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The Placenta

The placenta is a temporary organ required for the development of the embryo and fetus. It allows for the exchange of metabolic products between the fetus and the mother. You will have to look in textbooks for pictures of the development of the placenta. A summary of those events is listed after the pictures shown here. The images shown here are scanned from the placenta in your slide collection (slide # 68), which is from a near-term fetus.

Placental Functions

The placenta functions in metabolism, in the transport of substances and in endocrine secretion.  

Metabolism

During early pregnancy, the placenta synthesizes glycogen, cholesterol and fatty acids, which serve as sources of nutrients and energy for the embryo and fetus.

Transport

The placenta has a very large surface area, which facilitates the transport of substances in both directions.  The surface area at 28 weeks is 5 square metres, and at term it is almost 11 square metres.  About 5 to 10% of this surface area is extremely thin, measuring only a few microns.

The bulk of the substances transferred from mother to fetus consists of oxygen and nutrients.  The fetus eliminates carbon dioxide and waste materials (eg., urea and bilirubin)  into the maternal circulation.  

The exchange of gases occurs via diffusion.  The placenta is also highly permeable to glucose, but much less permeable to fructose and other common disaccharides.  Amino acids are transported through speciic receptors.  Some proteins are transferred slowly through the placenta, mainly via pinocytosis. The transfer of maternal antibodies (mainly IgG) is important in providing passive immunity to the newborn.  Another maternal protein, transferrin, carries iron to the placental surface, from there it is actively transported into the fetal tissues.  Steroid hormones easily cross the placental barrier; protein hormones are much more poorly transported (but maternal thyroid hormone gains slow access to the fetus, and fetal insulin can reduce symptoms of maternal diabetes). 

The placenta is also very permeable to alcohol and other drugs and to some viruses.  These agents can cause birth defects.

Placental hormone synthesis:

The syncytiotrophoblast is an important endocrine organ for much of the pregnancy.  It produces both protein and steroid hormones. The major placental hormones are listed below.

Human chorionic gonadotropin (hCG): Synthesis of hCG  begins before implantation, and is responsible for maintaining the maternal corpus luteum that secretes progesterone and estrogens.  It is the basis for early pregnancy tests.  Production peaks at eight weeks and then gradually declines. Structurally, this glycoprotein resembles LH.

Estrogens and progesterone: The placenta can produce progesterone independently from cholesterol precursors,  and estrogen in concert with the fetal adrenal gland, as it does not contain all the necessary enzymes itself.  By the end of the first trimester, the placenta produces enough of these steroids to maintain the pregnancy and  the corpus luteum is no longer needed.

Human placental lactogen (hPL) or human chorionic somatomammotropin (hCS):   This hormone is similar to growth hormone and influences growth, maternal mammary duct proliferation, and lipid and carbohydrate metabolism.  

Human placental growth hormone: This hormone differs from pituitary GH by 13 amino acids.  From 15 weeks until the end of pregnancy, this hormone gradually replaces maternal pituitary GH.  Its major function is the regulation of maternal blood glucose levels so that the fetus is ensured of an adequate nutrient supply.  Its secretion is stimulated by low maternal blood glucose levels; in turn, it stimulates gluconeogenesis in the maternal liver.

Human chorionic thyrotropin (hCT): Small amounts produced, functions similar to pituitary hormone.

Human chorionic adrenocorticotropin (hACTH): Small amounts produced, functions similar to pituitary hormone.

Insulin-like growth factors:  Stimulates proliferation and differentiation of the cytotrophoblast.

Endothelial growth factor:  First produced by 4 to 5-week-old placenta; stimulates proliferation of the trophoblast.

Relaxin: Produced by decidua cells;  softens the cervix and pelvic ligaments in preparation for childbirth.  

In addition, the placenta produces dozens of proteins that have been identified immunologically but whose function is poorly understood. 

The first three figures are from the umbilical cord (slide # 67).

