Lecture 2Lecture 2

DEVELOPMENT OF PLACENTA.DEVELOPMENT OF PLACENTA.

PLACENTA’S MORPHOLOGY PLACENTA’S MORPHOLOGY AND FUNCTIONSAND FUNCTIONS

Prof. Vlad TICA, MD, PhDProf. Vlad TICA, MD, PhD

FETAL TISSUES OF THE FETAL-MATERNAL COMMUNICATION SYSTEM

The extravillous and villous traphoblasts

Placental arm

The fetal membranes (the amnion-chorion leave)

Paracrine arm

Human placenta : hemochorioendothelial type

EARLY HUMAN DEVELOPMENT Zygote

Blastomeres

Morula

Blastocyst

Embryo

Fetus

Conceptus

FERTILIZATION OF THE OVUM AND CLEAVAGE OF THE ZYGOTE

58-cell blastocyst107-cell blastocyst

IMPLANTATION

Trophoblast is the most variable in structure, function and development

invasiveness provides for attatchment of blastocyst to decidua of uterine cavity

nutrition of the conceptus

function as endocrine organ in human pregnancy

essential to maternal physiological adaptations & maintenance of pregnancy

BIOLOGY OF TROPHOBLAST

DifferentiationCellular, syncytial / uninuclear , multinuclear

Formation of the Syncytium

Cytotrophoblasts are the cellular progenitors of the syncytiotrophoblast

 Cytotrophobl

astSyncytiotrophobla

st

Morphologically

uninuclear cells

multinuclear giant cells

cell boderswell

demarcatedlacking

nucleus single, distinct multiple & diverse

miotic figure present absent

Origin germinal cell cytotrophoblast

after apposition & adherence, intrusion of cytotrophoblast between endometrial epithelial cells

this process is facilitated by degradation of the extracellula matrix of endometrium /decidua catalyzed by

urokinase-type plasminogen activator

urokinase plasminogen activator receptor

multiple metalloproteinase

These functions of cytotrophoblasts invading the endometrium are indistinguishable from those of metastasizing malignant cells

IMMUNOLOGICAL ACCEPTANCE OF THE CONCEPTUS

Previous Theories:antigenic immaturity of the embryo-fetusdiminished immunological responsiveness of the

pregnant woman Decidua: immunologically privileged tissue site

The acceptance and the survival of conceptus in the maternal uterus must be attributed to immunological peculiarity of the trophoblasts, not the decidua

CURRENT STATUS OF RESEARCH

Expression of the HLA system in trophoblast unique set of lymphocytes

may provide explanation for immunological acceptance of the conceptus

IMMUNOCOMPETENCY OF THE TROPHOBLASTS

Many researchers focused on the expression of the major histocompatibility complex (MHC) antigens in trophoblast

MHC class II antigens are absent from trophoblasts at all stages of gestation

TROPHOBLAST HLA CLASS I EXPRESSION

Normal implantation is dependent upon controlled trophoblast invasion of maternal endometrium/decidua and the spiral arteries

a mechanism for permitting and then for limitting trophoblast invasion

Such a system involves the uterine large granular lymphocytes(LGSs) and the unique expression of specific nomomeric HLA class I antigens in the trophoblasts

HLA-I GENE EXPRESSION HLA genes

the products of multiple genetic loci of the MHC within short arm of chromosome 6

17 class I genes have been identified

three classical genes  A, B, C  => major class I(a) transplantation

antigens

three other class I(b) genes E, F, G  => class I HLA antigen

HLA-G gene

UTERINE LARGE GRANULAR LYMPHOCYTE (LGL)

Believed to be lymphoid and of bone marrow origin and natural killer cell lineage

Present in large numbers only at the midluteal phase of the cycle-at the expected time of implantation in the human endometrium

Near the end of luteal phase of nonfertile ovulatory cycles, the nuclei of LGLs begin to disintegrate

With blastocyst implantation, these cells persist in the decidua during the early weeks of pregnancy

Speculated that LGLs are involved in the regulation of trophoblast invasion

HLA-G EXPRESSION IN HUMAN TROPHOBLASTS

HLA-G antigen

identified only in extravillous cytotrophoblast in decidua basails and chorion laeve

not present in villous trophoblast, either in syncytium or in cytotrophoblasts

expressed in cytotrophoblast that are contiguous with maternal tissue (decidual cell)

It is hopothesized that HLA-G is immunologically permissive of antigen mismatch between mother and fetus

