Physiology of Embryo-Endometrial Cross...

INTRODUCTION

Human reproduction is an inefficient process.

Epidemiological evidences suggest that only

30% of all conceptions get clinically

recognized, and a large number of these are

lost spontaneously. Furthermore, the success

of assisted reproduction is low, as reasonably

good quality embryos fail to implant and there

is a high frequency of spontaneous abortions.

These epidemiologic and clinical evidences

indicate that uterine implantation governs

reproductive success and maternal

incompetence at the endometrial level can be a

constraining factor. Thus, understanding the

molecular events of embryo-maternal

interaction is of interest to reproductive

biologists, clinicians and couples affected by

infertility. The understanding is also essential

for designing rational management strategies

Key words: Endometrium, Decidua, Implantation, Biosensor, Invasion, Trophoblast, Abortion.*Corresponding Author: Deepak N. Modi, Molecular and Cellular Biology Laboratory, National Institute for Research in Reproductive Health, Parel, Mumbai, India.Email: [email protected], [email protected]

Physiology of Embryo-Endometrial Cross Talk

Molecular and Cellular Biology Laboratory, National Institute for Research in Reproductive Health, Parel, Mumbai,

India

Deepak N. Modi* and Pradeep Bhartiya

Implantation of the blastocyst stage embryo into the maternal endometrium is a critical determinant and a

rate-limiting process for successful pregnancy. Embryo implantation requires synchronized changes in the

endometrium before and after arrival of blastocyst into the uterine cavity. Extensive cross talks occur

between the fetal and maternal compartments around the time of implantation which are reflected by

morphologic, biochemical and molecular changes in the endometrial cells and the differentiating

trophoblast cells. The embryo induced morphologic changes include occurrence of epithelial plaque

reaction, stromal compaction and decidualization. Embryonic signals also alter the expression of a large

number of transcription factors, growth factors and their receptors and integrins. Thus the embryo

superimposes a unique signature on the receptive endometrium for successful implantation. Functionally,

the embryo-endometrial cross talk is essential for endowing a “selector activity” to the receptive

endometrium to ensure implantation of only a developmentally competent embryo. On selection, the

decidua creates a conducive microenvironment for trophoblast invasion leading to placentation. Clinical

evidences suggest that along with receptivity, a defective “selector” activity of the receptive uterus may be a

cause of infertility and recurrent miscarriages. Defects in trophoblast invasion are associated with

pregnancy complications like preeclampsia and intra-uterine growth retardation. It is envisaged that

understanding of the embryo-endometrial dialogue leading to the “selector” activity, aids in development of

appropriate therapeutic modalities for infertility related disorders and miscarriages. Conversely, it might

also benefit the development of anti-implantation drugs for contraception.

Biomed Res J 2015;2(1):83-104

Review

for implantation failure and treatment of

infertility.

Our current understanding of the process

of embryo implantation and the determinants

of successful pregnancy have mainly stemmed

from animal models and in vitro studies using

human tissues. Based on the data derived it is

clear that endometrial receptivity and embryo

implantation are complex processes involving

a delicately poised balance of maternal

hormones, endometrial factors and embryonic

influences. The current review focuses on

cellular and molecular events associated with

endometrial receptivity and implantation to

accomplish successful conception. The

embryo-endometrial cross talk at the time of

embryo apposition and implantation mainly in

the primates will be discussed. The general

understanding of the processes of endometrial

receptivity and implantation has been a subject

of recent reviews (Gellerson and Brosens,

2014; Ozturk and Demir, 2010; Young, 2013;

Young and Lessey, 2010).

Endometrial receptivity

A mutual communication between the

blastocyst and the uterus is indispensable for

implantation. Akin to many developmental

processes, it involves an elaborate sequence of

genetic and cellular interactions, to be

executed within an optimal temporal frame for

successful pregnancy. In order to receive a

developing embryo, the endometrium endures

a series of morphological and physiological

transformations. At the same time, the

fertilized ovum undergoes several rounds of

cell division and transforms into blastocyst.

