Placentation and trophoblast 1 Flashcards

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1
Q

Describe the placenta

A

An organ unique to pregnancy

Forms the interface between the mother and the fetus.

The placenta is fetal in origin at term it weighs 500-1000g

Acts as the lungs, gut and kidneys of the fetus

Acts as an endocrine organ releasing hormones into the maternal circulation such as hCG and progesterone

The placenta is a semi-allograft, the cells have genetic material from both the mother and the father

In a human pregnancy, fetal cells are in direct contact with maternal blood

This requires mechanisms to evade the maternal immune system

However the fetal and maternal circulations do not mix

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2
Q

Describe the process of placental development

A

Trophoectoderm proliferates and fuses to form a primitive syncytium (PS) beneath the implanted embryo

TC migrate or invade into the decidua

Lacunae (L) form by the action of proteases which later develop into the intervillous space

Cytotrophoblasts proliferate and migrate through the syncytium to form the anchoring villi

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3
Q

Further placenta structure description

A

Highly branched with a large surface area for exchange
Outer layer of fused cells- the syncytium
Underlying cytotrophoblast stem cells
Diffusion distance to vessels small
Growth is regulated by a number of factors including IGF I and II

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4
Q

Describe villous structure

A

2 circles, syncytium on the outside
cytotrophoblast stem cells on the inside
placental vessels like circles on the inside
Hofbauer cells are small circles around the placental vessels
the cytoplasm empty space are the ‘placental stromal cells’

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5
Q

Formation of syncytium

A

A positive feedback loop governs GCM1 activity, hCGβ expression, and placental cell differentiation. The binding of hCG to LH/CGR elevates cAMP which activates PKA.

PKA phosphorylates GCM1 on Ser269 and Ser275. This phosphorylation of GCM-1 results in hCG and syncytin 1/2 expression.

Syncytin-1 promotes placental cell fusion and differentiation. Syncytin-1 is a human endogenous retroviral envelope gene product that plays an important role in the formation and maintenance of normal syncytium throughout pregnancy.

Villous cytotrophoblast proliferation decreases with gestation by term the syncytium close to placental vessels

Syncytium is continually been shed in to the maternal circulation and is replaced by the underlying cytotrophoblasts

 (GCM1 - Glial Cells Missing Homolog 1)
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6
Q

Describe one of the pathways- extravillous cytotrophoblast invasion

A

Growth of the trophoblast column
Regulated by factors such as IGF1 produced by the underlying mesenchymal cells

HIF-1α and Stox1 stimulate proliferation and inhibit differentiation

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7
Q

Oxygen tension and gestational age

A

Up until 12th week the uterine spiral arteries are plugged with trophoblasts

Placental development therefore occurs under relative hypoxia 2-3% O2

While the spiral arteries are plugged nutrition is histiotrophic nutrients being secreted by the glandular cells

Following dissolution of the trophoblast plug the placenta switches to haemotrophophic nutrition

Low oxygen early in pregnancy is important normal pregnancy progression
Prolonged low oxygen leads to placental pathologies

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8
Q

Methods that are used to study human placental development

A

1)Trophoblasts invade the decidua and maternal arterial wall and come in to direct contact with maternal blood

However there is no deep interstitial invasion of the decidua

Mice do not exhibit the same obstetric complications as humans

2)Trophoblasts invade the decidua and maternal arterial wall and come in to direct contact with maternal blood

Deep interstitial invasion of the decidua does occur

Some evidence that they do exhibit the same obstetric complications as humans

Ethically unacceptable to experiment on these animals

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9
Q

Describe some in vitro methods used to study human placental development

A

Human tissue can only be obtained either in the first trimester from TOPs or at term

Trophoblast cell lines derived from choriocarcinomas JEG3, Jar and BeWo
grow well
have lost some characteristics

Developed following transfection with oncogenes such as t- and T-antigen of SV40 or more recently hTERT
grow well
have lost some characteristics but this can depend on how they are cultured

Human embryonic stem cell-derived trophoblast cells (hESCs)
characterisation has proved problematic

Human trophoblast stem cells (hTSCs) derived from the trophectoderm and first trimester placentae
express characteristics of first trimester trophoblasts
can be induced to differentiate along either syncytial or extravillous lineages
difficult to prepare and grow

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10
Q

Describe culture formats

A
Simple mono layer cultures
simple co-cultures
addition of extracellular matrix 
effect of flow
3D environment
organoid cultures
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11
Q

What factors influence trophoblast invasion

A

Trophoblast and cancer cells have mechanisms of invasion in common
However trophoblast invasion is tightly regulated.

