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17. FORMATION AND ROLE OF PLACENTA

Joan W. Witkin, PhD
Dept. Anatomy & Cell Biology, P&S 12-432
Tel: 305-1613
e-mail: jww3@columbia.edu

READING: Larsen, 3rd ed. pp. 20-22, 37-44 (fig. 2-7, p. 45), pp. 481-490

SUMMARY:

As the developing blastocyst hatches from the zona pellucida (day 5-6 post fertilization) it has
increasing nutritional needs. These are met by the development of an association with the uterine wall
into which it implants. A series of synchronized morphological and biochemical changes occur in the
embryo and the endometrium. The final product of this is the placenta, a temporary organ that affords
physiological exchange, but no direct connection between the maternal circulation and that of the
embryo.

Initially cells in the outer layer of the blastocyst, the trophoblast, differentiate producing an overlying

syncytial layer that adheres to the endometrium. The embryo then commences its interstitial implantation as cells
of the syncytiotrophoblast pass between the endometrial epithelial cells and penetrate the decidualized
endometrium. The invading embryo is first nourished by secretions of the endometrial glands. Subsequently the
enlarging syncytiotrophoblast develops spaces that anastomose with maternal vascular sinusoids, forming the
first (lacunar) uteroplacental circulation. The villous placental circulation then develops as fingers of
cytotrophoblast with its overlying syncytiotrophoblast (primary villi) extend from the chorion into the maternal
blood space. The primary villi become secondary villi as they are invaded by extraembryonic mesoderm and
finally tertiary villi as embryonic blood vessels develop within them.

During the first trimester of pregnancy cytotrophoblasts partially occlude the uterine vessels such

that only plasma circulates in the intervillous space. This provides a low oxygen environment for early
organ formation. Cytotrophoblasts also replace the endothelium and smooth muscle of endometrial
spiral arteries, releasing them from maternal influences. The highly branched villi allow for the passage
of respiratory, metabolic and other products between maternal and fetal blood systems across a barrier
comprised only of embryonic tissue (a hemochorial placenta). The cytotrophoblasts and overlying
syncytiotrophoblasts lining the villi are also the sources of numerous substances including peptide and
steroid hormones, and growth factors.

Note: Further functional aspects of the placenta, including the production of steroid hormones by fetal-
maternal interactions and events leading to parturition, will be considered in SBPMD.

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LEARNING OBJECTIVES:

Be able to describe:

1. how the endometrium is prepared for implantation.
2. maternal and embryonic cellular interactions involved in the adhesion of the blastocyst to the

luminal epithelium and its penetration into the endometrial stroma.

3. the establishment of the relationship between maternal and fetal blood supplies and how the area

of their interface expands to meet the increasing demands of the developing embryo.

4. how failures in these processes can produce problems in pregnancy.

GLOSSARY:
amnion – amniotic cavity immediately surrounds the embryo; the amniotic membrane is derived from

the epiblast and extraembryonic mesoderm

ART – assisted reproductive technology: inclusive term for procedures to increase the likelihood of

pregnancy such as the use of ovulation-inducing drugs and in vitro fertilization

chorion – the fetal component of the placenta, derived from trophoblast and extraembryonic mesoderm,

contains fetal blood vessels
chorion frondosum – region of chorion with villi whose association with the decidua basalis is the
essential unit of the placenta
chorion laeve – abembryonic region of chorion that is without villi, therefore, smooth (laeve)
chorionic gonadotropin (hCG) – hormone secreted by the trophoblast, resembles luteinizing hormone

and acts to maintain production of progesterone by the corpus luteum

corpus luteum – cells of ovulated follicle that remain in ovary and respond to LH by secreting progesterone

and estrogens

decidua – the portion of the endometrium that is sloughed at menstruation and parturition, includes the

region into which the embryo implants
decidua basalis – the portion of the decidua underlying the embedded embryo and into which chorionic
villi are anchored
decidua capsularis – the portion of the decidua that covers the embryo as it bulges into the uterine cavity
decidua parietalis – the decidua that lines the remainder of the uterus

