The Placenta and Fetal Membranes

부산백병원 산부인과R1. 조인호

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• Moore, fig3-5

• 58-cell blastocyst• 107-cell blastocyst• Fig 5-1

• Implantation– Moore, fig 3-4

• Biology of trophoblast– Trophoblast is the most variable in structure, f

unction 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

• Differentiation– Cellular, syncytial/ uninuclear , multinuclear

• Formation of the Syncytium

– Cytotrophoblasts are the cellular progenitors of the syncytiotrophoblast

  Cytotrophoblast Syncytiotrophoblast

Morphologically uninuclear cells multinuclear giant cells

cell boders well demarcated lacking

        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 extrac

ellula 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-fetus– diminished immunological responsiveness of the preg

nant 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 acce

ptance of the conceptus

• 주로 trophoblast HLA expression (monomorphic HLA-G class I) 과 uterine large granular lymphocyte (LGL) 로 설명하고 있다 . 그러나 아직은 완전하지 않다 .

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 trophoblas

ts 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 troph

oblast 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 de

cidua basails and chorion laeve– not present in villous trophoblast, either in syncyti

um or in cytotrophoblasts.– expressed in cytotrophoblast that are contiguous

with maternal tissue (decidual cell)• It is hopothesized that HLA-G is immunologic

ally 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 tissuee are not in direct contact with ma

ternal 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 trophoblas

ts in the decidua

• Integrin – one of four families of cell adhesion molecules

(CAMs) – cell-surface receptors that mediate the adhesi

on of cells to extracellular matrix proteins

Trophoblast Attachment in Decidua: Oncofetal Fibronectin

• onfFN(oncofetal fibronectin)– unique glycopeptide of the trophouteronectin mol

ecule• trophouteronectin or trophoblast glue

– formed by extravillous trophoblast, including those of chorion laeve

– Function• a critical role for migration and attachment of the troph

oblasts to maternal decidua• facilitates separation of extraembryonic tissues from t

he uterus at delivery

Embryonic and Placental Development

• Early Blastocyst– Trophoblast– hCG– Grow & expand

Embryonic Development after Implantation

Cytotrophoblast Invasion of Decidual Vessels

• Capillary network• arterioles• Spiral arteries

• Several curious features– trophoblasts in the vessels lumen do not appear to re

plicate– these cells are not readily dislodged by flow of blood– these cytotrophoblast appear to migrate against arteri

al flow and pressure– no obvious adhesion of these cells one to the other– invasion of maternal vascular tissue bt trophoblasts in

volves only the decidual spiral arteries, not the veins

Organization of Placenta

• Trophoblast Ultrastructure– Prominent microvilli of the syncytial surface (br

ush border)– pinocytotic vacuoles and vesicles

• absorptive and secretory placental function

• Chorionic Villi– 12th day 에 처음 발생– Primary villi

• proliferation of cytotrophoblast extend into syncytiotrophoblast

– Secondary villi• mesenchymal cord, derived from cytotrophoblast, in

vade solid trophoblast column – Tertiary villi

• after angiogenesis occurs from the mesenchymal cores in situ

– 17th day 에 fetal blood vessels are functional & placental circulation 이 establish 됨 .

• Characteristic of development of H-mole– some villi, in which absence of angiogenesis r

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

• Placental Cotyledons– Certain villi of the chorion frondosum extend fr

om 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

• Breaks in the Placental " Barrier“– Numerous findings of passage of cells betwee

n 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 leukocyte s bearing a Y chromosome have been identified in women for up to 5 years after giving birth to a son

• Placetal Size and Weight

– Total number of cotyledons remains the same throughout gestation

– Individual cotyledones continue to grow– Placental weights vary considerably

• Placental Aging– As villi continue to branch and terminal ramificati

ons become more numerous and smaller• > volume and prominence of cytotrophoblasts decreas

e

– As syncytium thins and forms knots• > vessels become more prominent and lie closer to th

e 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 mor

e closely packed

– 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 approxim

ation of these vessels to the syncytial surface

– By 4 months• the apparent continuity of the cytotrophoblast is br

oken• the syncytium forms knots on the more numerous,

smaller villi

– At term• Covering of villi may be focally reduced to a thin lay

er of syncytium with minimal connective tissue• Fetal capillaries seem to abut the tropohoblast• Villous stroma, Hofbauer cells, and cytotrophoblast

s 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 trophobla

st 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

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• Two umbilical a. separate at the chorionic

plate to supply branches to the cotyledons

Maternal Circulation

• Intervillous space -> chorionic plate -> vein• Spiral a. 는 수직으로 , vein 은 수평으로

주행– Ut. Contraction 하면 vein 차단– Intervillous space 내에 정체되어 모체와

태아간의 물질교환• 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 th

e 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, I

II, and lesser amounts of V and VI

Metabolic Functions • solute and water transport to maintain amnio

nic fluid homeostasis• produces a variety of bioactive compounds

– vasoactive peptides, growth factors, cytokines • Amnionic Fluid

– normally clear fluid that collects within the amnionic cavity increases in quantity as pregnancy advances until near term, when it normally decreases

– Average volume of about 1,000 mL is found at term

Umbilical Cord and related Structures

• Development

Structure and Function • Umbilical cord, or 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