194350 Human Lifecycle Physiology background reading

The Placenta
Implantation
After fertilisation, the zygote spends about 46 days travelling to the uterus. It is moved
through the uterine tube by the peristaltic action of the smooth muscle and the sweeping
movements of the cilia and the fluid produced by the ciliated epithelium. The embryo at first
divides approximately every 15 hours; the division time becomes progressively shorter.
During the initial cleavage steps, the embryo is enclosed within the restraining zona
pellucida and its total mass remains approximately constant. Cytoplasmic factors regulate
cleavage, which occurs without net growth so cell number increases but the cells become
progressively smaller. Initially, the cleavage divisions are synchronous and each cell
(blastomere) is identical, but then the cells divide at an independent rate. Later synchrony is
lost, so the pattern of doubling of cell number is also lost.
After the eight-cell stage, the cells change morphologically so some of the cells at the outer
edge of the embryo become flatter. About day 4, as it reaches the uterus, the embryo is a
mass of cells known as the morula (derived from the Latin word for mulberry). A fluid-filled
cavity forms between the inner and outer cell layers; the embryo is now known as a
blastocyst. By the 64-cell stage, the cells of the conceptus are irreversibly differentiated on
the pathway to becoming embryonic or extraembryonic tissue. Differentiation into a particular
cell type is related to positional information of the cells, which induces particular genes to be
expressed. Cells of the blastocyst initially differentiate into two distinct cell lines: the
trophoblast (which will develop into the placenta) and the inner cell mass (which will develop
into the embryo).
The blastocyst may remain free-floating in the uterine cavity until implantation at day 7. The
blastocyst accumulates fluid and expands; and the zona pellucida is shed so the blastocyst
comes into contact with the endometrium (lining of the uterus). Impanation (nidation) of the
blastocyst normally occurs in the upper part of the body of the uterus (the fundal region). The
blastocyst implants at the embryonic pole, where the inner cell mass lies. The outer cells of
the blastocyst secrete proteolytic enzymes and collagenase, which break down and destroy
some of the cells of the endometrium; implantation in humans is a very invasive mechanism.
Uterine muscle activity is low at this time because secretion of progesterone is high.

194350 Human Lifecycle Physiology

Jane Coad
j.coad@massey.ac.nz

Implantation is the consequence of a well-organized sequence of events involving

synchronised cross-talk between the receptive endometrium and a functional blastocyst. It
occurs in 3 stages: apposition, adhesion and invasion. The trophoblastic cells overlying the
inner cell mass initiate the adhesion and implantation processes. The blastocyst rolls freely
over the endometrium until it reaches a receptive area. This process is thought to be
mediated by glycoproteins called selectins which are expressed on the polar trophoblast
cells of the newly hatched blastocyst. The blastocyst then orientates itself so that the
embryonic pole implants first. The endometrium produces MUC1, a mucin-rich glycoprotein,
to prevent the blastocyst adhering to areas of the endometrium with poor chances of
implantation. The optimally receptive areas of the endometrium secrete chemokines and
growth factors to attract the blastocyst to the pinopods. The apposition of the blastocyst to
the endometrium triggers the production of adhesion molecules such as integrins and
cadherins which firmly anchor the blastocyst to the endometrial pinopods. This process is
enhanced because the endometrial surface expresses receptors for selectins. The tethering
of the blastocyst to the endometrium stimulates the polar trophoblastic cells to undergo rapid
mitosis and proliferate as the invasion of the uterine wall commences.
During the implantation or nidation window, microvilli on the surface of the uterine
endometrial cells fuse together to form single flower-like projections called pinopods or
uterodomes. These smooth bleb-like protrusions which lack the typical microvilli form under
the influence of progesterone (during the mid-luteal phase) only in the preferred sites of
embryo-endometrial interaction and thus act as markers of uterine receptivity. The pinopods
are only present for 2 to 3 days during which implantation must occur. It is evident that
implantation is a rather inefficient process in the human; the probability of conception during
a menstrual cycle (defined as fecundity) is about 30% and over three quarters of failed
pregnancies are thought to be due to implantation defects.
Once implantation has occurred, the lining of the uterus closes over the blastocyst and the
pregnancy is established. The trophoblast cells absorb nourishment from the decidua and
secrete human chorionic gonadotrophin (hCG) which stimulates growth and secretory
activity of the corpus luteum to produce steroid hormones, which support continued growth
of the decidua. Critical amounts of hCG are required for blastocyst survival.
The human placenta is haemochorial, which means that maternal blood comes into contact
with the placental trophoblast cells. The uteroplacental unit is made up of both fetal and
maternal components. The placenta as seen at delivery is just the fetal component or
chorionic plate. The maternal component or basal plate is the placental bed which underlies
the fetal component and the uteroplacental circulation that vascularizes the placental bed.
Between the chorionic and basal plates is the intervillous space where the maternalfetal
exchange occurs. Conversion of the maternal spiral arteries to dilated and flaccid vessels is
an essential step for successful pregnancy. Abnormal placental function is strongly
associated with fetal complications, but study of the human placenta, particularly the
maternal component, is not easy. Placentation in the human is unique, which means that
observations from other species can be applied to humans only with caution. Placental
reserve needs to exceed fetal requirements (otherwise the fetus could be compromised
under conditions of hypoxia).