HLA EXPRESSION IN THE HUMAN EMBRYO

as gestation progresses, cells from inner cell mass of blastocyst gradually develop both class I and II HLA antigen

these tissue are not in direct contact with maternal tissue or blood

IMPLANTATION AND INTEGRIN SWITCHING

Apposition, adherence, then intrusion and invasion of the endometrium/decidua by cytotrophoblast (implantation) appears to be dependent upon

trophoblast elaboration of specific proteinases

degrade selected extracellular matrix proteins of the endometrium/decidua

coordinated and alternating process referred to as "integrin switching“

facilitates migration and then attachment of trophoblasts in the decidua

INTEGRIN

one of four families of cell adhesion molecules (CAMs)

cell-surface receptors that mediate the adhesion

of cells to extracellular matrix proteins

TROPHOBLAST ATTACHMENT IN DECIDUA: ONCOFETAL FIBRONECTIN

onfFN(oncofetal fibronectin)

unique glycopeptide of the trophouteronectin moleculetrophouteronectin or trophoblast glue

formed by extravillous trophoblast, including those of chorion laeve

Function:a critical role for migration and attachment of the

trophoblasts to maternal deciduafacilitates separation of extraembryonic

tissues from the uterus at delivery

EMBRYONIC AND PLACENTAL DEVELOPMENT

Early Blastocyst

Trophoblast

hCG

Grow & expand

EMBRYONIC DEVELOPMENT AFTER IMPLANTATION

CYTOTROPHOBLAST INVASION OF DECIDUAL VESSELS

Capillary networkArteriolesSpiral arteries

SEVERAL CURIOUS FEATUREStrophoblasts in the vessels lumen do not appear to

replicate

these cells are not readily dislodged by flow of blood

these cytotrophoblasts appear to migrate against arterial flow and pressure

no obvious adhesion of these cells one to the other

invasion of maternal vascular tissue bt trophoblasts involves only the decidual spiral arteries, not the veins

ORGANIZATION OF PLACENTA

Trophoblast Ultrastructure

Prominent microvilli of the syncytial surface (brush border)

pinocytotic vacuoles and vesiclesabsorptive and secretory placental function

ORGANIZATION OF PLACENTA

Chorionic Villi12th day

Primary villiproliferation of cytotrophoblast extend into

syncytiotrophoblast

Secondary villimesenchymal cord, derived from

cytotrophoblast, invade solid trophoblast column

Tertiary villi after angiogenesis occurs from the

mesenchymal cores in situ

17th day - fetal blood vessels are functional & placental circulation established

ORGANIZATION OF PLACENTA

Characteristic of development of H-molesome villi, in which absence of angiogenesis

results in a lack of circulation, may distended with fluid and form vesicles

ORGANIZATION OF PLACENTA

Placental Cotyledons

Certain villi of the chorion frondosum extend from chorionic plate to the decidua and serve as anchoring villi

Each of the main stem villi (truncal) and their ramifications (rami) constitute a placental cotyledon (lobe)

For each cotyledon, a 1:1:1 ratio of artery to vein to cotyledon

ORGANIZATION OF PLACENTA

Breaks in the Placental "Barrier "

Numerous findings of passage of cells between mother and fetus in both directions

ex) erythroblastosis fetalis

A few fetal blood cells are found in the mother's blood

Fetal leukocytes may replicate in the mother and leukocytes bearing a Y chromosome have been identified in women for up to 5 years after giving birth to a son

ORGANIZATION OF PLACENTA

ORGANIZATION OF PLACENTAPlacetal Size and Weight

Total number of cotyledons remains the same throughout gestation

Individual cotyledones continue to grow

Placental weights vary considerably

As villi continue to branch and terminal ramifications become more numerous and smaller> volume and prominence of cytotrophoblasts decrease

As syncytium thins and forms knots> vessels become more prominent and lie closer to the

surface

The stroma of the villi in early pregnancy

branching connective ts. cells are seperated by abundant loose intercellular matrix

later stroma becomes denser, and the cells more spindly and

more closely packed

PLACENTAL AGING

Histologic changes that accompany placental growth and aging are suggestive of increase in the efficiency of transport to and exchange to meet increasing fetal metabolic requirements

decrease in thickness of the syncytium

partial reduction of cytotropholastic cell

decrease in the stroma

increase in the number of capillaries and approximation of these vessels to the syncytial surface

By 4 months:

the apparent continuity of the cytotrophoblast is broken

the syncytium forms knots on the more numerous, smaller villi

PLACENTAL AGING

At term: Covering of villi may be focally reduced to a thin layer of

syncytium with minimal connective tissue

Fetal capillaries seem to abut the tropohoblast

Villous stroma, Hofbauer cells, and cytotrophoblasts are markedly reduced

villi appear filled with thin-walled capillaries

Other changes suggestive of a decrease in the efficiency for placental exchange:

Thickening of the basement membrane of trophoblast capillaries

Obliteration of certain fetal vessels

Fibrin deposition on the surface of villi in basal and chorionic plates as well as elsewhere in the intervillous space

PLACENTAL AGING

BLOOD CIRCULATION IN THE MATURE PLACENTA

A section through the placenta in situ amnion → chorion

→ chorionic villi → intervillous space → decidual plate → myometrium

FETAL CIRCULATION

2 umbilical arteries

deoxygenated, or "venous-like" blood flows to the placenta

1 umbilical vein

with a significantly higher oxygen content

Hyrtl anastomosis

2 umbilical a. separate at the chorionic plate to supply branches to the cotyledons

MATERNAL CIRCULATION

Intervillous space -> chorionic plate -> vein

Spiral a., vein

Ut. Contraction

Intervillous space

Ramsey's concept

THE PRINCIPLE FACTORS REGULATING THE FLOW OF BLOOD IN THE

INTERVILLOUS SPACE arterial blood pressure

intrauterine pressure

pattern of uterine contraction

factors that act specifically upon the arteriolar walls

THE AMNION

Innermost fetal membrane and is contiguous with amnionic fluid

Avascular structure Provide almost all of the tensile strength of the fetal

membranes

protect against rupture or tearing

STRUCTURE single layer of cuboidal epithelial cells

basement membrane

acellular compact layer

fibroblast-like mesenchymal cells

zona spongiosa

Missing element of human amnion

smooth muscle cell, nerves, lymphatics, blood vessels

DEVELOPMENT

AMNION CELL HISTOGENESIS Amnion epithelial cells

derived from fetal ectoderm (embryonic disc)

active metabolically; synthesis of tissue inhibitos of metalloproteinase-1

Amnion mesenchymal cells

derived from the embryonic mesoderm

synthesis of interstitial collagens that make up the compact layer of the amnion

highly capable of synthesizing cytokines - IL-6, IL-8, MCP-1 increased in response to bacterial toxin and IL-1

ANATOMY

Reflected amnion

Placental amnion

Umbilical amnion

TENSILE STRENGTH

Decidua and chorion laeve are quite elastic and can expand to twice normal size during pregnancy

Amnion provides the major strength of the membrane

Tensile strength of amnion resides almost exclusively in the compact layer

composed of cross-linked interstial collagens I, III, and lesser amounts of V and VI

Development

UMBILICAL CORD AND RELATED STRUCTURES

STRUCTURE AND FUNCTION OF UMBILICAL CORD

Umbilical cord (funis)

fetal umbilicus - fetal surface of the placenta

diameter: 0.8 - 2.0 cm

average length: 55 cm (usual length: 30 - 100 cm)

Nodulation, false knot

Extracellular matrix: Wharton's jelly

PLACENTAL FUNCTIONSPLACENTAL FUNCTIONS

MATERNO- PLACENTAL UNIT

PLACENTAL FUNCTIONSTransfer of nutrients and waste products between the

mother & fetus

TRANSFER

RESPIRATORY

EXCRETORY

NUTRITIVE

Produces or metabolizes the hormones & enzymes necessary to maintain the pregnancy

HORMONAL

BARRIER IMMUNOLOGICAL

ENZYMATIC

HAEMATOPOETIC

PLACENTAL FUNCTIONS

TRANSFER OF SUBSTANCES ACROSS PLACENTA

RESPIRATORY FUNCTION

Intake of O2 & output of CO2 takes place by simple diffusion

O2 supply to fetus rate of 5ml/kg/min & this achieved with cord flow of 165-330ml/min

EXCRETORY FUNCTION

Waste products urea, uric acid, creatinine are excreted to maternal blood by simple diffusion

NUTRITIVE FUNCTION

Glucose is the major energy substrate provided to the placenta and fetus

It is transported across the placenta by facilitated diffusion via hexoze transporters

Although the fetus receives large amounts of intact glucose, a large amount is oxidized within the placenta to lactate, which is used for fetal energy production

Transport is facilitated by the close approximation of maternal and fetal vascular systems within the placenta

It is important to recognize that there normally is no mixing of fetal and maternal blood within the placenta

TRANSPORT FUNCTION

Amino acid concentrations in fetal blood are higher than in maternal blood

Amino acids are therefore transported to the fetus by active transport

Lipids - TG`s & FA directly transported from mother to fetus in early pregnancy but synthesised in fetus later in pregnancy. Thus, fetal fat has got dual origin

Water & electrolytes – Na+, K+, Cl- by simple diffusion. Ca, Ph, iron by active transport

TRANSPORT FUNCTION

Protective barrier to the fetus against noxious agents circulating in maternal blood

