Decidualization

Question 1

What is decidualization?

Answer 1

Morphological and biological differentiation of endometrial stromal cells in preparation for a blastocyst to implant (pregnancy)

Question 2

When does decidualization occur in the menstural cycle

Answer 2

occurs spontaneously in the luteal (secretory phase) known to be at day 23 of a cycle but studies have shown it occurs earlier

Question 3

What is the decidua?

Answer 3

specialised layer of endometrial tissue which helps form the placenta.

decidua is the result of decidualization

Question 4

What does the decidua help control?

Answer 4

controls the invasion of trophoblast (trophectoderm - outer layer of embryo which forms the placenta)

Question 5

Why does decidualization need to occur correctly?

Answer 5

abnormal decidualization results in:
- infertility
- miscarriage
- intrauterine growth restriction
- pre-eclampsia

Question 6

How to determine if decidualization has occurred correctly?

Answer 6

currently no way of knowing if:
1. endometrium has undergone appropriate decidualization
2. if placenta is developing appropriately

Question 7

What is the connection between IVF and decidualization?

Answer 7

Once the IVF field can determine factors which help the endometrium prepare for pregnancy this will help the success rates of IVF

Question 8

What regulates decidualization in each menstrual cycle?

Answer 8

progesterone which is secreted during the luteal phase stimulates and maintains decidual phenotype

Question 9

If progesterone is known as the main phsyiological stimulator of decidualization why have researchers began studying if there are other regulators involved?

Answer 9

decidualization markers are found 9-10 days after ovarian progesterone is secreted which indicated that decidual-specific genes are not under direct transcriptional control of the cells progesterone receptors being activated

suggesting that other factors must also contribute to the decidual phenotype

Question 10

In the endometrium where does decidualization of the stromal cells begin?

Answer 10

around the blood vessels first then expands out

suggesting that factors involved may travel through blood

Question 11

What is the window of implantation/receptive window in the menstrual cycle?

Answer 11

Time period when the endometrium is receptive to embryo implantation

In a typical cycle this is between day 19-21

Question 12

in vitro studies demonstrate the process and markers released through the decidualization process. What markers were released through the process?

Answer 12

1. stromal fibroblasts during the mid/late luteal phase receive progesterone
2. stromal fibroblasts become decidualized stromal cell which secret:
   - prolactin
   - IGFBP-1
3. if porgesterone keeps being released and implantation occurs this becomes decidua

Question 13

Due to the progesterone dependant process of decidualization it involved reprogramming many cell functions including altering hormone receptor expression and remodelling of extracellular matrix and cytoskeleton. These changes need other regulators like?

Answer 13

intracellular enzymes
growth factors
cytokines and their receptors
transcription factors
apoptosis modulators

Question 14

What approaches are used in studies identify unknown factors regulating decidualization?

Answer 14

Humans: in vitro studies using isolated stromal cells from endometrium
mice: genetic knockout (through CRSPR/Cas9)

Question 15

Gene deletions studies in mice have shown that individually the below genes have what effect:
enzymes: COX-2 (prostaglandin pathway)
cytokines: LIF, IL11
steroids: progesterone receptor A
transcription factors: Hoxa-10, Hoxa-11

Answer 15

all shown infertility when deleted
which proves that decidualization is absolutely required for pregnancy

Question 16

The deletion of interleukin-11 receptor alpha in female mice displayed what results?

Answer 16

• embryos would die mid-gestation
• decidualized stroma were reduced and defective

Question 18

Mice studies demonstrated that interleukin 11is involved is decidualization in mice. Does IL11 have a role in human endometrial stromal cell decidualization?

Answer 18

1. through immunohistochemistry staining displayed positive staining for IL11 in the secretory phase of the cycle
2. the addition of IL11 in endometrium stromal cell cultures that were treated with progesterone and estrogen showed an increase in prolactin secretion (decidualization marker)

Question 19

Pro-inflammatory cytokines IL-1beta produced what response in decidualization markers when added to stromal endometrial cells?

Answer 19

produced a negative response in decidualization markers e.g. prolactin

Question 20

Which epigenetic regulators were found to work with progesterone to help regulate decidualization?

Answer 20

histone acetylation and microRNA

Question 21

During decidualization there are higher levels of immune cells in the endometrium. What is the theory behind this?

Answer 21

Endometrial cells need to become tolerate to an embryo which is allergenic to the endometrium. Hence why there is higher recruitment of immune cells during this time

Question 22

Uterine natural killer cells express different cell surface antigen (CD56bright) compared to circulating natural killer cells.
What is the uterine specific natural killer (NK) cells role in decidualization?

Answer 22

There are high number of these cells during in the endometrium in the mid-late secretory phase and in the decidua during pregnancy.

They produce specific cytokines which are thought to help initiate and maintain decidualization.

This was concluded through mice studies: NK deficient mice displayed late pregnancy disorders

Question 23

Role of dendritic cells in humans have not been concluded. In mice, however, what did studies show when they were deleted?

Answer 23

caused impaired decidualization and pregnancy failure

Question 24

Studies to further understand decidualization are moving towards using gene studies coupled with bioinformatics analysis. How is this useful?

Answer 24

helps identify novel pathways associated in the process.

There has already been studies which find different gene expression during decidualization stages.

If factors can be found from these gene expression changes they could be used for clinical biomarkers of decidualization

Question 25

What is the relationship between abnormal decidualization and pre-eclampsia

Answer 25

abnormal decidualization leads to defective trophoblast function (party of embryo that creates the placenta) and pre-eclampsia

studies have isolated endometrial stromal cells from women with severe history of pre-eclampsia and the cells failed to decidualize in vitro

Question 26

Can we develop serum biomarkers for abnormal decidualization to prevent or treat disease?

Answer 26

decidualization begins in areas surrounding vascular cells indicating the biomarkers may be able to measured in serum.

However, this requires large patient cohorts to determine clinical use

Question 27

Can we develop tissue biomarkers for abnormal decidualization to prevent or treat disease?

Answer 27

endometrial tissue can be collected from women who have had previous complications

Markers could be determined histologically if known what to look for