194350 Human Lifecycle Physiology

Jane Coad
j.coad@massey.ac.nz

Cytotrophoblast and syncytiotrophoblast

The cytotrophoblasts, which form the inner monolayer of placental stem cells, are large clear
discrete cuboidal cells each with a single nucleus, a few organelles and a well-defined cell
membrane. These cells have marked mitotic activity and DNA synthesis. The
syncytiotrophoblast increases in volume throughout the second week as cells detach from
the proliferating layer of cytotrophoblast and fuse with the mass of syncytiotrophoblast. The
syncytiotrophoblast has an invasive phenotype, secreting enzymes, which attack the
endometrium, and hormones, which sustain the pregnancy. It is also involved in absorption
of nutrients. The syncytiotrophoblast invasion is aggressive; between 6 and 9 days
postfertilization the embryo becomes completely implanted into the endometrial stroma. The
hydrolytic enzymes produced cause breakdown of the extracellular matrix between the cells
of the endometrium thus eroding a pathway. The surface of the syncytiotrophoblast has tiny
processes extending from it that penetrate between the endometrial cells, pulling the
conceptus into the uterine wall. As implantation progresses, the expanding
syncytiotrophoblast gradually envelops and encircles the blastocyst. The endometrial
epithelium regenerates over the site of implantation. By 9 days, the embryo is completely
embedded within the endometrial wall with the syncytiotrophoblast forming a complete
mantle around the entire conceptus.
As the syncytiotrophoblast penetrates the uterine wall, it comes into contact with the
maternal endometrial capillaries and superficial veins. Fragments of these are engulfed
within the syncytiotrophoblast forming fluid-filled trophoblastic lacunae (literally little lakes);
these coalesce to form larger lacunae which are the precursors of the intervillous spaces. As
maternal blood vessels are progressively invaded, the lacunae fill with maternal blood.
Maternal capillaries near the syncytiotrophoblast expand to form maternal sinusoids which
rapidly anastomose with the trophoblastic lacunae. As this development continues, the
lacunae become separated by columns of syncytiotrophoblast, or trabeculae, which
effectively form a framework on which the villous tree of the placenta develops. The
trabecular columns project radially from the blastocyst. The cytotrophoblast at the core of the
columns proliferates locally to form extensions, which grow into the columns of
syncytiotrophoblast.
Cytotrophoblast migration and invasion
The cytotrophoblast layer has several distinct roles:
1. acting as proliferative progenitor or stem cell layer to generate and construct the
developing syncytiotrophoblast which covers the villi;
2. forming the proliferative cell columns of the anchoring villi;
3. detaching from the cell columns and migrating into the maternal stroma to form
interstitial cytotrophoblasts; and
4. migrating as non-proliferative extravillous cytotrophoblast cells to remodel the spiral
arteries and replace the maternal endothelial cells.