High MW > 500 daltons

BARRIER FUNCTION

IMMUNOLOGICAL FUNCTION Fetus & placenta contain paternally determined

antigens, foreign to the mother

Inspite of this, no evidence of graft rejection

Probably:

1. Fibrinoid & sialomucin coating of trophoblast may suppress the troblastic antigen

2. Placental hormones, steriods, HCG have got weak immunosuppressive effect, may be responsible for producing sialomucin

3. Nitabuch`s layer which intervenes b\n decidua basalis & cytotrophoblast probably inactivates the antigenic property of tissue

4. There is little HLA & blood group antigens on trophoblast surface. So antigenic stimulus is poor

5. Production of block antibodies by mother, protects fetus from rejection

IMMUNOLOGICAL FUNCTION

Fetal, placental & maternal compartments form an integrated hormonal unit

The feto-placental-maternal (FPM) unit creates the

ENDOCRINE ENVIRONMENT

that maintains and drives the processes of pregnancy and pre-natal development

PLACENTAL HORMONES Human Chorionic Gonadotropin

(hCG)

Human Chorionic Somammotropin (hCS)

or Placental Lactogen (hPL)

OTHER HORMONES

Chorionic Adrenocorticotropin

Chorionic Thyrotropin

Relaxin

PTH-rP

hGH-V

Estrogen (E)

Progesterone (P)

HYPOTHALAMIC-LIKE RELEASING HORMONES

GnRH

CRH

cTRH

GH-RH

PLACENTAL PEPTIDE HORMONES

Neuropeptide-Y

Inhibin & Activin

ANP

To understand the FPM one should know:

1. The major hormones involved:hCG

ProgesteroneEstrogen

Human Chorionic Somatomammotropin (hCS)(placental lactogen)

2. How the FPM compartments work together to produce the steroid hormones

3. The transfer of hormones between the FPM compartments

HUMAN CHORIONIC GONADOTROPIN (hCG)

Pregnancy hormone – glycoprotein

Half life – 24 hrs

Levels peak at 60-70 days, then remain at a low plateau for the rest of pregnancy

Placental GnRH have control of hCG

FUNCTIONS:

1.Rescue & maintenance of function of corpus luteum prevents degeneration of corpus luteum stimulates corpus luteum to secrete E + P

which, in turn, stimulate continual growth of endometrium

2.hCG stimulates Leydig cells of male fetus to produce testosterone in conjunction with fetal pituitary gonadotrophins. Thus indirectly involed in development of external genitalia

3.Suppresses maternal immune function & reduces possibility of fetus immunorejection

HUMAN CHORIONIC GONADOTROPIN (hCG)

HUMAN CHORIONIC SOMAMMOTROPIN (hCS) or PLACENTAL LACTOGEN

Structure similar to growth hormone

Produced by the placenta

Levels throughout pregnancy

Large amounts in maternal blood but DO NOT reach the fetus

Biological effects are reverse of those of insulin: utilization of lipids; make glucose more readily available to fetus, and for milk production.

hCS levels proportionate to placental size

hCS levels placental insufficiency

HUMAN CHORIONIC SOMAMMOTROPIN (hCS) or PLACENTAL LACTOGEN

ESTROGEN (E)Forms:

Estriol (most important )

Estradiol

Estrone

Levels increase throughout pregnancy

90% produced by placenta (syncytiotrophoblast)

Placental production is transferred to both maternal and fetal compartments

Two of the principle effects of placental estrogens are:

Stimulate growth of the myometrium and antagonize the myometrial-suppressing activity of progesterone

In many species, the high levels of estrogen in late gestation induces myometrial oxytocin receptors, thereby preparing the uterus for parturition

Stimulate mammary gland development

Estrogens are one in a battery of hormones necessary for both ductal and alveolar growth in the mammary gland

ESTROGEN (E)

PROGESTERONE (P)

Levels increase throughout pregnancy

80-90% is produced by placenta and secreted to both fetus and mother

Progestins, including progesterone, have 2 major roles during pregnancy:

Support of the endometrium to provide an environment conducive to fetal survivalIf the endometrium is deprived of progestins,

the pregnancy will inevitably be terminated

Suppression of contractility in uterine smooth muscle, which, if unchecked, would clearly be a disaster

This is often called the "progesterone block" on the myometrium

]

Toward the end of gestation, this myometrial-quieting effect is antagonized by rising levels of estrogens, thereby facilitating parturition

PROGESTERONE (P)

Progesterone and other progestins also potently inhibit secretion of the pituitary gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH)

This effect almost always prevents ovulation from occuring during pregnancy

PROGESTERONE (P)

THANKS !