 

 

  Figure 1 Triangle_3Dpurp.gif (899 bytes)shows a low power view of the mucous connective tissue (also called Wharton’s jelly) that forms the bulk of the umbilical cord. Fibroblasts are the predominant cell type. They secrete fibres, whose abundance increases with age, and a jelly-like ground substance (removed during preparation). 

fig02umbart_t.jpg (6592 bytes) The umbilical cord is surrounded by the amniotic epithelium. It contains 2 umbilical arteries carrying deoxygenated blood from the fetus to the placenta, and one umbilical vein, carrying oxygenated blood from the placenta to the fetus. One of the umbilical arteries is shown in Figure 2Triangle_3Dpurp.gif (899 bytes), while Figure 3 shows part of the umbilical vein. Both the arteries and the vein have thick muscular walls (thicker in arteries) arranged in two layers, an inner longitudinal and outer circular layer. Elastic membranes are poorly developed or absent in these vessels. Blood is seen in the lumen of both the artery and vein shown here.fig03umbvein_t.jpg (7740 bytes)

 

 

 

 

 

fig04chorplate_t.jpg (11369 bytes)Figure 4Triangle_3Dpurp.gif (899 bytes)shows a low power view of the chorionic plate and the chorionic villi extending outward from it (from slide #68). The chorionic plate consists of the fused amnion and chorion. The inner part is lined by the simple cuboidal amniotic epithelium. Its location is shown here but you cannot identify it at this magnification. The connective tissue of the amion and chorion have fused and cannot be distinguished. The chorionic plate contains the ramifications of the umbilical arteries and veins which extend into the villi (see Figure 22.29, Ross et al.). No blood vessels can be distinguished in the section of chorion shown here.

Villi emerge from the chorionic plate as large stem villi that branch into increasingly smaller villi called branch villi. Profiles of these villi are seen surrounded by maternal blood and fibrinoid matter. (Fibrinoid matter consists of fibrin and other material that stains intensely with eosin, and increases in abundance as the placenta ages.) Some of the large villi, called anchoring villi, extend from the chorionic plate all the way to the maternal side where they also attach. The villus cut in longitudinal section at the far left could be an anchoring villus. A few of the numerous smaller villi are identified by asterisks.

 

fig05lmmatplac_t.jpg (12469 bytes)Figure 5Triangle_3Dpurp.gif (899 bytes) shows a low power view of the basal plate which constitutes the maternal placenta. The basal plate or decidua basalis is that part of the uterus to which the villi anchor. Along with connective tissue elements, the basal plate contains specialized cells, called decidua cells, which are transformed stromal cells that  play a nutritive role (they are rich in glycogen and lipids). At this magnification, they are very difficult to distinguish. A large villus (lying next to a mass of fibrinoid material) attaches to the basal plate at the bottom of the figure. Blood vessels can be seen within the villi of all sizes. Most of the oxygen and nutrient exchange occurs through the smaller villi. The maternal blood circulates through the intervillous spaces.

 

fig06decidua_t.jpg (8664 bytes)Figure 6Triangle_3Dpurp.gif (899 bytes) shows a high power view of decidual cells in the area of the decidua parietalis. (This figure is made from slide #69). Decidual cells are large, polyhedral cells with pale cytoplasm which are usually found in clusters. Part of a gland is also seen.

 

fig07anchor_t.jpg (12342 bytes)Figure 7Triangle_3Dpurp.gif (899 bytes) shows a very low power view through the bulk of the placenta. A large villus, probably an anchoring villus, lies among the profiles of numerous smaller branch villi, a few of which are identified with asterisks.

 

 

fig08syncyt4_t.jpg (10437 bytes)Figure 8Triangle_3Dpurp.gif (899 bytes) shows a high power view through villi in the placenta. The bulk of the villi consists of connective tissue in which blood vessels are found. The outer part of the villus is surrounded by the syncytiotrophoblast which stains dark blue. When the nuclei are fairly evenly spaced, the syncytiotrophoblast looks like a cuboidal epithelium. Sometimes nuclei are gathered in clusters to form a syncytial knot. In other areas (x) there are few nuclei and the syncytium is so attenuated that it appears that the villus has no covering. At this stage in the pregnancy, the cytotrophoblast underlying the syncytiotrophoblast has almost completely disappeared. Maternal red blood cells and clumps of fibrinoid can be seen in the intervillous spaces.