194350 Human Lifecycle Physiology

Jane Coad
j.coad@massey.ac.nz

The extravillous cytotrophoblast cells migrate from the villi beyond the leading edge of
syncytiotrophoblast into the stroma. From about 12 days postfertilization, these cells invade
the maternal capillaries and spiral arteries of the decidua. The extravillous cytotrophoblast
cells initially plug the lumen of the maternal vessels that have been invaded and
subsequently replace the maternal endothelium of these vessels. Plugging of the lumen of
the invaded maternal blood vessels prevents bleeding and is achieved by day 14, which
coincides with the expected date of the next menstrual period. The plugs prevent flow of
maternal blood into the intervillous space in early pregnancy but allow a slow seepage of
plasma. The developing placenta forms an effective barrier between the mother and
developing embryo that persists up to 10 weeks gestation when the trophoblastic plugs are
dislodged and intervillous blood flow is established. It is at this time that peak hCG secretion
occurs. The increasing oxygen level and concomitant oxidative stress also stimulates
cytotrophoblast proliferation and differentiation and the increased expression of antioxidant
enzymes. Embryogenesis occurs in a relatively hypoxic environment. The developing
embryo is thought to be particularly vulnerable to damaging oxygen free radicals during the
sensitive period of organogenesis and the first-trimester placenta has limited antioxidant
capacity; thus, limiting fetal exposure to oxygen may be protective.
Spiral artery conversion
Between the 4th and 16th week of gestation, villus growth and considerable remodelling of the
placenta occur, including remarkable changes to the maternal blood vessels underlying the fetal
placenta ensuring that the spiral arteries are capable of delivering large volumes of blood to the
placental intervillous spaces at an appropriate rate and pressure to protect the delicate fetal villi
perfused by the low-pressure developing fetal circulation which are immersed in maternal blood
which circulates at a much higher pressure and velocity. Failure of the transformation of the spiral
arteries is associated with a number of common complications of pregnancy including
preeclampsia and fetal growth restriction.
The extravillous cytotrophoblast cells are involved in physiologically remodelling the maternal
spiral arteries which is completed by the end of the first trimester. After an apparent rest phase of
a couple of weeks (weeks 1416), there is a resurgence of the endovascular trophoblastic
migration. The second wave of cytotrophoblast cells moves down the myometrial segments of the
spiral arteries to their origin at the branching from the radial arteries. The cytotrophoblast cells are
involved with the destruction of the maternal artery musculoelastic tissue and the replacement of
the maternal endothelial wall with trophoblast resulting in a change in the vessel wall
vasoresponsiveness. The result is conversion of the thick-walled muscular spiral arteries to
compliant dilated sac-like uteroplacental vessels that have low impedance to blood flow.
The remodelled vessels can passively dilate and accommodate a greatly increased blood
flow (about 30% of maternal cardiac output) but they are not responsive to vasoactive
agents. The effect of this interaction between the trophoblastic cells and the maternal blood
vessels is that a low-pressure, high-conductance vascular system is established, which
provides an adequate maternal blood flow to the placenta and thus a plentiful provision of
oxygen and nutrients to the fetus. The maternal uteroplacental circulatory system is mostly
complete by mid-gestation. In contrast, the fetal villous tree continues to branch and develop
throughout the pregnancy, ensuring that the capacity of the placenta matches the growth of
the fetus.