The blastocyst has an outermost layer of

specialized cells, trophoblast cells, that

surround the pluripotent inner cell mass. The

trophoblast cells come in direct contact with

the receptive endometrium establishing a firm

attachment with the endometrial epithelial

cells termed as apposition. Subsequently, the

trophoblasts invade the endometrium and

establish contact with the maternal circulation

to form the placenta.

The endometrium is refractory to embryo

implantation throughout the menstrual cycle

except for a few days after ovulation.

Approximately, on days 21–24 of the human

menstrual cycle (8–10 days post ovulation),

the uterus becomes "receptive", enabling

blastocysts to adhere to the luminal

epithelium. Termed as “window of

receptivity”, the achievement of this stage is

highly dependent on the ovarian steroids,

estrogen and progesterone. The estrogen in the

follicular phase leads to proliferation of

endometrial epithelial cells, the progesterone

surge that occurs in response to ovulation leads

to differentiation of the estrogen primed

endometrium to endow receptivity. Any

disturbance in the levels of these hormones

adversely affects endometrial physiology

leading to failure of implantation. The

endocrine regulation of the menstrual cycle

and role of hormones in endowing receptivity

84

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Embryo-endometrial cross talk

to the endometrium has been a subject of

extensive studies (Jabbour et al., 2006; Young,

2013).

Morphologically, the receptive phase

endometrium is characterized by presence of

columnar epithelium with microvilli, an

increase in stromal cell proliferation and

appearance of pinopod-like structures on the

luminal epithelium (Tu et al., 2014). The

morphological features of the “receptive”

endometrium are associated with expression

of a range of biochemical and molecular

markers, crucial for endowment of this phase

of the uterus. Several markers like

transcription factors, integrins and their

ligands, cytokines and growth factors, have

been associated with the receptive phase (Tu et

al., 2014; Wang and Dey 2006; Zhang et al.,

2013,). A molecular signature of the “receptive

window” using global gene profiling

technologies have been identified that can

phenotype different phases of the menstrual

cycle including the receptive stage to

objectively classify the implantation window

(Garrido-Gómez et al., 2013; Haouzi et al.,

2012). These findings open the field for the

diagnosis of the endometrial defects in assisted

reproductive technology programs (Ruiz-

Alonso et al., 2013).

Embryo induced morphologic changes in

the receptive endometrium

In a conception cycle, the egg that has

fertilized in the fallopian tube undergoes a

series of cell divisions and reaches uterine

lumen at the blastocyst stage. At this time the

trophoblast cells are differentiated and the

embryo is ready to hatch. From rodents to

humans, this embryo induces a second round

of differentiation both at the morphologic and

biochemical level (Banerjee and Fazleabas,

2009). Distinct from the “receptive” stage

endometrium, the embryo induced

differentiation of the receptive endometrium is

rather limited and largely derived from

experimental studies in the non-human

primates and endometrial biopsies obtained

from conception cycles in humans. Three

major non-human primate models to identify

and dissect embryo induced morphological

and physiological changes in the receptive

stage endometrium are: 1) Timed hysterect-

omies and/or biopsies of the endometrium of

baboons or rhesus macaques sequentially

mated with males of proven fertility; 2)

Endometria obtained from mated bonnet

monkeys where the presence of the embryo

has been verified using a preimplantation

factor assay; and 3) Endometrial tissue

obtained from baboons where human

chorionic gonadotropin (hCG) has been

infused in the uterine lumen in a manner that

mimics the transit of blastocyst. The models

have inherent advantages and disadvantages

but are highly complementary and provide

valuable information in terms of identification

and deciphering the functional consequence of

embryo induced changes in uterine

receptivity.

Modi and Bhartiya 85

Biomed Res J 2015;2(1):83-104

Epithelial changes: The earliest endometrial

response prior to implantation is characterized

by an increased proliferative activity of the

luminal and glandular epithelium. Distinct

from the epithelial proliferation observed in

the follicular phase, this proliferative activity

in the pregnant uterus is restricted to focal

areas. In the luminal epithelium, there are large

clump of nuclei with distinct entero-

reduplication and poorly packed chromatin

along with loss of basement membrane. These

changes are termed as “epithelial plaque

reaction” (Jones and Fazleabas, 2001; Rosario

et al., 2005a). The formation of epithelial

plaques is restricted to pregnant endometrium

and reported in a variety of primate species

including humans (Rossman, 1940). While

consistently detected in the conception cycle,

the epithelial plaque reaction is hormonally

regulated and does not require presence of an

embryo, as infusion of hCG directly in the

uterus leads to formation of epithelial plaques

similar to those observed in pregnant monkeys

(Fazleabas et al., 1999; Jones and Fazleabas,

2001). The functional significance of

epithelial plaques is not clear. It is speculated

that the plaque may provide nutrition by means

of intracellular glycogen (Enders et al., 1985;