Most of the cells in the connective tissue core of the villi are fibroblasts. Only their nucleus can be seen, as their cytoplasm blends in with the fibres of the CT. Cells with a discernable amount of cytoplasm located within the core of the villus are macrophages called Hofbauer cells. They are often difficult to find. (Cells with a discernable amount of cytoplasm immediately underneath the syncytiotrophoblast should be identified as cytotrophoblast cells. As this is a late-term placenta, you will not see too many.)

 

fig09matplac_t.jpg (10083 bytes)Figure 9Triangle_3Dpurp.gif (899 bytes) is very similar to Figure 8 except that it was sectioned near the basal plate. Some decidual cells in the basal plate are indicated. The basal plate (and maternal septa) are also lined with syncytiotrophoblast.

 

 

 

Summary of  the events in the development of the placenta.

30 hours: Beginning of mitotic divisions (blastomeres).

3 days: Morula (12-16 cells) enters uterus.

4 days: Spaces appear in central blastomeres. Fluid from uterine cavity enters. Spaces unite to form one cavity. Inner cells pushed together. Formation of blastocyst with inner cell mass (embryoblast cells) and outer ring of trophoblast cells (~ 50-60 cells). Zona pellucida starts to degenerate. 

5 days: Zona pellucida has degenerated and now blastocyst can increase in size (late blastocyst).

6 days: Blastocyst attaches to uterine epithelium, usually adjacent to inner cell mass. Area where inner cell mass is located is called the embryonic pole.

7 days: Trophoblast proliferates and differentiates into inner cytotrophoblast and outer syncytiotrophoblast. Nutrition is by diffusion and erosion of maternal tissues. Syncytiotrophoblast secretes enzymes to invade maternal tissues. (~45% of embryos undergo early spontaneous abortion). Hypoblast forms; believed to occur via delamination from the inner cell mass. 

8 days: Finger-like processes of syncytiotrophoblast continue to invade. Cytotrophoblast cells undergo mitosis and enter syncytiotrophoblast. Secretion of hCG begins. Uterine stroma cells become decidua cells (glycogen/lipid-laden) around blastocyst. Inner cell mass forms bilaminar disc (upper layer called epiblast, lower called hypoblast). 

Amniotic cavity appears at embryonic pole:  a layer of epiblast cells is displaced toward the embryonic pole by fluid that has begun to collect between epiblast cells. These cells, now called amnioblasts, differentiate into a thin membrane that separates the new cavity (amnion) from the cytotrophoblast.  Hypoblast cells give rise to layer of cells (exocoelomic membrane) lining lower cavity, called exocoelomic cavity (to be primary yolk sac). 

9 days: Cells from hypoblast give rise to loosely arranged tissue, called extraembryonic mesoderm that surrounds amnion and primary yolk sac. Lacunae appear in syncytiotrophoblast. Endometrial capillaries rupture, glands erode. Syncytiotrophoblast has spread to totally surround blastocytst. 

10 days: Lacunae in syncytiotrophoblast fill with maternal blood and glandular secretions. Maternal sinusoids (capillaries) anastomose with lacunae = start of uteroplacental circulation. Lacunar networks begin to form = future intervillous spaces. Embedding of embryo is completed.

11-12 days: Directional blood flow from maternal arteries to maternal veins through lacunae. Isolated spaces appear in enlarging extraembryonic mesoderm. Epithelium of endometrium completely regenerated.

13 days: Spaces in extraembryonic mesoderm fuse to form extraembryonic coelome, amnion remains attached to chorion at connecting stalk. Extraembryonic coelome separates somatic (lines trophoblast and amnion) from splanchnic (around primary yolk sac) extraembryonic mesoderm. Primary yolk sac decreases in size. (Secondary) yolk sac forms from hypoblast. Early start of primary villi. Chorion: 2 layers of trophoblast and extraembryonic somatic mesoderm.

