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ScienceOfRepro > Placentation and the Trophoblast I > Flashcards

Placentation and the Trophoblast I Flashcards

1
Q

When is the placenta present?

A

Placenta = organ unique to pregnancy

Only present during pregnancy

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2
Q

What does the placenta form?

A

maternal-foetal interface

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3
Q

Where does the placenta originate and how much does it weigh?

A

➝ fetal in origin and at term it weighs 500-1000g

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4
Q

What does the placenta act as?

A

➝ lungs, gut and kidneys of the fetus
➝ endocrine organ, releases a lot of hormones into the maternal circulation - e.g. hCG, progesterone

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5
Q

What kind of cells does the placenta have and what is this called?

A

Semi-allograft = the cells have genetic material from both mother and father

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6
Q

Do foetal and maternal circulations mix?

A

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

Placenta is bathed in maternal blood

= requires mechanisms to evade the maternal immune system

However the fetal and maternal circulations do not mix
-Foetal cells and maternal cells are in direct contact, but the circulations are separate

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7
Q

What is implantation?

A

Implantation = Multi-step process by which the free-floating blastocyst attaches to the endometrium, invades through the epithelium and into the stroma underneath and begins to establish the placenta

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8
Q

How does placenta develop?

A

➝Apposition - Blastocyst attaches to epithelial layer of uterine wall
➝Attachment - Trophoectoderm cells divide and migrate b/w the epithelial cells through the Basement Membrane, into underlying uterine wall
➝Invasion – Trophoectoderm cells fuse to form primitive syncytium = syncytiotrophoblast – continue migrating into the decidua. They form an increasing primitive syncytium (A) and form holes (lacunae) within the syncytium. Lacunae later develop into the intervillous space. Behind the primitive syncytium, cells (cytotrophoblasts) divide + migrate through primitive syncytium and into uterine wall – these form anchoring villi

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9
Q

Describe how villi form?

A

➝ Trophectoderm proliferates and fuses to form a primitive syncytium beneath the implanted embryo
➝ Trophectoderm cells migrate or invade into the decidua
➝ Lacunae 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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10
Q

What happens during placenta formation in days 7-8?

A

➝ blastocyst attaches itself to the surface of the endometrial wall (decidua basalis)
➝ trophoblast cells start to assemble to form a syncytiotrophoblast in order to facilitate invasion of the decidua basalis

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11
Q

What happens during placenta formation in days 9-11?

A

➝ syncytiotrophoblast further invades the decidua basalis and by day 11 its almost completely buried in the decidua

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12
Q

What happens during placenta formation in day 12?

A

➝ decidual reaction occurs – high levels of progesterone result in the enlargement and coating of the decidual cells in glycogen and lipid-rich fluid

➝ this fluid is taken up by the syncytiotrophoblast and helps to sustain the blastocyt early on before the placenta is formed

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13
Q

What is a physical characteristic of the placenta?

A

Highly branched = ↑ surface area for exchange of nutrients/resp gases

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14
Q

What is the syncytium?

A

➝ outer layer of the villi

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15
Q

What do the spiral arteries do?

A

Deliver maternal blood to intervillous space

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16
Q

where is decidua basalis layer found?

A

Dedidua basalis = directly underneath placenta

➝As placenta develops, Anchoring villi branch to form 2° + 3° villi
➝Villi contain blood vessels that supply the placenta from the foetus – exchange of nutrients/resp gases b/w mother/foetus
➝Spiral arteries deliver maternal blood to intervillous space
➝Veins drain blood from intervillous space back into maternal circulation
➝Outer surface of villi is formed from a fused syncytium

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17
Q

What is growth regulated by?

A

➝ IGF I and IGF II

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18
Q

What is the structure of the villi like?

A

➝ On the outside there are fused cells (syncytium) and directly underneath is the cytotrophoblast stem cells.
The vessels are very close to the surface that enables effective and rapid exchange
——————-
➝Each villus contains a highly branched vascular network of arteries + veins, carry blood to/from developing foetus
➝Syncytium = fused layer of cells
➝Vessels v close to villi surface for rapid + effective exchange of nutrients
➝Villi contain macrophages (Hofbauer cells) – unknown function, maybe immune protection of placenta, regulate formation + branching of vessels

slide 6

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19
Q

What cells are found inside the villi?

A

Macrophages - Hofbauer cells

➝Unknown function - Maybe immune protection of placenta, regulate formation + branching of vessels

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20
Q

What is found inside the villi and what is their function?

