteroplacental blood circulation.

Development of the Extraembryonic Coelom

The extra-embryonic coelom is a cavity that contains the chorion. It is located between Heuser’s membrane and the trophoblast.

Key Points

The extra-embryonic coelom develops at the same time as the primitive yolk sac through the proliferation and differentiation of hypoblast cells into mesenchymal cells that fill the area between Heuser’s membrane and the trophoblast. The entire structure is enclosed by the chorionic plate.

The extra-embryonic mesoderm is subdivided into two layers: the extra-embryonic splanchnopleuric mesoderm, which is outside the primitive yolk sac; and the extra-embryonic somatopleuric mesoderm, which is adjacent to the cytotrophoblast.

The chorion is one of the membranes that exist during pregnancy between the developing fetus and mother.

Key Terms

  • chorion: The protective and nutritive membrane that attaches higher vertebrate fetuses to the uterus.
  • Heuser’s membrane: Heuser’s membrane (or the exocoelomic membrane) is a short-lived combination of hypoblast cells and extracellular matrix.
  • coelum: Also called the chorionic cavity, this is a portion of the conceptus that consists of a cavity between Heuser’s membrane and the trophoblast.

Development of the Extra-Embryonic Coelom

This is an artificially colored image of the contents in the cavity of the uterus seen at approximately 5 weeks of gestational age by obstetric ultrasonography. It shows the gestational sac, yolk sac, and embryo.

Gestational sac: An artificially colored image of the contents in the cavity of the uterus seen at approximately 5 weeks of gestational age by obstetric ultrasonography.

The extra-embryonic coelom (or chorionic cavity) is a portion of the conceptus consisting of a cavity between Heuser’s membrane and the trophoblast. During the formation of the primitive yolk sac, some of the migrating hypoblast cells transdifferentiate into mesenchymal cells that fill the space between Heuser’s membrane and the trophoblast to form the extra-embryonic mesoderm.

As development progresses, small lacunae begin to form within the extra-embryonic mesoderm that become larger and form the extra-embryonic coelom.

The extra-embryonic mesoderm is divided into two layers: the extra-embryonic splanchnopleuric mesoderm, which lies adjacent to Heuser’s membrane around the outside of the primitive yolk sac; and the extra-embryonic somatopleuric mesoderm, which lies adjacent to the cytotrophoblast layer of the embryo.

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The extra-embryonic coelomic cavity is also called the chorionic cavity—it is enclosed by the chorionic plate. The chorionic plate is composed of an inner layer of somatopleuric mesoderm and an outer layer of trophoblast cells. It is the fetal
aspect of the placenta that gives rise to chorionic villi.

Chorion Development

The chorion is one of the membranes that exist during pregnancy between the developing fetus and the mother. It consists of an extra-embryonic mesoderm and two layers of trophoblast and surrounds the embryo and other membranes.

Villi emerge from the chorion, which invade the endometrium, destroy the uterine decidua, and allow the transfer of nutrients from maternal blood to fetal blood.

Chorionic villi are at first small and nonvascular, and consist of only trophoblast, but they increase in size and branch. Blood is carried to the villi by the paired umbilical arteries, which branch into chorionic arteries and enter the chorionic villi as cotyledon arteries.

After circulating through the capillaries of the villi, the blood is returned to the embryo by the umbilical veins. Until about the end of the second month of pregnancy, the villi cover the entire chorion, and are almost uniform in size; but, after this stage, they develop unequally.

2nd weeks

Following all the excitement associated with the first gestational week, the newly formed blastocyst is ready to settle into a supportive environment and continue the growth process. Week 2 is often referred to as the week of twos. It’s the week when the embryoblast, extraembryonic mesoderm and trophoblast each separate into two distinct layers. Additionally, there are two cavities that develop within the embryonic unit at this time as well.

While every step is integral for adequate foetal development, one of the most important features of the second week is the completion of implantation and establishment of fetomaternal interactions. This article will follow the developing embryo through the completion of implantation and development of the non-embryonic components of the conceptus. It will also discuss some complications associated with implantation.

Implantation of the blastocyst

Implantation is a complex biochemical and mechanical process that begins in the first week of gestation and extends into the second week. There are many influencing factors that affect the process. These can be grouped into maternal and embryonal factors. However, both entities work synchronously in order to effectively achieve implantation. The process of implantation can be subdivided into three phases:

  • There is a period of apposition where the blastocyst establishes weak interactions with the uterine wall.
  • The attachment phase occurs when definitive binding of the blastocyst to the uterine epithelium is more established, such that the blastocyst cannot be flushed from the uterine cavity.
  • Finally invasion occurs when the blastocyst begins to burrow into the endometrium.