Rossman, 1940). The plaque response may

stimulate precocious development of the

maternal vasculature below the epithelium

(Enders et al., 1985).

Beyond the plaque reaction, thinning of

the basal lamina and thickening and diffusion

of the apical and lateral gap junctions in

luminal epithelial cells has been reported in

pregnant human, bonnet and baboon

endometrium (Demir et al., 2002; Rosario et

al., 2008). Along with these changes, a few

granulocytic stromal cells are also observed in

the luminal epithelium of pregnant bonnet and

rhesus monkeys prior to implantation (Ghosh

et al., 1993; Rosario et al., 2008). It is

conceivable that these changes occur to

promote adhesiveness to the trophoblast cells

at the time of apposition and invasion.

Stromal changes: An almost universal

reaction of the endometrial stromal cells in

response to an embryo is decidualization. In its

broadest sense, decidualization is defined as

the postovulatory endometrial remodeling

which includes secretory transformation of

uterine stroma, influx of specialized uterine

natural killer cells, and vascular remodeling. A

more restricted definition of decidualization is

an epithelioid transformation of the

endometrial stromal cell with highly

specialized and distinctive functions.

Decidualization only occurs in species in

which placentation involves breaching of the

luminal epithelium by the trophoblasts. The

extent of this differentiation process often

correlates with the degree of trophoblast

invasion (Dunn et al., 2003; Gellersen et al.,

2007).

Morphologically, the elongated spindle

like stromal cells of the secretory phase

Biomed Res J 2015;2(1):83-104

86 Embryo-endometrial cross talk

endometrium transform into cobblestone like

enlarged decidual cells with multiple club

shaped projections arising from the cell

surface and contain abundant glycogen stores

and lipid droplets (Welsh et al., 1985; Wynn et

al., 1974). In humans, this transformation

occurs even in absence of an embryo and is

referred to as the pre-decidual response. In a

conception cycle, under the continuous

support of steroid hormones and blastocyst

derived signals, decidualization of the entire

endometrium is observed (Brosens et al.,

2002; Gellersen and Brosens, 2014). The

decidua forms a dense cellular matrix that

allows coordinated trophoblast invasion while

simultaneously protecting the conceptus from

maternal and environmental insults (Kliman,

2000; Redhorse et al., 2004). In the non-

human primates, decidualization is observed

in conception cycle or on treatment with hCG

(Jones and Fazleabas, 2001; Rosario et al.,

2005a). These observations suggest that unlike

in humans, embryo/embryonic factors are

required for the endometrial stromal cells to

undergo decidualization in monkeys.

Vascularization: A characteristic feature of

the endometrium in a conception cycle is the

enhanced microvasculature. In the pregnant

bonnet monkeys, a large number of small

blood vessels are detected in the stroma

underlying luminal epithelium and the

functionalis region of the endometrial bed

(Rosario et al., 2005a). Increased vascularity

and angiogenesis at the implantation site of

rhesus monkeys has been reported (Sengupta

and Ghosh, 2002). A similar increase in the

number of small blood capillaries in the

stroma of the endometrial functionalis have

been demonstrated in baboons infused with

physiological doses of hCG in the uterine

lumen (Banerjee and Fazleabas, 2009; Jones

and Fazleabas, 2001). These observations

suggest that maternal tissues initiate neo-

vascularization which may be required for

immune cell differentiation and infiltration

(See below).