A

➝ highly branched vascular network that take blood to and from the developing fetus

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21
Q

Describe how the syncytium is formed?

A

Syncytium is formed by combined action of hCG + Syncytin-1/2 (endogenous retroviral protein):
➝ hCG binds to the LH/CGR receptor
➝ = stimulates cAMP production
➝ cAMP activates a scramblase (membrane protein) = redistributes phosphatidylserine from inner surface of plasma membrane to outer surface of plasma membrane
➝ cAMP also increases PKA activity = phosphorylates GCM1 protein
➝ GCM1 = transcription factor, moves to the nucleus and regulates the expression of Syncytin-1 + Syncytin-2
➝ Syncytin-1 + Syncytin-2 are transported to plasma membrane, induce cell fusion + syncytium formation

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22
Q

How does the syncytium regenerate?

A

Underlying cytotrophoblasts fuse with the syncytium to replace lost material

➝ Syncytium is regenerated constantly throughout gestation → slows down towards term
➝Desmoplacin stain = junctions b/w cells – membranes are lost, forming multinucleated cells

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23
Q

Describe how villous stem cells go down the extravillous pathway

A

➝Extravillous pathway cells are derived from the cytotrophoblast columns and shell
➝ Form 2 diff subtypes - endovascular extravillous trophoblasts, interstitial extravillous trophoblasts
➝ The 2 cell types work together to remodel the maternal spiral arteries
➝ In initial stages of pregnancy, the endovascular extravillous trophoblasts form a trophoblast plug = prevents maternal blood from entering the intervillous space
➝ Interstitial extravillous trophoblasts invade into decidua and migrate towards maternal spiral arteries

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24
Q

Describe Extravillous Cytotrophoblast Invasion

A

➝ As the cells from the column move into the decidua they undergo epithelial➝mesenchymal transition - lose polarity, lose adherence, become more motile + invasive
➝ Start to express diff cell surface markers
➝ Initially express: α6β4, αVβ6 and E cadherin. As cells migrate away from the column, acquire diff surface molecules: αVβ3, α1β1, VE-cadherin, VCAM-1, and PECAM-1

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25
Q

When are the uterine spiral arteries plugged, with what, and why?

A

➝ Until 12th week of gestation, uterine spiral arteries are plugged with trophoblasts
➝ Trophoblast plug reduces the amount of oxygen that the villus tissue is exposed to in early gestation
➝ During early gestation, developing foetus is v sensitive to ox conc, so must be reduced

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26
Q

Under what conditions does placental development occur?

A

Under relative hypoxia:
2-3% O₂

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27
Q

When the spiral arteries are plugged, how does foetus receive nutrients?

A

While the spiral arteries are plugged, nutrition is histotrophic = nutrients are secreted by the glandular cells

slide 10

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28
Q

Following dissolution of the trophoblast plug, how does placenta deliver nutrition to foetus?

A

Haemotrophic nutrition

Week 12 gestation

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29
Q

What is important in early pregnancy for normal pregnancy progression?

A

Low oxygen

➝8-10 weeks gestation 2-3%
➝12-13 weeks gestation 7-8%

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30
Q

During early gestation, what is the fetus sensitive to?

A

Oxygen conc

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31
Q

What does prolonged low oxygen lead to?

A

➝ placental pathologies

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32
Q

What is placentation like in mice and what is different?

A

➝ Trophoblasts invade the decidue and maternal arterial wall and come into 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

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33
Q

What is placentation like in great apes?

A

➝ Trophoblasts invade the decidua and maternal arterial wall and come into direct contact with maternal blood
➝ Deep interstitial invasion of the decidua does occur
➝ May exhibit the same obstetric complications as humans
➝ Ethically unacceptable to experiment on these animals

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34
Q

Alternatives to animal models to study human placental development?

A

Human tissue - obtained at first trimester from TerminationOfPregnancy/at term upon delivery

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35
Q

When can human placental tissue be obtained?

A

➝ first trimester from TOPs or at term

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36
Q

What are trophoblast cell lines derived from?

A

➝ derived from choriocarcinomas JEG3, Jar and BeWo
➝ Grow well but lose some characteristics

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37
Q

What is another method of producing trophoblast cell lines?

A

Transfection with oncogenes e.g. t- and T- antigen of SV40 or more recently hTERT(telomerase activity)
➝ Grow well but lose some characteristics

38
Q

What are the advantages and disadvantages of Human embryonic stem cell-derived trophoblast cells (hESCs)?