14 days: Primary yolk sac pinches off. Cytotrophoblast sends cords of cells into syncytiotrophoblast = primary chorionic villus. Prochordal plate forms at rostral end of bilaminar disc (thickening of hypoblast, site of future mouth). 

16 days: Allantois forms = diverticulum from caudal yolk sac into connecting stalk. Secondary villi form when mesoderm pushes into primary villi. Secondary villi = mesoderm + cytotrophoblast + syncytiotrophoblast. Secondary villi cover all of chorionic sac. Tertiary villi form when mesenchymal cells in villi differentiate into blood vessels. Vessels also form in the mesenchyme of the chorion, connecting stalk and embryo. 

21 days: Embryonic blood begins to flow through capillaries of chorionic villi. Diffusion of nutrients/wastes between maternal and embryonic circulations through walls of villi. Cytotrophoblastic shell forms when cytotrophoblast cells proliferate and push through syncytiotrophoblast to attach chorionic sac to endometrium. Stem villi (anchoring villi): attached to maternal tissue via cytotroph shell. Branch villi: grow from sides of stem villi, are main site of nutrient/O2 exchanges. 

Maternal part of the placenta

 There is a narrow window between days 20-24 in the ''ideal'' menstrual cycle when implantation can occur.  The hormonally-conditioned endometrial epithelial cells contain adhesion molecules (integrin units) that allow implantation. Correspondingly, trophoblast cells also express integrins on their surface.  Possibly, bridging ligands connect the integrin molecules of the embryo and endometrium.  The surface of the trophoblast is probably not uniform because both in vivo and in vitro, the trophoblast attaches at the area of the inner cell mass. 

The syncytiotrophoblast invades between uterine epithelial cells.  This invasion in enzymatically mediated, but the biochemical basis is not well understood. 

The fibroblast-like stromal cells of the edematous endometrium swell with the accumulation of glycogen and lipid droplets.  They are now called decidual cells. (This name -''decidua'' is Latin for ''a falling off'' - reflects their fate;  they will be sloughed off  at birth.) The decidual cells form a tightly adherent, massive cellular matrix that first surrounds the implanting embryo and later occupies most of the endometrium. This development is called the decidua reaction.  

Different terms are used to describe the different locations:   

Decidua basalis: deep to the conceptus and forms the maternal part of the placenta.

Decidua capsularis: covers the conceptus.

Decidua parietalis: all the rest of the endometrium.

Many decidual cells degenerate near the embryo in the region of the syncytiotrophoblast.  Together with maternal blood and uterine secretions, they provide a rich source of  nutrition. Another function of the decidua reaction may be to protect maternal tissue from uncontrolled invasion of the syncytiotrophoblast.  Decidua cells may also be involved in hormone production.  

A primary function of the decidua reaction may be to provide an immunologically privileged site for the embryo.  Concurrent with this reaction, the leucocytes that infiltrated the endometrial stroma during the late progestational phase secrete interleukin-2, which prevents maternal recognition of the embryo as a foreign body during the early stages of implantation.  Failure of implantation is a serious problem for in vitro fertilization and embryo transfers. 

Circulation in the placenta

Maternal blood is discharged in a pulsatile fashion into the intervillous space by 80 to 100 spiral arteries in the decidua basalis. It spurts toward the chorionic plate and flows slowly around the villi, eventually returning to the endometrial veins and the maternal circulation.  The maternal arteries which open into the intervillous spaces are partially occluded by a plug of cytotrophoblastic cells, presumably to regulate blood flow.  There are about 150 ml of maternal blood in the intervillous spaces, which is exchanged 3 or 4 times a minute.

During the first 12 weeks, the fluid in the intervillous spaces is a filtrate of maternal plasma without blood cells. During this period, the fetus has embryonic hemoglobin which binds oxygen under very low tension.  After 12 weeks, maternal blood cells appear in the intervillous spaces, and the fetus produces fetal hemoglobin which requires a higher oxygen tension.  

Fate of the placenta

At first, chorionic villi cover the whole placenta. As chorion grows, villi associated with decidua capsularis are compressed and their blood supply is reduced. 