This period usually occurs between the 19th and 24th day of the menstrual cycle. This coincides roughly with the 6th to 10th day following ovulation.

Maternal factors affecting implantation

In anticipation for successful fertilization each month, the inner uterine wall (endometrium) undergoes a series of changes in order to facilitate the blastocyst. Recall that there are three layers of the endometrium – the strata basalis, spongiosum and compactum.

The deepest layer is the stratum basalis, which functions as the regenerative layer and proliferates to form the stratum spongiosum and stratum compactum. Stratum compactum is the most superficial and the stratum spongiosum resides between the two. Together, the strata compactum and spongiosum form the stratum functionalis; which is the functional layer of the endometrium that facilitates implantation.

The development of the stratum functionalis is mitigated by surges in estrogen (which are released from the maturing ovarian follicle, under the influence of follicle stimulating hormone). If fertilization did not occur during the previous menstrual cycle, the fall in reproductive hormones result in the degeneration of the stratum functionalis. The shedding of this layer during the menstrual phase of the cycle accounts for the vaginal bleeding known as menstruation.

In the subsequent cycle, as follicle stimulating hormone levels rise and stimulate maturation of another ovarian follicle, the resultant increase in estrogen levels leads to proliferation of the stratum basalis. This is known as the proliferative phase, during which time there is thickening of the endometrium. Following an increase in luteinizing hormone and the release of a secondary oocyte, the remaining corpus luteum continues to release estrogen and progesterone to maintain the stratum functionalis. The spiral arteries of the uterus become longer and more tortuous under the influence of the sex hormones.

Endometrium - dorsal view
Endometrium (posterior view)

Following successful fertilization the uterine epithelia, which is characterized by ciliated columnar cells with microvilli, undergoes morphological changes to accommodate the growing embryo. The expression of these cilia (extended processes located at the apical aspect of the cells) is regulated by both progesterone and estrogen. The underlying motile microtubules allow the cilia to move the developing embryo toward a favourable site on the uterine wall. This process usually starts around the end of the first gestational week, when the conceptus is classified as a blastocyst.

The process of bringing the conceptus close to the uterine wall is referred to as adplantation (apposition). As the blastocyst rolls along the surface of the uterus, the pole of the blastocyst with the inner cell mass is adjacent to the uterine wall. Early attachments to the microvilli (short, non-motile, apical epithelial processes) also facilitate the initiation of implantation.

Once the uterine lining is receptive for implantation, the endometrium is said to be in the implantation window. However, this is a complex process that depends on the presence of numerous cytokines, immunomodulators, and increased binding capacity of the epithelium in order for implantation to work. Recall from the first week of gestation that the resulting conceptus is genetically unique when compared with its parents. Therefore, the mother’s immune system should identify the blastocyst as a parasitic entity that should be destroyed.

A key element in the implantation phase that is thought to modify this anticipated immune response (and other parts of implantation) is known as leukaemia inhibitory factor (LIF). This is a member of the interleukin – 6 (IL-6) family that has the ability to influence several unrelated gene expressions (i.e. it’s a pleiotropic entity). Within the reproductive system, it is produced by both the endometrial epithelium as well as the developing blastocyst. Leukaemia inhibitory factor has the following functions with regards to endometrial receptivity:

  • The decidualization of the stromal cells (discussed below) is by LIF. This response is generated by way of a cyclic adenosine monophosphate (cAMP) pathway that activates a biochemical cascade involving estrogen and progesterone, IL-5, IL-6, prostaglandins, and cyclooxygenase 2 (COX-2). The resultant cellular morphological change creates a more favourable implantation environment. This particular reaction is important because it plays a significant role in immunomodulation. It is particularly difficult for thymocytes (T-cells) to invade decidual tissue; similarly, decidual cells have a hard time recruiting T-cells from the percolating blood. Therefore, the probability of the maternal immune system mounting a cytotoxic T-lymphocyte (CTL) response against the allogeneic conceptus is markedly reduced.
  • In addition, LIF upregulates numerous epidermal growth factors such as heparin – binding epidermal growth factor like protein (HB-EGF), epiregulin (EPR), and amphiregulin (AREG). These proteins act as ligands for the epidermal growth factor receptors and subsequently stimulate the proliferation of the endometrial epidermis.
  • LIF also stimulates the activity of implantation genes, including members of the Wnt family (Wnt 4, 5a, and others) and MutS homolog homebox 1 gene (MSX 1). These and other implantation genes result in differentiation of the luminal and glandular epithelia (decidualization), proliferation of the stromal cells, and decrease in the polarity of the epithelium to foster adhesion.
  • Uterodomes (also known as pinopods) are micro-protrusions of the luminal surface of the uterine epithelium that interdigitate with the blastocyst during adplantation and attachment. While they are present throughout the luteal phase of the menstrual cycle, they increase in number under the influence of LIF. In lower other mammals, pinopods are thought to play a significant role in pinocytosis (cell drinking). However, this is not its primary role in humans. As a result, they are referred to as uterodomes based on their appearance.
  • Under normal circumstances, the luminal surface of the uterus is coated with a thick layer of glycocalyx. This is a carbohydrate, glycoprotein rich layer that promotes repulsion of foreign entities from the cell membranes. It also has a large quantity of mucins (MUC-1 and MUC-4). LIF mediates significant local downregulation of MUC-1 in the area of the epithelium adjacent to the hatched blastocyst, which reduces repulsion of the blastocyst. However, relatively high levels of mucins are normally present in unfavourable implantation sites to prevent attachment.
  • Finally, the presence and activity of a member of the junctional adhesion molecule family (JAM-2) is also noted to be increased within the uterus during the 1st to 2nd gestational weeks. Junctional adhesion molecules have the ability to interact within the family (i.e. JAM-JAM binding) as well as with other integrins on non-uterine cells. They therefore promote cellular attachment to the epithelial membrane. Both LIF and progesterone have been shown to upregulate the expression of these adhesion molecules.
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As mentioned earlier, the luminal uterine stroma undergoes morphological transformation under the influence of LIF, estrogen and progesterone. This process – known as decidualization – involves accumulation of lipids and glycogen at a cellular level. The cells (i.e. decidual cells) subsequently acquire a polyhedral shape (as opposed to their previous columnar appearance). The process begins locally at the site of fetomaternal attachment, but gradually radiates until the entire endometrium has been transformed. On a molecular level, bone morphogenetic protein 2 (BMP-2) is needed for this transformation to occur; its deficiency is a known cause of infertility. The decidua provides an immunologically safe space for the embryo, in addition to providing nutrition for its development.

Fetal factors affecting implantation

As the blastocyst is hatched from the zona pellucida, it comes into contact with the endometrium. Surface proteins on the trophoblast known as trophinin interact with similar trophinin molecules on the endometrial surface. This plays a role in the differentiation of the trophoblast into two distinct layers:

  • In the periphery, there are multinucleated cells that have no discernible cell walls. This area is referred to as the syncytiotrophoblast. There is no mitotic activity in this area.
  • Deep to the syncytiotrophoblast is a cluster of mitotically active cells known as the cytotrophoblast. This cluster of cells rapidly replicates and migrates to the periphery in order to support the growing syncytiotrophoblast.

Of note, by the end of week 2, the bilaminar disc develops a localized region of thickened cells in the hypoblast. This area is referred to as the prechordal plate. Not only does the prechordal plate help with the organization of the head region during development, but it also indicates the future head region and the location of the mouth.

The syncytiotrophoblast is a highly invasive structure that penetrates the endometrium in order for the blastocyst to become embedded. The trophinin-trophinin binding also induces endometrial epithelial apoptosis in the mother in order to accommodate the invading cell mass. The blastocyst then utilizes the nutrients from the recently destroyed maternal cells as it continues to grow. Furthermore, the syncytiotrophoblast (under the influence of LIF) begins to produce human chorionic gonadotropin hormone (β-hCG). The presence of β-hCG prevents corpus luteum degeneration, resulting in the continued release of estrogen and progesterone. The detection of the glycoprotein in maternal circulation and urine also forms the basis of the pregnancy test.

Another recently discovered element that contributes to implantation is the protein preimplantation factor. It is derived from the embryo and has been shown to aid in maternal immunomodulation, embryo-endometrial adhesion, and endometrial apoptosis.

Review of the initial sequence of implantation

Let’s recap the initial implantation sequence:

  • Endometrial development occurs each month in anticipation of successful fertilization.
  • Successful fertilization occurs and the zygote develops into a blastocyst.
  • The blastocyst roles along the endometrium towards a favourable implantation site.
  • Concurrently, there is maternal immunomodulation, downregulation of repelling entities and upregulation of adhesion moieties.
  • The blastocyst hatches from the zona pellucida.
  • Adplantation occurs when weak carbohydrate binding occurs between the embryo and the glycocalyx.
  • As the embryo gets closer to the endometrium, stronger bonds are formed. These involve interactions with integrins, L-selectin, osteopontin, cadherins, trophinin, as well as CD44 and CD98.
  • Attachment stimulates maternal decidualization and embryonal trophoblast differentiation.
  • Trophoblastic invasion coincides with desmosomal detachment of maternal cells, as well as apoptosis of adjacent decidua.
Blastocyst implantation
Blastocyst implantation

Amniotic cavity

While implantation ensues, the embryoblast also undergoes differentiation to form a bilaminar disc. The flat, circular disc is comprised of a thicker epiblast with high columnar cells and a thinner hypoblast with small cuboidal cells. A small space develops relative to the epiblast; it is the precursor of the amniotic cavity.