A

➝ 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 + grow

39
Q

All of the human placental development models

A

All of these models – the phenotype of the cells depends on the culture conditions used

40
Q

How do co-cultures work?

A

➝ mixing two cell types together and growing them in a monolayer
➝ they can be separated using the multi cell insert (the cells on the insert are on a mesh and anything they produce diffuses down to the other cells)

41
Q

af 40
Culture formats

A

slide 14

42
Q

Models analysing factors that regulate trophoblast invasion

A

2 diff complementary models:

➝ 1 – Ex vivo model – using human placental tissue. Using piece of first trimester placental tissue. Anchoring villus. Dissected + placed on ECM. Monitor migration of cells from the villus tissue by time lapse microscopy/normal photography. Can manipulate process using both pharmacological + molecular techniques

➝ 2 – In vitro model – using multi cell inserts. Red line = ECM. On top of ECM = extravillous trophoblasts. Stimulus is placed in lower chamber. Tthis stimulates trophoblasts to migrate through the matrix

43
Q

What factors regulate trophoblast invasion?

A

➝ hCG
➝ EGF
➝ HGF
➝ IGF-1
➝ IGF-2

44
Q

What do trophoblast and cancer cells have in common?

A

➝ mechanisms of invasion in common, but trophoblast invasion is tightly regulated

45
Q

What are the growth factors that influence trophoblast invasion?

A

➝ HGF
➝ IGF-1
➝ Prolactin

slide 16

46
Q

What matrix proteases influence trophoblast invasion?

A

➝ MMP-2
➝ MMP-9
➝ MMP-10
➝ MMP-12

slide 16

47
Q

What inhibitory factors influence trophoblast invasion?

A

➝ TNF
➝ TGF beta
➝ IGFBP-1

slide 16

48
Q

What cells are found in the decidua basalis?

A

➝ Immune cells
➝ 70% = uterine natural killer cells
➝ 20% = macrophages

49
Q

When are immune cells recruited in the placenta?

A

Recruited following implantation

50
Q

Where do immune cells localise in the placenta?

A

Maternal spiral arteries

51
Q

What is the function of immune cells in the decidua basalis?

A

Secrete various factors which have 2 roles:
➝ Prepare spiral arteries for invading trophoblasts
➝ Release chemokines to attract the invading trophoblasts

52
Q

What do the decidua basalis immune cells precede?

A

➝ Trophoblast invasion

53
Q
A
54
Q

Abnormal placenta development can lead to….

A

Common pregnancy disorders e.g:
➝ Early pregnancy loss
➝ Pre-eclampsia
➝ Fetal growth restriction

55
Q

What are the consequences of failure to thrive in utero?

A

↑ risk of developing hypotension and diabetes

56
Q

Extravillous trophoblasts have a role in remodelling
………

A

maternal spiral arteries

57
Q

Describe the plugging and remodeling of maternal spiral arteries?

A

➝ In early pregnancy, extravillous trophoblasts migrate from anchoring villi into the decidua + also form plugs that block maternal spiral arteries.
These 2 diff functions lead to 2 diff cellular phenotypes:
-Interstitial extravillous trophoblasts
-Endovascular extravillous trophoblasts

➝ The invading interstitial extravillous trophoblasts migrate towards the spiral arteries, interact w vascular smooth muscle cells lining these vessels and replace them

➝ The endovascular extravillous trophoblasts plug the spiral artery, then migrate down the lumen of these vessels, interacting w the endothelial cells = leads to their loss

➝ They plug the maternal spiral arteries

➝They interact with and replace the cells of the vessel wall

= increased blood flow to the developing baby

-Under normal circumstances, spiral arteries respond to vasoconstrictors + vasodilators – under maternal control
-Removing the ability of these vessels to contract = foetus removes ability of mother to regulate blood flow into intervillous space

58
Q

In the non-pregnant state, what is the diameter of the spiral arteries?

A

➝ 200 microns

59
Q

What is the structure of spiral arteries before remodelling?

A

➝ endothelial cell lumen surrounded by connective tissue (elastin/collagen) and then surrounded by some muscle cells

60
Q

What is the structure of spiral arteries after remodelling?

A

➝ the diameter of the vessel increases
➝ This results in a change from a low flow high resistance vessel to a high flow low resistance vessel

61
Q

What is a marker of trophoblasts?

A

➝ cytokeratin 7

62
Q

What are the two phases of spiral artery remodelling?