Immune cell infiltration: The leukocyte

population in the endometrium consists of T

cells, macrophages and large granular

lymphocytes. T cells and macrophages

account for a substantial proportion of the

leukocyte population in human endometrium

throughout the menstrual cycle (Jones et al.,

1998; King, 2000). The largest leukocyte

population in the human endometrium are the

large granulated lymphocytes which express

natural killer (NK) cell antigen CD56. The

uterine NK (uNK) cell population is distinct

from peripheral blood NK cells in phenotypic

and molecular characteristics (Cooper et al.,

2001; Fukui et al., 2011; King et al., 1991;

Lysakova-Devine and O'Farrelly, 2014).

Around the time of implantation, uNK cells

comprise 70–80% of the leukocyte population

in the endometrium and numbers increase if

conception occurs (King, 2000; Kodama et al.,


Biomed Res J 2015;2(1):83-104

1998). It remains to be identified whether the

increase in cell number is solely the result of in

situ proliferation or homing from the

peripheral circulation. In a conception cycle,

the uNK cells differentiate into decidual NK

(dNK) cells, functionally distinct from non-

pregnant uterine counterparts (Kodama et al.,

1998). The functional significance of uNK and

dNK cells in the primate endometrium is

largely speculative. Based on mouse studies

and clinical observations, it appears that NK

cells are crucial for pregnancy and failure of

uNK transformation to dNK cells leads to

pregnancy loss (Fukui et al., 2011; Gong et al.,

2014; Quenby and Farquharson, 2006).

Whether this transformation occurs

exclusively in response to embryo derived

signals or due to decidualization of the stromal

cells, needs to be investigated.

Embryo induced molecular trans-

formations in the receptive endometrium

The molecular dialogue between the embryo

and endometrium involves a complex network

of signaling molecules that mediate cell–cell

or cell–extracellular matrix (ECM)

interactions, and include factors such as

cytokines, growth factors, cell-adhesion

molecules and matrix metalloproteinases.

There is some evidence indicating that the

levels of steroid receptors, growth factors and

cytokines are modulated in the endometrium

during early pregnancy. The following section

reviews the in situ molecular changes

occurring in the primate endometrium in

response to embryonic signals.

Estrogen receptors (ER) and Progesterone

receptors (PR)

Sex steroids exert their effects through their

receptors, estrogen receptor (ER) and

progesterone receptor (PR). As compared to

non-conception cycle, both ER and PR

expression is higher in the conception cycle

around implantation in bonnets, baboons and

rhesus (Ghosh and Sengupta, 1988, Rosario et

al., 2008). Post apposition ER expression is

lost in the epithelium and stroma but retained

in the wall of spiral arteries, blood vessels, and

myometrial smooth muscle cells (Hild-Petito

et al., 1992; Perrot-Applanat et al., 1994).

While PR is most abundantly expressed in

the uterine glands and stroma in the receptive

phase, expression of PR is down-regulated in

the glands but present in the stroma

surrounding the glands and spiral arteries, wall

of spiral arteries, blood vessels, and smooth

muscle cells of the myometrium (Ghosh and

Sengupta, 1988; Hild-Petito et al., 1992;

Perrot-Applanat et al., 1994).

Homeobox genes HOXA10 and HOXA11

HOX genes are essential for endometrial

growth, differentiation and receptivity by

mediating some functions of progesterone.

Both HOXA10 and HOXA11 are expressed in

human endometrial epithelial and stromal

cells, and their expression is significantly

Biomed Res J 2015;2(1):83-104


higher in mid- and late-secretory phases,

coinciding with time of embryo implantation

and high levels of estrogen and progesterone

(Daftary and Taylor, 2006; Godbole et al.,

2007; Modi and Godbole, 2009; Taylor et al.,

1998; Xu et al., 2014).

Unlike steroid receptors, the expression of

HOXA10 is induced in the endometria of

bonnet monkeys in the conception cycle.

Abundant expression of HOXA10 protein is

detectable in stromal and glandular cells of the

pregnant bonnet monkeys (Godbole et al.,

2007). Interestingly, treatment of endometrial

cells with spent blastocyst culture medium

and/or hCG resulted in increased transcription

of HOXA10 (Blitek et al., 2011; Fogle et al.,

2010; Sakkas et al., 2003). However, unlike

the glands and the stroma, in luminal

epithelium of the conception cycle, HOXA10

expression is reduced and expression is

virtually absent in the pre-epithelial plaques

(Godbole et al., 2007; Modi and Godbole,

2009). These observations are surprising, as in

the mouse, suppression of HOXA10 in

epithelial cells leads to inhibition of embryo

implantation; overexpression leads to increase

in litter size in mouse (Bagot et al., 2000).