decidual reaction – peri-implantation changes in the endometrium: decidual cells differentiate within
the stroma, accumulating abundant glycogen and lipid and synthesizing a variety of substances that
promote the maintenance of the implanting embryo; the endometrium becomes highly secretory,
well-vascularized and edematous

endometrium – the inner layer (mucosa) of the wall of the uterus
functionalis – region of the endometrium that is lost at menstruation
compacta – superficial, compact zone of the functionalis, site of implantation
hemochorial placenta – type of placenta in which the chorion is the only barrier between maternal and fetal

inner cell mass – (also known as the embryoblast) the cluster of cells in the blastocyst that will give
rise to the epiblast and hypoblast (see Chapter 2), located at the embryonic pole of the blastocoel
outer cell mass – outer layer of cells of the blastocyst, will give rise to the trophoblast, the progenitor of

blood

the chorion

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receptivity – state of preparedness by the endometrium for implantation (nidation) by a conceptus
trophoblast – derivative of cells of the outer cell mass of the blastocyst

cytotrophoblast – the inner proliferative layer of the lining of chorionic villi, the source of the outer
syncytiotrophoblast
syncytiotrophoblast – the outer layer of the lining of the chorionic villi, formed by multiplication of
cells of the cytotrophoblast without cytokinesis

villus – finger-like projection

stem villus – a villus that extends directly from the chorionic plate
primary villus – early protrusion of trophoblast into lacunae of maternal blood consisting of a core of
cytotrophoblast covered by syncytiotrophoblast
secondary villus – the result of invasion of a primary villus by extraembryonic mesoderm
tertiary villus – a secondary villus that has been invaded by fetal blood vessels
terminal villus – a villus that terminates (floats) within the maternal blood space
anchoring villus – a villus that is anchored into the decidua basalis

vitelline veins – blood vessels that return embryonic blood from the secondary yolk sac
yolk sac – primary yolk sac is the former blastocoel now lined by extraembryonic endoderm.

Extraembryonic mesoderm then migrates to line the basal side of this endoderm resulting in the
formation of the secondary (definitive) yolk sac.

TEXT:

The nourishment of the embryo and later, the fetus, is accomplished through development of the

placenta, which allows for the intimate relationship between (but not the confluence of) the fetal and maternal
blood supplies. The placenta is formed as a result of interactions between the invading blastocyst and the tissue
of the uterine wall. The process of formation of the placenta involves several critical stages and processes:
receptivity of the uterus; apposition of the blastocyst to the endometrial epithelium; adhesion of the
trophoblast to the endometrial epithelial cells; invasion of the epithelium, its basal lamina and the endometrial
stroma; and placentation, i.e., the establishment of the final vascular arrangement, in humans, a hemochorial
placenta.

The establishment and maintenance of the pregnancy is dependent upon signals between the embryo/

fetus and the mother. Implantation has been described as a double paradox. It is a cellular paradox because it
involves apposition and adhesion of the apices of two epithelia. It is an immunological paradox because it is
essentially an allogenic transplant as the embryo contains both paternal and maternal genetic material.
Implantation is more susceptible to mishap than is conception. Approximately 70% of all conceptions result in
miscarriage. Most occur within 14 days of conception and are unrecognized by the woman.

A brief description of events within the ovary and uterus follows for the purposes of understanding

THE OVARY AND UTERUS

implantation and formation of the placenta.

