Trophoblast and decidualisation Flashcards
What is the problem with NK cells during pregnancy?
NK cells in pregnancy are not killers, they are helpers: they produce growth factors and cytokines. However, too many NKs cells aren’t good, as a large number of NK cells is associated with recurrent pregnancy loss as it causes too much promotion of trophoblast invasion, which leads to miscarriage. Additionally, it leads to more neo-angiogenesis;Positive correlation between NK cells and number of blood vessels.
This can potentially lead to early exposure of blood flow and oxidative stress which is dangerous for the foetus.
Pre-eclampsia is a two stage disease. what may the first stage be due to?
Immune recognition:
Maternal NKs cells can talk to and bind to trophoblast cells.
Immune mismatch leads to higher incidence rates of PE. Foetal C2 (inherited paternally) are expressed on the trophoblast and are far more likely to develop PE than foetal C1. This is the first evidence which supports that there are particular pairings that predispose women to developing PE.
give an overview on the placenta
• An organ unique to pregnancy.
• The placenta forms the interface between the mother and the foetus.
• The placenta develops from the foetus and it weighs 500 – 1000g at term.
• The placenta acts as the lungs, gut and kidneys of the foetus.
—>It also acts as an endocrine organ releasing hormones into the maternal circulation such as hCG.
• The placenta is a semi-allograft – it contains genetic material from both the mother and the father, thus, it should technically be considered as foreign, but it isn’t as it contains mechanisms to evade the immune system.
• In a human pregnancy, the foetal cells are in direct contact with the maternal blood, however, the circulations do not mix.
Describe the development of the placenta
Attachment of the blastocyst to the decidua is a combination of invasion and outgrowth (characteristic of human pregnancies).
• Initially cells in the outer layer of the blastocyst, the trophoblast, proliferate and fuse to form a primate syncytium (PS) layer, below the implanted embryo, which adheres to the endometrium.
• The embryo then commences its interstitial implantation as cells of the syncytiotrophoblast pass between the endometrial epithelial cells and penetrate the decidualized endometrium.
• The PS starts to digest itself partially, producing proteases which form lacunae, which later develop into the intervillous space.
• Whilst the cytotrophoblasts proliferate and migrate through the shell to form the anchoring villi.
describe the primitive syncytium formation
• The PS is formed by fusion of neighbouring trophoblast cells.
• As the pregnancy progresses, the S.A of the placenta must increase, thus, cells underneath also begin to fuse with the PS – this is known as secondary syncytial formation.
Fusion of trophoblasts is driven by the Syncytin-1/2 gene.
Trophoblasts produce HCG which binds to itself and activates a downstream cascade which leads to phosphorylation of protein kinase A, this phosphorylates GCM1 which acts as a TF (fusion process).
Phosphorylated GCM1 translocates into the nucleus and causes transcription + translation of Syncytin, which is expressed on the plasma membrane and leads to fusion of the trophoblasts.
Constant positive feedback as HCG is produced by the trophoblasts autocrine action = continuous process.
what continuously happens to the syncytium?
The syncytium is continually shed into the maternal circulation and is replaced by underlying cytotrophoblasts. Amount of shedding increases with pathology. Content of shed particles include RNA and proteins – may be a potential mechanism of how the placenta communicates with the mother? Or a how a distressed placenta communicates with the mother?
Apoptosis is hard to study as although phosphatidylserine is present on outer surface it is not in terms of the placenta.
Describe the placental circulation
• The decidua basalis contains uterine arteries (maternal spiral arteries) and veins. Being spiral is an adaptation as it allows for them to stretch as the endometrium thickens/thins in response to oestrogen and progesterone.
• The spiral arteries release maternal blood into the intervillous space, which bathes foetal tissue and is recycled back via uterine veins once exchange has occurred.
• The foetal circulation is formed of umbilical veins and arteries:
- Umbilical veins (x1) take rich-oxygenated blood back to the baby.
- Umbilical arteries (x2) take deoxygenated blood from the baby to the placenta.
• The umbilical arteries and veins form the chorionic plate (derived completely from the foetus) and branch to form chorionic villi which is the functional unit of the placenta:
- Oxygen and nutrients diffuse form the maternal blood (from the intervillous space) to the umbilical veins, whilst waste products from the umbilical arteries diffuse into the intervillous space.