While this might reflect the fundamental

differences in the mechanisms associated with

implantation in rodents and primates,

observations in the monkey indicates that

products of HOXA10-modulated transcript-

ome in luminal epithelium may be inhibitory

for implantation, and hence may be down

regulated by embryonic stimuli. As

transcription factors, HOX genes regulate

other downstream target genes leading to

proper development of endometrium and

receptivity to implantation. A number of

molecular and morphological markers specific

to the implantation window are regulated by

HOX genes, including pinopodes, β3 integrin

and insulin-like growth factor-binding

protein-1 (Daftary and Taylor, 2006; Modi and

Godbole, 2009). All the HOX targets are also

modulated in the endometria in response to the

embryo (Nimbkar-Joshi et al., 2009).

Cytokines and growth factors

Leukemia inhibitory factor (LIF), Interleukin-

6 and -11 (IL-6 and IL-11) are members of a

single family of cytokines that share the signal

transducer receptor unit gp130 in target cells to

elicit biologic effects. All these three cytokines

play key roles in implantation. First identified

in the mouse where targeted disruption of the

LIF gene showed implantation failure

(Stewart et al., 1992), reduced LIF expression/

secretion has been reported in infertile women

with defects in implantation (Mikolajczyk et

al., 2006; Tawfeek et al., 2012). While LIF

seems to be a critical requirement for

implantation, the expression is not modulated

by embryonic signals as the levels do not alter

in the implantation phase endometria of

bonnet monkeys in conception as compared to

non-conception cycle (Rosario et al., 2005b).

However, in rhesus the expression of LIF and


Biomed Res J 2015;2(1):83-104

its receptors are increased in the endometria of

pregnant monkeys as compared to non-

pregnant controls (Sengupta et al., 2003). LIF

is crucial for implantation in primates as

administration of an antagonist for LIF

receptor or antibody against LIF directly in to

the uterine cavity of monkeys and mice, results

in failure of pregnancy (Sengupta et al., 2006;

Terakawa et al., 2011; White et al., 2007). The

results indicate that LIF is essential in the

process of blastocyst implantation. LIF is also

a promotor of trophoblast invasion (Suman et

al., 2013a; 2013b).

IL-6 and IL-11 are pleiotropic cytokines

required for implantation. IL-11 expression is

increased during decidualization (Godbole

and Modi, 2010), recombinant IL-6 and IL-11

promote decidualization of human

endometrial cells in vitro (Dimitriadis et al.,

2005; Menkhorst et al., 2010). IL-6 and IL-11

are also promoters of trophoblast invasion

(Champion et al., 2012; Modi et al., 2011;

Suman et al., 2009; 2013). IL-11 and the

receptor IL-11Rα are detected in the decidua

mainly at implantation sites in cynomolgus

and rhesus monkeys (Champion et al., 2012;

Dimitriadis et al., 2005). It is also detected in

the vascular endothelial cells and epithelial

plaques. Likewise, the expression of IL-6 is

significantly higher in endometria of animals

in the conception cycles as compared to non-

conception of rhesus and bonnet monkeys

(Rosario et al., 2005b; Sengupta et al., 2003).

Several growth factors like Tumor Growth

Factor (TGF) beta, Epidermal Growth Factor

(EGF) and Tumor Necrosis Factor (TNF)

alpha are pro-inflammatory cytokines that

have emerged to be critical mediators for

implantation owing to their direct effects on

immune cells (Dimitriadis et al., 2005;

Omwandho et al., 2010). In the window of

implantation, a significant increase in

endometrial TGF beta and its receptor occurs

in the glandular epithelium of animals in the

conception cycles as compared to non-

conception cycles (Rosario et al., 2005b;

Sachdeva et al., 2001). TNF alpha and its

receptor population increases in the

endometria of animals in the conception

cycles as compared to non-conception cycles

(Nimbkar-Joshi et al., 2009; Rosario et al.,

2005c). EGF and its receptors are detected in

both the glands and stromal compartments of

the receptive phase endometrium; expression

is increased mainly in the stromal cells of the

pregnant animals (Slowey et al., 1994). An

increase in endometrial LIF, EGF, TGF and

TNF by endometrial cells in presence of

embryonic stimuli prior to apposition suggests

induction of an inflammatory like condition in

the implantation phase endometrium, which

may be a requirement for initiation of

pregnancy; the increase in expression in

stromal compartment implies involvement

with decidualization.