The endometrium (Fig. 17-1)

The uterus is made up of a wall of smooth muscle, the myometrium, lined by a thick mucosa, the

endometrium, which is a layer of loose connective tissue lined by simple columnar epithelium
containing glands and supplied by a specialized vascular system. Branches of arteries arise in the basal

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Fig. 17-1. Changes in the uterine mucosa correlated with those in the ovary. Implantation of the blastocyst results in development
of a large corpus luteum of pregnancy. Progesterone from the corpus luteum increases the secretory activity of the endometrium.
(Langman’s Medical Embryology, 8th ed., TW Sadler, Lippincott Williams & Wilkins, Philadelphia (2000), p. 45 (modified).

zone of the endometrium and spiral through the overlying region, the functionalis. The characteristics of
the functionalis change dramatically in response to the hormonal state over the menstrual cycle and
during pregnancy. On day 1 of the 28 day cycle the functionalis begins to slough. By day 5
gonadotropin releasing hormone (GnRH) from the brain stimulates the pituitary to release two
gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). These hormones
promote the development of ovarian follicles. Estrogen (E) from the follicular cells promotes rebuilding
of the glands and blood vessels of the endometrium (follicular phase of the ovary = proliferative phase
of the endometrium). Following release of the ovum from the follicle (day 14), the remaining cells in
the ovulated follicle are stimulated by LH to become the corpus luteum, which secretes high levels of
progesterone (P). Progesterone causes the endometrial glands to become secretory (luteal phase of the
ovary = secretory phase of the endometrium). There is a problem however, because the steroid
hormones that the corpus luteum secretes inhibit GnRH secretion on which LH depends, and the corpus
luteum will degenerate if there are insufficient tropic hormones. At this point the functionalis of the
uterine wall breaks down. However, if there is a fertilized ovum, the corpus luteum is “rescued” because
the cells of the trophoblast synthesize an analog of LH called chorionic gonadotropin (hCG – human
chorionic gonadotropin). As the pregnancy progresses, the trophoblast also synthesizes P and E and by
the third month, the pregnancy can proceed without P and E from the mother.

Fetal-maternal interactions

The period between days 20 and 24 of the menstrual cycle (days 6 through 10 post ovulation)

provides a “window of receptivity” for implantation of a conceptus. It is essential that receptivity of the
uterus be synchronized with development of the embryo. Experiments on nonhuman primates and other
mammals as well as IVF (in vitro fertilization) observations have shown that the “implantation window”
is regulated by maternal factors and is preceded and followed by refractory periods. This is discussed
further below.

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The decidual reaction

During the luteal phase, that is, following ovulation, some of the stromal cells of the

endometrium enlarge and accumulate glycogen and lipid. These decidual cells disappear unless
pregnancy occurs, and the corpus luteum is maintained, providing a source of progesterone. With
pregnancy, continuing stimulation by progesterone and estrogen causes widespread decidualization,
which is greatly amplified by the presence of the implanting blastocyst. The glands of the decidua
function initially as a source of essential nutrients for the embryo until it establishes associations with
the maternal blood supply. The decidua also contributes to the protection of the embryo from
immunologic rejection and the uterine wall from excessive invasion by the embryo.

The decidua (Fig. 17-2)

The decidua is the portion of the uterine wall that is lost at parturition. Its characteristics differ in

various regions of the uterus defined by the implantation site. Immediately beneath the embryo the
chorionic villi anchor into the region known as the decidua basalis. This forms part of the placenta. The
thin layer of endometrium that surrounds the implanted embryo is the decidua capsularis. By 20 weeks
this fuses with the endometrium lining the remainder of the uterus, the decidua parietalis, obliterating
the uterine lumen.

Fig. 17-2. The decidua and fetal membranes. A., the end of the 2nd month and B., the end of the 3rd month. Sadler, TW,
Langman’s Medical Embryology 8th ed., Lippincott, Williams & Wilkins, Philadelphia (2000), p. 140.

PLACENTA

The first step in formation of the placenta is implantation. This involves a series of events:

apposition, adhesion and invasion. In humans (and other primates and rodents) the embryo becomes
completely embedded within the endometrium and the implantation is termed interstitial.