By the eighth week, the villi under the decidua capsularis have begun to degenerate and leave smooth chorion (chorion laeve). Meanwhile, villi near decidua basalis increase in number, branch profusely and enlarge to form villous chorion (chorion frondosum). 

Until the18th week: Placenta grows in thickness, covers 15-30% of decidua. (18th week post-fert = 20th week gestation from LNMP). 

By the 4th month, the cytotrophoblast begins to break up.  It is gone by 5 months.  The syncytiotrophoblast has a huge number of microvilli; over 1 billion per square cm at term.  

By the end of the 4th month: decidua basalis almost completely replaced with fetal part. Invading chorionic villi erode endometrial tissue and enlarge intervillous space. This leaves wedge-shaped areas of decidual tissue called placental septa that project toward the chorionic plate. These septa divide fetal part of placenta into convex areas called cotyledons. Cotyledon = two or more stem villi and their many branch villi. There is communication between compartments because septa don't reach chorionic plate. 

Fate of fetal membranes 

Amnion and chorion: Amnion grows faster than chorion, so they fuse to form amniochorionic membrane, which fuses with decidua capsularis. D. capsularis will degenerate, and a-c membrane will fuse with parietalis (ca. 22 weeks). 

Allantois: Involved in early blood formation and development of bladder. Its blood vessels become umbilical vein and arteries. Adult remnant = median umbilical ligament. 

Yolk sac: Role in transfer of nutrients during second and third weeks. Blood development occurs from third to sixth week. Gives rise to primordial germ cells of gonads. Dorsal part incorporated as primitive gut. Atrophies as pregnancy advances, almost gone by 20 weeks. 

Formation of blood vessels and blood:

The process: Mesenchymal cells called angioblasts aggregate to form blood islands. Small cavities appear in the blood islands. Some angioblasts flatten to become endothelial cells and arrange themselves around the cavities. Blood develops from endothelial cells. Vessels bud and fuse with other vessels. 

ca 15 days: Blood vessel formation begins in extraembryonic mesoderm covering yolk sac, connecting stalk and chorion. 

ca 17 days: Blood vessel formation begins in embryo.

ca 18 days: Heart begins to form (two endothelial tubes). 

ca 21 days: Blood forms in vessels of yolk sac and allantois (which appears on day 16)

ca 22 days: Heart muscle begins to beat.

ca 24-25 days: Heart tubes fuse to form single tube (during lateral folding of embryo).

ca 29 days: Blood formation in embryo begins (liver, spleen, bone marrow, lymph nodes).

 

Why is the Fetus Not Rejected by the Maternal Immune System?

Normally  foreign tissues are rejected through the activation of cytotoxic lymphocytes, and sometimes also through humoral immune responses.  The fetus and placenta are immunologically distinct from the mother, but are not recognized as foreign tissue and rejected by her immune system. 

Several reasons have been suggested as to why the fetus is not rejected but no definitive answers have been found. 

One possibility is that the fetal tissues don't present foreign antigens.  Neither of the two main classes of  major histocompatibility antigens are expressed on the syncytiotrophblast and non-villous cytotrophoblast (cytotrophoblastic shell).  But these antigens are present on the cells of the fetus and the stromal tissues of the placenta.  The expression of the minor  histocompatibility antigens follows a similar pattern.  However, other minor antigens are expressed on the trophoblastic tissues.  Furthermore, breaks can eventually appear in the placental barrier, and fetal red and white blood cells have been found in the maternal blood.  It is not clear why they don't sensitize the maternal immune system.  

Another theory says that the mother's immune system is ''paralysed'' during pregnancy.  Yet the mother can mount immune responses to infections and tissue grafts.  There is the possibility of a selective repression of the immune response to fetal antigens, but the Rh incompatibility response shows that this is not universally the case.  

A third possibility is that local decidual barriers either prevent immune recognition of the fetus by the mother or prevent competent immune cells from the mother from reaching the fetus.  There is evidence for a functioning decidual immune barrier, but in many cases that barrier is known to be breached through trauma or disease.

It is possible that current spontaneous abortions involve immunological interrelationships between the fetus and the mother.  

 



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