Biomed Res J 2015;2(1):83-104


Integrin and their ligands

Integrins are heterodimeric glycoproteins

which undergo dynamic temporal and spatial

changes in their distribution in the

endometrium during the menstrual cycle in

women (Lessey and Arnold, 1998; Reddy and

Mangale, 2003). Likewise the ECM ligands

for these receptors are likely to play a role in

the establishment of a receptive endometrium.

The integrins and their cognate ligands show

dynamic changes in levels of expression and

polarization during early pregnancy. In the

baboon, the collagen receptor alpha1beta1 and

fibronectin receptor alpha4beta1 expressed in

glandular epithelium during window of

receptivity are lost with the establishment of

pregnancy. The vitronectin receptor,

alpha4beta3 is expressed in the glandular

epithelium in pregnant animals. The

osteopontin receptor, alphavbeta3, is

expressed in both glandular epithelium, and

decidualizing stromal cells of pregnant

animals (Fazleabas et al., 1997; Mangale and

Reddy, 2007). In the mouse decidua,

interactions between integrin alphav beta3 and

vitronectin is required to maintain a balance

between cell proliferation and apoptosis, along

with modulation of inflammatory responses

(Mangale et al., 2008).

Recently the dynamics of integrin

expression mainly alphavbeta3 in the uterine

epithelium has been detailed in early

pregnancy using the bonnet model. The results

revealed that expression of alpha v increases in

luminal epithelial cells of pregnant animals,

show a shift in localization at the site of

attachment (Nimbkar-Joshi et al., 2012). At

the non-attachment pole, the alpha(v) integrin

is mainly in the basal zone of the luminal

epithelial cells. However, at the attachment

pole, alphav is redistributed and also detected

in the apical pole. The differential subcellular

distribution of integrin is directed by

embryonic stimuli as treatment of epithelial

cultures with conditioned medium of human

embryos obtained at IVF leads to increased

distribution of alphav on the apical membrane

(Nimbkar-Joshi et al., 2012). These

observations imply that embryonic stimuli not

only directs cellular reprogramming by

changing gene expression, but also controls

intracellular protein trafficking leading to

preferential sorting of proteins.

From the above studies it is clear that

embryo induces distinct changes in the

receptive stage endometrium and affects

almost all the compartments in preparation of

pregnancy. These changes seem to be induced

in response to secretions by the embryonic

cells and are highly localized in nature. A

summary of the morphological and molecular

changes that occur in the receptive

endometrium in presence of an embryo are

shown in Fig 1.


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Functional Consequence of the

Endometrial-Embryo Cross-Talk

From the discussion above it is clear that

remarkable changes occur in the molecular

profile of endometrium at the time of

apposition and implantation, distinct from

those during the window of receptivity. The

changes seem to be induced in response to

secretions by the embryonic cells and are

localized in nature. However, the functional

connotations of such observations remain far

from clear. This is mainly due to our inability

to perform genetic manipulations in the

endometria of primates. Nevertheless, in

recent years, elegant models have been in vitro

designed to decipher functional consequences

of embryo induced changes in endometrial

cells ( . Weimar et al., 2012) While it would be

beyond the scope of this article to review these

studies, the data derived from these studies,

combined with changes seen in vivo, it appears

that the embryo signals the endometrial bed

prior to implantation making it competent for

embryo quality control and trophoblast

invasion.

Decidua as a “selector” for embryo quality

control

The exceptional rate of early pregnancy loss

may be due to the high prevalence of

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Figure 1: Morphological and molecular changes in the endometrium in response to embryonic signals. The

receptive endometrium senses the endometrium and undergoes extensive biochemical and morphological remodeling.

The molecular changes that occur in the stromal and epithelial compartments are highlighted.


chromosomal abnormalities in the embryo.