Apposition (Fig. 17-3)

The blastocyst enveloped in its zona pellucida and surrounding follicle cells reaches the lumen of

the uterus by day 4-5 post fertilization (day 18-19 of the menstrual cycle). At about day 5-6.5, the
trophectoderm begins to differentiate. At the embryonic pole the underlying mitotic, diploid layer of the

17-5

Fig. 17-3. Normal sites of implantation
in the uterine wall (generally dorsally).
Larsen, WI, Human Embryology, 3rd ed.,
Churchill Livingstone, New York (2001),
p. 22 (modified).

trophectoderm, the cytotrophoblast, produces a superficial polyploid, nonmitotic syncytial layer, the
syncytiotrophoblast. This syncytiotrophoblast is apposed to the uterine wall as the embryo hatches
from the zona pellucida.

The normal site of this interaction is the outer compact zone of the endometrium in the upper 2/3
of the body of the uterus (usually in the dorsal wall). The blastocyst at this stage is about 0.1-0.2 mm in
diameter and the mucosa into which it implants is about 5 mm thick. The slit-like cavity of the uterus is
minimal (only about 1 mm antero-posteriorly) due to the edematous mucosa. It has been postulated that
the narrowing of the uterine cavity creates a physical retention system, pressing the blastocyst against
the compact zone of the endometrium.

Other implantation sites are termed “ectopic” and pose a variety of problems. Tubal pregnancies

(within the Fallopian tube – frequently due to closure of the oviduct following pelvic inflammatory
disease) are life-threatening, as growth of the embryo will cause tubal rupture around the 8th week.
Implantation in the opening to the cervix (the cervical os) is called placenta praevia and results in severe
bleeding during pregnancy. If the fertilized ovum escapes from the infundibulum of the oviduct,
implantation can also occur at sites within the body cavity. These are also highly dangerous and must be
surgically removed.

Adhesion (Fig. 17-4)

At the site of apposition, the process of adhesion of the blastocyst to the endometrial luminal

epithelium begins. It should be said at this point that the earliest stages – adhesion and initial epithelial
penetration have never been seen in humans, but events have been deduced from observations in higher

Fig. 17-4. The syncytiotrophoblast
invades the uterine epithelium and by
8 days has expanded into the stroma.
The blastocyst is nourished by uterine
glands until an association is formed
with the maternal vasculature. Larsen,
WI, Human Embryology, 3rd ed.,
Churchill Livingstone, New York
(2001), p. 40.

17-6

primates and other mammals. The success of ART (assisted reproductive technique) has been improved
greatly through this research.

Some markers of readiness of the endometrium have been demonstrated. For instance increased

secretion of a cytokine, leukemia inhibitory factor (LIF) that can be detected in uterine fluid is
associated with successful implantation. A likely role for LIF is upregulation of endometrial expression
of heparin-binding epidermal growth factor (HB-EGF), which in turn stimulates growth of the
trophoblast and hatching of the blastocyst. Interestingly hCG from the blastocyst in turn further
stimulates the production of LIF.

The luminal epithelial cells of the endometrium have a mucus-coated microvillous border, which

is non-adhesive and anti-infective. The expression of the mucin, MUC-1, varies over the menstrual
cycle and is upregulated by progesterone. As the embryo approaches the maternal surface, it encounters
this glycocalyx. In vitro studies indicate that in the adhesion phase, paracrine secretions from the
embryo induce a change in the ectodomain of MUC-1 molecules of the endometrial epithelial cells that
are beneath and near the attached embryo. In mice only healthy embryos are able to change MUC-1
expression. This suggests that the heavy mucus layer may act as a barrier to implantation of poor quality
embryos.

During the “window of receptivity” there are also changes in the cytoskeleton of endometrial

epithelial lining cells such that disruptions in the terminal web cause microvilli in some cells to decrease
in number and size and then to fuse or disappear. The apex of the cell then takes the form of a
protrusion called a pinopode, which is thought to facilitate adhesion between the syncytiotrophoblast
and endometrial epithelial cell membranes.

Throughout apposition and adhesion of the blastocyst, it is essential that the endometrium not

only be protected from infection, but at the same time allow for the blastocyst to implant without
rejection. The trophoblast contributes to this by expressing HLA-G, a special form of the MHC I
antigen that does not stimulate resident cytotoxic T cells. In addition the populations of both T and B
cells are reduced at the site of invasion.