A

➝ Trophoblast independent phase
➝ Trophoblast dependent phase

63
Q

How are vascular cells lost from spiral arteries and what are they replaced by?

A

➝ change from a contractile phenotype of smooth muscle cells to a vessel that is highly modified
➝ loss of smooth muscle and endothelial cells
➝ replaced by fetal cells invading extravillous trophoblasts

64
Q

What are 4 mechanisms implicated in spiral artery remodeling?

A

➝ migration
➝ de-differentiation
➝ loss of adhesion
➝ vascular cell apoptosis

65
Q

What is apoptosis?

A

➝ Programmed cell death
➝ Cell death without the inflammatory response

66
Q

What are the morphological changes in apoptosis?

A

➝ Cell shrinkage
➝ Chromatin condensation
➝ DNA fragmentation
➝ Membrane blebs and blisters

67
Q

What are the biochemical changes in apoptosis?

A

➝ Cleavage of laminin 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

68
Q

What is apoptosis induced by?

A

Cellular stress e.g:
➝ Nutrient deprivation
➝ Hypoxia
➝ Viral infection

69
Q

What is apoptosis mediated by?

A

Caspases (family of enzymes)

But caspase-independent apoptosis does occur

70
Q

What happened in an experiment where endothelial cells and vascular smooth muscle cells were cultured with trophoblasts?

A

➝ increase in the number of apoptotic cells present in both the controls
➝ significantly more apoptosis in the presence of trophoblasts

71
Q

What is one of the events that occurs in end stage apoptosis?

A

Cleavage of PARP

72
Q

How can PARP be detected?

A

Western blotting

73
Q

What do smooth muscle cells secrete?

A

➝ a factor that attracts trophoblasts

74
Q

What do trophoblasts use to induce apoptosis and in what cells?

A

➝ Fas/FasL
➝ Endothelial cells and vascular smooth muscle cells

75
Q

What binds to FAS ligand to prevent apoptosis?

A

NOK2

76
Q

What kind of phenotype do vascular smooth muscle cells have and what phenotype can they become?

A

➝ plastic phenotype
➝ move from a contractile phenotype to a de-differentiated non contractile phenotype

77
Q

What is the switch in vascular smooth muscle phenotype stimulated by?

A

TGFβ + PDGF

78
Q

What are changes in vascular smooth muscle phenotype characterized by?

A

Loss of contractile proteins e.g. actin, calponin

79
Q

What does 3D culture of trophoblasts stimulate?

A

➝ expression of a much more physiological phenotype

80
Q

Why are endothelial cells and smooth muscle cells cultured together?

A

➝ allows the cells to form without sticking to a plate

81
Q

What is a transcription factor expressed in vascular smooth muscle cells that are differentiating?

A

KLF4

82
Q

What are 4 genes involved in VSMC dedifferentiation?

A

➝ PDGF
➝ KLF4
➝ CXCL10
➝ IL-6

83
Q

What is the function of MMP10?

A

➝ matrix degradation and possibly synthesise elastin derived peptides which stimulate trophoblast invasion

84
Q

What is the function of IL-8?

A

IL-8 - stimulates trophoblast invasion

85
Q

What is the function of IL-11?

A

➝ regulates VSMC phenotype

86
Q

What is CCL20?

A

CCL20 = a chemokine

87
Q

Describe how trophoblasts remodel VSMC?

A

➝ Communication between the vascular wall and the trophoblasts
➝ Trophoblasts stimulate vascular smooth muscle to release factors which recruit more trophoblasts
➝ Trophoblasts can induce vascular cell apoptosis
➝ Endovascular trophoblasts interact with the vascular endothelial cells primarily
➝ interstitial trophoblasts produce factors that interact with the vascular smooth muscle cells
➝ Trophoblast conditioned media stimulates PDGF to de differentiate vascular smooth muscle and stimulates the release of MMP

88
Q

What is the function of MMPs?

A

➝ Breaking down the extracellular matrix
➝ Synthesize the elastin derived peptides which are chemoattractants for trophoblasts

89
Q

All of the human placental development models

A

All of these models – the phenotype of the cells depends on the culture conditions used

90
Q

What is the function of loss of endothelial cells in the spiral arteries?

A

➝ The spiral arteries under normal circumstances will respond to vasoconstrictors and dilators
➝ they are under the control of the maternal needs
➝ by removing the ability of the vessels to contract the fetus removes the ability of the mother to regulate the flow of blood into the intervillous space
➝ result in increased blood flow to the developing baby

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