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 !
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