194350 Human Lifecycle Physiology

Jane Coad
j.coad@massey.ac.nz

Vascularisation of the placental villi

Fetal blood cells are derived from blood islands in the extraembryonic mesoderm
surrounding the yolk sac. The blood vessels that perfuse the placenta also develop in this
tissue. In the 3rd week postfertilization, the extraembryonic mesoderm associated with the
cytotrophoblast penetrates into the core of the primary stem villi transforming them into
secondary stem villi. This mesoderm develops into the blood vessels and connective tissue
of the villi. It forms at the same time as the embryonic vasculature with which it will
eventually connect. Haemangioblast cells (precursors of blood cells) appear and capillaries
form. The linking of the blood vessels of the villi with the vessels of the embryo results in a
circulating blood system so the villi begin to be perfused by the fetal circulation at about 28
days after fertilization.
By the end of the 4th week after fertilization, the villi cover the entire blastocyst surface
forming a spherical shell of villi projecting outwards into the maternal tissue. It is possible to
remove a sample of the developing placental villi for genetic testing. The placental barrier
now effectively limits diffusion of gases, nutrients and waste materials. There are four layers:
the endothelium lining the villus capillary, the connective tissue in the villus core, a layer of
cytotrophoblast cells and a maternal-facing layer of syncytiotrophoblast. By mid-gestation,
most of the cytotrophoblast layer of many villi disappears and the placental barrier becomes
very thin.
From the 4th week to the 16th week, the villus growth over the entire surface of the
blastocyst is remodelled. Most of the villi orientated towards the uterine cavity degenerate
and regress, leaving behind an area that develops into the typical placental structure and
shape seen at delivery. The chorion is formed from the placental tissue where the early villi
have regressed.

Development of the amnion

The amniotic cavity first appears at about day 7. The primitive ectoderm cells enclosing the
cavity become flattened forming amnioblasts, cells which become the fetal-facing amniotic
membrane. These cells secrete amniotic fluid, thus the embryo is enclosed in the fluid-filled
amniotic sac.
Amniotic fluid
Amniotic fluid has an important role in protecting the fetus, cushioning it from external impact
and stresses preventing fetal injury. It also allows symmetrical fetal growth and movement,
preventing fetal parts from adhering together or to the amnion, allows practice breathing and
swallowing exercises and increases placental surface area. Amniotic fluid has bacteriostatic
properties and is also important in maintaining a constant body temperature; it is also
involved in maintaining amnion integrity, discouraging myometrial contractions and
maintaining cervical length and consistency. In the first half of gestation, before skin
keratinization takes place, fluid and electrolytes can diffuse freely across the skin. After 20
weeks, the skin becomes keratinized and transudation from maternal and fetal blood vessels
contributes less to the amniotic fluid.

194350 Human Lifecycle Physiology

Jane Coad
j.coad@massey.ac.nz

Growth and maturation of the placental villi

The placental villi continue to grow for most of the pregnancy. There is a widely held belief
that the placenta ages during the pregnancy and that at term it is about to decline into
functional senescence. Instead, the continuous morphological changes should perhaps be
viewed as an increase in functional efficiency rather than ageing. Thus in early pregnancy,
the placenta is a highly invasive and proliferative tissue and in later pregnancy, although its
growth rate slows down, it continues to mature and increase in efficiency. Placental
efficiency is favoured by the attenuated maternalfetal barrier and reduced diffusion distance
rather than by an increase in weight. By term, the surface area of the placental villi is
estimated to be 12-14m2.
On the basal (maternal) surface, the placenta is subdivided into cotyledons by wedge-like
placental septa, which appear in the 3rd month. The placental (decidual) septa grow into the
intervillous space from the maternal side of the placenta, separating the villi into 10-40
cotyledons. The placental septae do not fuse with the chorionic plate so maternal blood can
flow freely from one cotyledon to another. This means that the villi are bathed in a lake of
maternal blood which is constantly exchanging; this organization of placental perfusion is
described as haemochorial. Haemochorial placentation is efficient because the trophoblast is
in contact with maternal blood optimizing maternalfetal transport of gases, nutrients, water
and ions. The trophoblast can also endocytose the immunoglobulin IgG. In addition,
hormones produced by the fetoplacental unit can easily access the maternal circulation.
There are, however, some costs to the haemochorial arrangement; bleeding may be
extensive at parturition and cells can be transferred between mother and fetus, for instance,
resulting in microchimerisms or erythroblastosis fetalis (haemolytic disease of the newborn
due to Rhesus incompatibility).