1)Growth factors and cytokine
HGF
IGF-1
Prolactin

2)Matrix proteases
MMP-2, 9, 10, 12

3)Tissue inhibitors matrix
metalloproteinases

4)Inhibitory factors
TNF
TGFβ
IGFBP-1

Upsetting the balance between stimulatory and inhibitory factors can lead to pregnancy complications

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12
Q

Maternal immune cells regulating trophoblast invasion

A

Immune cells in decidua basalis

70% uterine natural killer cells (uNK cells)

20% are macrophages

They are recruited following implantation

They localise to maternal spiral arteries

They precede the invasion trophoblasts

They secrete factors that regulate trophoblast invasion?

Failure of the placental to develop normally can lead to common pregnancy disorders such as early pregnancy loss, pre-eclampsia and fetal growth restriction.

Failure to thrive in utero has lifelong consequences including increased risk of developing hypotension and diabetes

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13
Q

Overview of extravillous trophoblast differentiation

A

early in pregnancy cells of the placenta (trophoblasts) invade the decidua
they plug the maternal spiral arteries
they interact with and replace the cells of the vessel wall
ultimately this will result in increased blood flow to the developing baby

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14
Q

Describe spiral artery remodelling

A

Two phases

Trophoblast independent
Immune cell
Pregnancy hormones

Trophoblast dependent

We know this by studying ectopic pregnancies

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15
Q

How are vascular cells lost from spiral arteries?

A

Migration
De-differentiation
Loss of adhesion (Anoikis)
Vascular cell apoptosis

Extravillous trophoblasts in uterine spiral arteries bring about changes leading to the loss of vascular cells - crucial for the vascular remodelling

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16
Q

Describe apoptosis

A

Programmed cell death

Cell death without the inflammatory response

Characterised by distinct morphological
Cell shrinkage
Chromatin condensation
DNA fragmentation 
Membrane blebs and blisters

Characterised by distinct biochemical changes
Cleavage of lamins and actin filaments in the cytoskeleton
The breakdown of chromatin in the nucleus leading to nuclear condensation
Translocation of phosphatidylserine to outer membrane
Cleavage of key enzymes such as poly ADP ribose phosphate (PARP) involved in DNA repair

Induced by cellular stress such as nutrient deprivation, hypoxia and viral infection

Mediated by a family of enzymes called caspases. Although caspase independent apoptosis does occur

Trophoblast use Fas/FasL to induce apoptosis in EC and VSMC

17
Q

Trophoblast induced apoptosis in in-vivo co-culture model

A

Transplanted placental villi into the mammary fat pads of Scid mice for 3 weeks.

CK+ve TC invaded and interacted with vessels.

Induction of vascular cell apoptosis in vivo and in vitro co-cultures

Extravillous trophoblasts in uterine spiral arteries bring about changes leading to the loss of vascular cells - crucial for the vascular remodelling

18
Q

Modulation of VSMC phenotype

A

Dedifferentiated SMC
Migratory
Proliferative
Produce extracellular matrix components

phenotypic modulation:
TGF B (transforming growth factor-B)

Differentiated SMC
Non-migratory
Low growth rate
Primary function is to carry out contraction

To go back to dedifferentiated form- need Platelet derived growth factor (PDGF-BB)

19
Q

Describe trophoblast dependent remodelling

A

Trophoblast conditioned media generated

Control or conditioned media added to vascular spheroids for 24 hours

RNA extracted from vascular spheroids

Gene expression altered by
trophoblast examined by Illumina Bead-chip array

20
Q

Gene expression in trophoblast dependent remodelling

A

PDGF, KL4, CXCL 10, IL-6
These are genes involved in VSMC differentiation

MMP10- Matrix degradation and possibly elastin derived peptides
which stimulate trophoblast invasion

IL-8- Stimulates trophoblast invasion. IL-11, regulats VSMC phenotype

CCL20- chemokine

Gene ontologies
Blood vessel morphogenesis
Inflammatory response
Angiogenesis
Blood vessel development
Vasculature development
Response to stress