Epiblastic cells forming the floor of the cavity subsequently separate to form amnioblasts that will form the amnion (surrounding the amniotic cavity). The sac and cavity will eventually become filled with amniotic fluid later on in the pregnancy. They provide shock absorption and facilitate movement of the foetus during development.

Umbilical vesicle

Peripherally, the hypoblast is continuous with another structure known as the exocoelomic (Heuser’s) membrane. It also forms the roof of the enclosed exocoelomic cavity. Combined, the membrane and the hypoblast form the visceral lining of the yolk sac. However, since the human embryo does not possess a yolk, it is more appropriate to refer to it as the primary umbilical vesicle.

Endodermal cells arising from the exocoelomic membrane extends circumferentially to enclose the embryonic disc and both cavities. It is subsequently referred to as the extraembryonic mesoderm. Both cavities facilitate embryonic folding as growth and morphological changes occur. The umbilical vesicle may play a role in nutrient transfer to the embryo. Furthermore, it is an important source of primordial germ cells.

Early fetomaternal circulation

While the aforementioned cavities and bilaminar disc develop, the syncytiotrophoblast began to lacunate (I.e. form lacunae). The lacunae are filled with an amalgam of cellular debris and maternal blood, known as the embryotroph. This fluid gains access to the embryonic disc via diffusion and delivers nutrients as well as oxygen to the embryo. The lacunae subsequently become confluent, forming lacunar networks, which serves as the primordial uteroplacental circulation. As the networks continue to fuse, the syncytiotrophoblast has a sieve-like appearance, particularly around the embryonic pole of the conceptus. This will subsequently give rise to the intervillous spaces of the placenta.

The capillaries around the implanted embryo become engorged, dilated and their walls become thin. From here onwards, they are known as sinusoids. The syncytiotrophoblast continues to erode the walls of the sinusoids, resulting in more maternal blood flowing freely into the lacunar networks. Much of the derived nutrients is conveyed to the embryo by the trophoblast. However, the trophoblast grows a lot faster than the embryo in the early phases. As such, it is likely to have a higher nutritional requirement than the embryo.

Chorionic sac

As time progresses, the extraembryonic mesoderm increases in size. Numerous cavities known as the extraembryonic coelomic spaces begin to appear deep to the cytotrophoblast and superficial to the exocoelomic membrane. These spaces coalesce to form the extraembryonic coelom. This coincides with a decrease in the volume of the primary umbilical vesicle; which is then referred to as the secondary umbilical vesicle. The cells of the secondary umbilical vesicle arise from migratory extraembryonic endodermal cells of the hypoblast. There is a remnant of the primary umbilical vesicle within the extraembryonic coelom that is referred to as an exocoelomic cyst.

Cellular columns, lined with syncytial coverings, extending into the syncytiotrophoblast indicate the ending of the second gestational week. This phenomenon marks the formation of the primary chorionic villi. Splanchnic and somatic derivatives of the extraembryonic mesoderm line the umbilical vesicles, and the trophoblast and amnion, respectively. The somatic extraembryonic mesoderm, along with both trophoblastic layers, gives rise to the chorion. The space enclosed by the chorion is the chorionic sac; it contains the embryo, as well as the amniotic sac and umbilical vesicle. The latter three structures are attached to the chorion by the connecting stalk. The former extraembryonic coelom is now referred to as the chorionic cavity.

Implantation completed

By the 10th day following fertilization, the embryo is completely embedded in the endometrium. There is a small defect in the epithelium that is sealed by a fibrin-based blood clot known as the closing plug. By day 12, the area is completely healed. The 14 day embryo maintains the form of a flat bilaminar embryonic disc at the end of second week. The thickened prechordal plate develops as a localized thickening of hypoblast and indicates the future site of mouth and organizer of the head region.

Summary of 2nd Week

Here is a simplified summary of the events of the second week:

  • The hatched blastocyst moves along the endometrium towards a favourable point of implantation.
  • The endometrium is converted into an immunologically privileged site with optimum blood supply
  • Weak attachments are strengthened.
  • Differentiation of the trophoblast and endometrial stroma facilitate invasion of the endometrium.
  • Several cavities and membranes are formed.
  • β-hCG production is stimulated.
  • Complete implantation with endometrial scarring is achieved by day 10.
  • Complete regeneration around the scar results around day 12.
  • At the end of week 2, the chorionic cavity is formed.

References

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