- The umbilical veins then supply the baby via umbilical cord.
- The blood from the intervillous space is then recycled back into the uterine veins.
• The chorionic villi are highly branched to maximise exchange. It is attached to the decidua via anchoring villi.
NOTE:
Decidua basalis is completely maternal.
Chorionic plate is completely foetal.
The region in-between is shared – intervillous space contains maternal blood which bathes foetal tissue.
mad
what are some of pathological concerns of the placenta?
- Failure of the placenta to develop normally can lead to common pregnancy disorders such as early pregnancy loss, pre-eclampsia (PE) and foetal growth restriction (FGR).
- Failure to thrive in utero has lifelong consequences including increased risk of developing hypertension, CVD and metabolic conditions such as diabetes.
give an overview on the villous structure
- Highly branched to increase S.A for exchange.
- The surface of the villi is formed from a single layer of fused cells (= short diffusion pathway), derived from the underlying cytotrophoblast stem cells—>Cell fusion requires Glial Cells Missing 1 (GCM1), syncytin-1 and 2 and caspase-8.
- Growth is regulated by number of factors such as IGF 1 and 2 (insulin-like growth factors).
- Villi have immunological, endocrine and nutritional functions.
describe foetal vessel development
Foetal vessels in the villi develop really early on in pregnancy.
• Early gestation – branching angiogenesis driven by VEGF.
• Followed by non-branching angiogenesis driven by placental growth factor (PLGF).
• Poor vascular development is associated with FGR, PE and early pregnancy loss.
Describe the structure of the blastocyst
Blastocyst structure:
The first differentiation event of the embryo occurs at D 5/6.
- ICM – develops into the foetus.
- Cytotrophoblast – inner layer of the trophoblast which develops into the placenta.
- Syncytiotrophoblast – outer layer of the trophoblast. Thick layer that lacks cell boundaries and grows into the endometrial stroma. It secretes HCG to maintain the CL (to maintain progesterone secretion).
explain the 2 lineages a trophoblast can differentiate into
Trophoblast stem cells–>cytotrophoblasts progenitor cells–> differentiate down into 2 lineages: extravillous pathway + villous pathway:
• VILLOUS PATHWAY = these are cytotrophoblasts which proliferate and fuse to form the multi-nucleated syncytiotrophoblast layer that forms the outer surface of the chorionic villi, which are responsible for exchange.
• EXTRAVILLOUS PATHWAY = these are cytotrophoblasts which proliferate and differentiate into an invasive phenotype, which invade the decidua.
o Endovascular trophoblast – these trophoblasts migrate through the lumen of the spiral arteries.
o Interstitial trophoblast – these trophoblasts migrate from the interstitium (will interact with the SMCs first, then the endothelial cells).
describe cytotrophoblast invasion
• Growth of the trophoblast column is regulated by factors produced by the underlying mesenchymal cells such as IGF. HIF-1st and Stox1 stimulate proliferation and inhibit differentiation.
• Proliferation occurs behind the wave front and as you get further away from the anchoring villi, they start to differentiate.
The endovascular cytotrophoblasts migrate through the lumen of the spiral arteries, whilst the interstitial cytotrophoblasts migrate from the interstitium (interact with the SMCs, then the endothelial cells).
The cytotrophoblasts stop being trophoblast-like and adopt characteristics of endothelial cells – they lose some adhesion molecules and gain others. Ultimately, these cytotrophoblasts replace the endothelial cells of the spiral arteries – this is known as the epithelial to endothelial cell transformation.
As a result, the spiral arteries go from being very muscular, to a trophoblast saggy-like vessel.
what are the factors which influence trophoblast invasion
Trophoblast invasion is a fine balance between factors which stimulate invasion and factors which prevent invasion. Upsetting the balance can lead to unhealthy pregnancies.
FOR:
• Growth factors and cytokines e.g. HGF, IGF-1 and prolactin.
• Matrix proteins e.g. MMP-2, 9, 10 and 12.
AGAINST:
• Inhibitory factors e.g. TNF, TGFB and IGF-BP-1.
• Tissue inhibitor matrix metalloproteinases (TIMPs).