Genetic analysis of blastomeres taken from

good quality embryos obtained at in vitro

fertilization (IVF) showed that around 70%

harbor complex chromosomal abnormalities

(Chow et al., 2014; Mertzanidou et al., 2013).

Such observations raise the question of how to

safeguard the mother against prolonged

investment in potentially developmentally

abnormal embryos. One school of thought

believes that abnormal embryos by themselves

are incompetent towards implantation

resulting in pregnancy failure. In recent years

however, experimental evidence indicate that

spontaneous decidualization of endometrium

coupled to menstruation is a judicious strategy

to meet the challenge. The decidua may play a

key role in discriminating normal and

abnormal blastocysts to allow pregnancy.

Evidences to support this hypothesis were

obtained from co-culture of decidual cells with

morphologically normal and abnormal human

embryos obtained at IVF. While morpho-

logically normal embryos had no major effects

on production of a selected set of cytokines;

media derived from decidual cells co-cultured

with morphologically arrested or abnormal

blastocysts led to down-regulation of IL-1b, -

6, -10, -17, -18, eotaxin and heparin-binding

EGF-like growth factor (Teklenburg et al.,

2010a). Such down-regulation is associated

with closure of endometrial competence for

implantation and menstruation (Evans and

Salamonsen, 2014). Microarray analysis of

decidual cells challenged with conditioned

medium from good and poor quality embryos,

identified 449 decidual genes deregulated in

response to medium conditioned by poor-

quality embryos (Brosens et al., 2014). One of

the down regulated genes in response to

signals in conditioned media derived from

poor quality embryos was HSPA8. The protein

functions in protein assembly and folding,

clatherin-mediated endocytosis, assembly of

multiprotein complexes, transport of nascent

polypeptides, and regulation of protein folding

(Stritcher et al., 2013). The observation

suggests that soluble signal from

developmentally impaired human embryos

induce endoplasmic reticulum (ER) stress

response in decidualizing cells. An in vivo

proof for the in vitro observations came from

studies in uteri of mice flushed with

conditioned culture medium of development-

ally competent and incompetent embryos.

Analysis of the uterine transcriptome revealed

that medium derived from competent embryos

evoked a supportive intrauterine environment,

whereas medium derived from poor quality

embryos led to ER stress (Brosens et al.,

2014). Thus, it implies that the endometrium

not only senses signals derived from the

embryo and responds to create a pro-

implantation condition, but is also capable of

terminating the window of endometrial

receptivity to enable the mother to dispose of

compromised embryos. The observation adds

another dimension to the potential of


Biomed Res J 2015;2(1):83-104

decidualizing endometrial stromal cells as

sensors of embryo quality during

implantation.

Thus, we propose a dual-phase response of

the endometrium. The steroid primed

receptive phase endometrium responds to the

incoming embryo creating an obligatory

environment for implantation. At the same

time the decidua gains a 'selector' activity to

recognize developmental competence of the

implanting embryo. Based on the blastocyst

competence as judged by the decidua, either

pregnancy is continued or the maternal

response is aborted and culminates in

menstruation.

Regulation of trophoblast invasion

Once the endometrium encounters a

developmentally competent blastocyst and

decides to continue with pregnancy, the

embryo apposes and trophoblast cells begin to

breach the luminal epithelium and invade in to

the maternal decidua to establish placentation.

Trophoblast cells are inherently invasive and

can invade any tissue. However, in the

pregnant endometrium the invasion is highly

controlled. It is believed that the decidualized

stromal cells secrete a complex array of

molecules that permit the controlled

migration/invasion. While several of the

molecules are already expressed by the

receptive endometrium, others are induced

post decidualization and receiving of the

embryonic signals. Co-culture of trophoblast

and decidual cells or spent medium increases

trophoblast invasion (Godbole et al., 2011;

Menkhorst et al., 2012). We have

demonstrated that decidual cell secretome

enhances invasion of trophoblast cells through

altered expression of matrix metalloproteases

(MMPs) and tissue inhibitors of matrix

metalloproteases (TIMPs) (Godbole et al.,

2011). Conversely, in response to

trophoblasts, the decidual cells also gain a

migratory and invasive phenotype (Gellersen

et al., 2010; Weimar et al., 2013). Thus,

decidualization and embryo driven changes in

the uterine cells creates a microenvironment

favorable for implantation and placentation.