Invasion (Fig. 17-4)

At the site of implantation there are changes in the polarization of the epithelial cells involving

remodeling of tight junctions and adhering junctions and redistribution of apical and basolateral
membrane domains. As the blastocyst invades the endometrium, the syncytiotrophoblast cells form
junctional complexes with the lateral borders of the endometrial epithelial cells. Once they are firmly
attached, the syncytiotrophoblasts insinuate between the epithelial cells and then burrow through their
basal laminae. The decidual cells themselves may contribute to the breakdown of the basal lamina and
other components of the basement membrane as laminin and collagen-IV disappear before the
trophoblast reaches the basal surface of the endometrial epithelium. As they go, the syncytiotrophoblast
cells also secrete agents that induce apoptosis in local endometrial cells, which they phagocytize.

A note on secreted signaling factors, the extracellular matrix and integrins

Successful navigation through the peri-implantation period requires highly complex maternal-

fetal communication. This involves a great variety of substances that are produced by the corpus
luteum, the endometrium, the pre-implantation embryo, the invading trophoblast and the developing

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placenta itself. The corpus luteum is the source of the steroid hormones, progesterone and estrogen.
Alterations in these hormones and their receptors are at the basis of many of the events associated with
implantation and formation of the placenta. The pathways from the binding of steroid hormones to the
ultimate effects are highly complex, involving modulation of the transcription of a variety of substances
including signaling molecules, growth factors, integrins and components of the extracellular matrix.
This is an area of active research in which there are as yet many unanswered questions.

Among the most well-studied changes are those in the integrins, which, depending upon the forms of
their α and β subunits mediate cell-cell or cell-matrix attachment, invasion and migration; and through effects
on the cytoskeleton, control cellular function. The αvβ3 integrin that provides binding to a wide variety of
ECM molecules is maximally expressed during the window of receptivity. There are changes in integrin
expression by both the endometrium and trophoblast over the course of the formation of the placenta as noted
below (specific subunits that are expressed are not required for this course).

EXTRAEMBRYONIC CAVITIES AND MEMBRANES (Fig. 17-2)

A number of membranes and cavities serve in the maintenance of the developing embryo. The

amniotic cavity develops as an ectodermally lined space that will eventually surround the fetus. The
primary yolk sac forms when the blastocoel becomes lined with extraembryonic endoderm. This then
develops into the secondary or definitive yolk sac as acellular mesenchyme and then extraembryonic
mesoderm spread along the basal lamina of the endoderm. The definitive yolk sac plays important roles
in the first trimester. Its circulation (the vitelline circulation) is the first component of the blood vascular
system to develop in the embryo. Vitelline veins deliver nutrients from the yolk sac to the embryo, via
the hepatic portal system. In addition, the best evidence is that the first hematopoietic cells differentiate
in association with the yolk sac. The allantois forms as a diverticulum from the cloaca (not depicted in
the figure, but described in Chapter 18, development of the gut). This structure is important in non-
mammalian vertebrates in disposing of nitrogenous wastes, but is largely vestigial in humans. The
membrane that is the focus of the present discussion is the chorionic membrane, which is the embryonic
constituent of the placenta. Its development is described below.

DEFINITIVE PLACENTA – UTEROPLACENTAL CIRCULATION
Formation of the chorionic villi (Figs. 17-5 through 17-9)

The fully developed placenta is a combination of a fetal portion, formed by the chorion

(described below) and a maternal portion, formed by the decidua. The embryonic trophoblast must

Fig. 17-5. By 9 days the embryo is
completely implanted. Lacunae appear in
the syncytiotrophoblast into which maternal
blood will spill as the trophoblast invades
maternal vascular sinusoids. Larsen, WI,
Human Embryology, 3rd ed., Churchill
Livingstone, New York (2001), p. 40.

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