molecular aspects of implantation Flashcards
what are the changes to the endometrium in the proliferative phase?
– Small glands with epithelial cells close together (overlapping)
– Dense stroma
what are the changes to the endometrium in the early secretory phase?
– Glands expanding
– Secretory vesicles at basal side of epithelial
cells
what are the changes to the endometrium in the mid secretory phase?
– Further expansion of glands with secretory vesicles at apical side of epithelial
cells
– Presence of secreted material in lumen
what are the changes to the endometrium in the late secretory phase?
– Longextendedglandswithnosecretoryvesicles
– Oedema in stroma
where are steroid hormone receptors expressed?
when is there maximum expression of ER and PG?
expressed in nuclei of stromal and epithelial cells.
ER
– Maximum expression in late proliferative/early secretory phase of cycle
PR
– Maximum in early secretory phase and then decreases – Decreases in epithelial cells before stroma
what leukocytes are in the endometrium?
uterine NK cells
macrophages
Tcells
No B cells
population of leukocytes in the stroma
when is the window of implantation?
time during which the endometrium is receptive the embryo (days 20-23 of cycle)
what is the implantation window characterised by?
expression of a specific set of factors in the endometrium
luminal epithelial cells may develop pinopod extensions
what are the three stages of implantation?
Apposition
– Orientation of the blastocyst on the lumen of the
endometrium
Adhesion
- Interaction between trophoblast cells and luminal epithelial cells in endometrium
Invasion
– Breakdown of connective tissue between luminal
epithelial cells and passage of embryo through to the underlying stroma.
what are abnormalities of endometrial function?
recurrent implantation failure after IVF (RIF) - failure to achieve a pregnancy after transfer of good quality embryos
recurrent miscarriage - implantation occurs but pregnancy is lost due to abnormal placental formation
what interactions are there in implantation?
Involves an interaction between the embryo and the endometrium
Initial interaction is between trophoblast cells of embryo and luminal epithelium
Later interactions will be between trophoblast cells and stroma
what are the three populations of trophoblast cells
Villous Trophoblast – Invasive
» come into contact with maternal stroma – Anchoring
Endovascular Trophoblast
– Invade maternal blood vessels
Syncytiotrophoblast
– Formed inside maternal blood vessels by cell fusion
what do decidualised stomal cells secret which are markers of decidualization
prolactin and IGFBP1
what is decidualisation controlled by?
cAMP and progesterone
what are intergrins?
molecules present in the cell membrane
they are made of heterodimers
alpha and beta subunit, many different alpha and beta subunits exist
what do integrins do?
Mediate cell binding to Extracellular Matrix (ECM)
Transduce signals from ECM into cells
Regulate gene expression including those of ECM degrading enzymes (proteases)
what integrins are expressed in the endometrium during the window of implantation
highest expression in epithelium and blood vessels
alphaVbeta3 is expressed in luminal and glandular equally
alpha1 and beta 4 expression is higher in glandular epithelium and high in cells of blood vessel walls
is there abnormal expression of integrins in woman with reproductive failure?
Abnormal expression of αvβ3 in women with infertility (Lessey et al 1995)
No difference in expression of αvβ3, α1 or α4 in women with unexplained recurrent miscarriage (Tuckerman et al 2006).
No difference in expression αvβ3, α1 or α4 in women with RIF and levels are not
predictive of pregnancy outcome (Coughlan et al 2013)
are integrins involved in embryo implantation?
May be involved in the attachment of the embryo to the luminal epitheium
β3 integrin is up-regulated by embryonic IL1
what is MUC1
a glycoprotein on the luminal epithelial cells
in implantation window - you get decreased expression of MUC1
what is though to be the role of MUC1 in embryo implantation?
MUC1 prevents embryo access to luminal epithelium
Glycosylations need to be removed to allow implantation to occur
– Embryonic IL1 could bring this about
MUC1 reduced in women with recurrent miscarriage
– May allow implantation of defective embryos which are subsequently lost
what three families are matrix metalloproteinases (MMPs)
- collagenases
- gelatinises
- stromeolysins
what controls endometrial MMP production?
progesterone (decreases production, increased MMP production see at the end of the cycle when progesterone levels decreased
IL1 and TNFalpha
what controls MMP production by trophoblast cells?
controlled by:
- hormone e.g. hCG and progesterone
- cytokines e.g. IL1, TNF and IL6
- integrins binding to extracellular matriculates
what are MMPs produced by?
trophoblast cells
endometrial cells
NK cells
what are the roles of proteases in endometrial function?
Implantation
– breakdown of extracellular matrix to allow
embryo through epithelial cells
– breakdown of extracellular matrix tissue to allow trophoblast cells invade stroma
Menstruation
– breakdown of endometrial tissue
what cytokines does the endometrium produce?
– Pro-inflammatory cytokines (IL1, TNFα, IFNγ, LIF,
IL11, IL6)
– Th1(IL2, TNFα, IFNγ) and Th2 (IL10 , IL4) cytokines
– TGFβ
– GM-CSF, CSF
– IL12, IL18, IL15
the receptors for many of these cytokines are found on the blastocyst
where are cytokines expressed/produced in the endometrium?
Expressed mainly by epithelial cells in non- pregnant endometrium
Expressed by decidual and epithelial cells after implantation
what does implantation involve?
interaction between the embryo and the endometrium
initial interaction is between the trophoblast cells of the embryo and luminal epithelium
later interactions will be between trophoblast cells and stroma
what are cytokines expressed as in the non-pregnant endometrium and after implantation?
Expressed mainly by epithelial cells in nonpregnant endometrium Expressed by decidual and epithelial cells after implantation There is increases seen in expression of many cytokines at the time of implantation
what it IL1 role thought to be?
IL1ra inhibits embryo implantation in mice IL1-β, IL1ra and IL-1R t1 are expressed by the human embryo IL1-β production by human embryos can affect epithelial production of numerous factors important in implantation – β3 integrin – MUC1 – LIF