194350 Human Lifecycle Physiology

Jane Coad
j.coad@massey.ac.nz

Placental blood flow

The fetal blood reaches the placental blood system via the two umbilical arteries which spiral
around the umbilical vein. On reaching the chorion, the vessels usually each supply half of
the placenta. The arteries (which are vessels carrying blood away from the fetal heart and
therefore carry deoxygenated blood) divide repeatedly to form a branching network of
smaller arteries and capillaries running through the intervillous space. The fetal blood flow
through the placenta is about 500 ml/min, propelled by the fetal heart. Smooth muscle fibres
contracting in the villi may help to pump blood back from the placenta to the fetus.
The maternal blood enters the intervillous space via about 50100 of the remodelled spiral
arteries. There is a pressure gradient from the maternal arteries to the intervillous space to
the maternal veins. The blood leaves the intervillous space via the endometrial veins. Most
organs have a progressive decrease in arterial diameter as the blood nears its target tissue.
In the uteroplacental vessels, the remodelled spiral arteries increase in diameter as the
vessels approach the intervillous space. Therefore, the intervillous space is a low-pressure
system; the blood gently flows through and washes over the fetal placental tissue. The
placenta has little resistance to maternal blood flow and a high vascular conductance so
there is little fall in pressure across the intervillous space. The main determinant of the rate
of maternal blood flow is the vascular resistance in the myometrial arteries. Myometrial
contractions can decrease or stop afferent blood flow to the intervillous space. This effect is
probably due to the compression or occlusion of the veins draining this space. During a
contraction, the space distends so the fetus is not totally deprived of oxygen.
The placenta at term
The mature placenta is an oval/round disc with a diameter of about 1822 cm and 23 cm
thick in the middle, petering out towards the edges. At the placental margins, the basal and
chorionic surfaces of the placenta unite to form the fetal chorionic membrane. On average,
a placenta weighs about one-sixth of the weight of the fetus, about 470-500 g. The amniotic
membrane is smooth so the fetal aspect of the placenta, the chorionic plate, appears shiny
and grey. The amnion is a single layer of epithelial cells and avascular connective tissue
which is weakly attached and can be easily removed from the delivered placenta. The basal
plate is maternal surface of the placenta which appears grooved and lobed with a dull red
coloration. This basal surface is a mixture of extravillous trophoblasts, maternal decidua cells
and immune cells such as macrophages and natural killer cells, extracellular matrix, fibrinoid
and blood clots. The chorionic membrane retains the ridged appearance owing to the
regression of the early villi.
The umbilical cord is usually inserted slightly eccentrically into the chorionic plate. The
umbilical cord gets progressively longer with the duration of the pregnancy as fetal activity
and traction on the cord increases its length. At term, the umbilical cord is normally between
50 and 60 cm long. If the cord is abnormally short, it can cause bleeding problems. If it is
long (>70cm), it may prolapse through the cervix or entangle with the fetus, possibly forming
knots that could obstruct fetal circulation during delivery, causing potentially fetal distress
and death. For a normal vaginal delivery, a cord length of at least 32cm is thought to be
necessary to avoid fetal distress, cord tearing and possible abruption. Most umbilical cords
are twisted; usually the twists are counterclockwise left twists every few centimetres. True
knots in the umbilical cord occur in about 1% of births. The vessels of the cord, two arteries
carrying blood from the fetus and one vein carrying blood to the fetus, are embedded in
Whartons jelly. This jelly is a connective tissue that protects the vessels of the cord.

194350 Human Lifecycle Physiology

Jane Coad
j.coad@massey.ac.nz