Numerous growth factors that regulate the

proliferation and invasion of trophoblast cells

have been identified at the fetal-maternal

interface. The various factors secreted by the

decidual cells and/or the associated cell types

and their influence on trophoblast invasion has

been recently reviewed (Knöfler, 2010; Modi

et al., 2012). Amongst the various factors, IL-

6, LIF and IL-11 are abundantly produced by

the endometrial stromal and decidual cells,

and play a key role in trophoblast invasion

(Fitzgerald et al., 2008; Modi et al., 2012;

Suman et al., 2013a; Suman and Gupta, 2014).

IL-6 and LIF stimulates invasion of primary

trophoblast and JEG-3 choriocarcinoma cells

via the STAT3 signaling pathway (Jovanović

and Vićovac, 2009; Suman and Gupta, 2014).

The role of IL-11 in trophoblast invasion is

less clear as it inhibits the invasion of primary

Biomed Res J 2015;2(1):83-104


trophoblast and HTR-8/SVneo cells, but

increases invasion of the choriocarcinoma

JEG-3 cells (Suman et al., 2009; 2012; 2013b).

The discrepancy may originate from

differences in the transcription factor content

of the two cell lines. However, the data

suggests that locally produced IL-6, LIF and

IL-11 act to finely tune invasion. While the

cumulative effects of various factors and their

roles under in vivo conditions need

investigations, the observations together

suggest that decidualization driven

transformation of endometrial stromal cells

creates a uterine microenvironment that

controls trophoblast invasion.

Clinical Repercussions of the Embryo-

Endometrial Cross-Talk

Endometrial receptivity is a major rate limiting

step and bottleneck for the success of assisted

reproductive technologies. The discovery that

embryonic signals potentiate the already

primed uterus has opened several avenues for

understanding of the process of implantation

and initiation of pregnancy. Given the

experimental evidence demonstrating the

embryo-endometrial cross talk plays a key role

in endowing receptivity as well as selectivity

to the endometrium, a logical consequence of a

reduced ability to recognize embryonic signals

is implantation failure and/or miscarriage.

Suboptimal response to signals of high quality

embryos will result in a suboptimal

environment for subsequent development and

placenta formation, a major cause of

pregnancy related complications like fetal

growth restriction and gestational

hypertension leading to preeclampsia.

In converse, impaired endometrial

selectivity can result in superfertility. The

hypothesis stems from the observations that

women with recurrent miscarriages are highly

fecund and time to pregnancy is reduced in

those women with a history of five or more

miscarriages (Teklenburg et al., 2010b). Since

developmentally incompetent blastocyst

implant (due to failure of selectivity), these

would lead to late first trimester abortions.

Thus lack the “selector” activity in the

endometrium may be a causative factor

towards compromised pregnancy. Indeed, a

loss of selection sensing has been observed in

endometrial stromal cells derived from

women experiencing recurrent miscarriages

(Salker et al., 2010). Furthermore, when

flushed through the mouse uterus, secreted

factors from decidualizing cultures of stromal

cells derived from patients with recurrent

miscarriages prolonged the window of

receptivity and also increased the incidence of

pathological implantation sites, immune

defects and fetal demise (Brosens et al., 2014).

Additionally, endometrial stromal cells from

patients with recurrent miscarriages show

altered responses to hCG, and failure to

discriminate between high and low quality

human embryos (Salker et al., 2010; Weimar

et al., 2012). Thus, the “selector” activity of


Biomed Res J 2015;2(1):83-104

the decidua may be a key to successful

pregnancy and defects in the process may

cause recurrent miscarriages.

Once the embryo has implanted, the

trophoblast cells invade to establish

placentation. Multiple stages of placentation

could be compromised that can lead to

diseases. Pre-eclampsia affecting 3–5% of

pregnancies, which is characterized by

gestational hypertension and severe

proteinuria, and is a major cause of fetal and

maternal deaths. While pre-eclampsia is

detected later in gestation (20 weeks onwards),

its pathogenesis is established early in

gestation where trophoblast invasion is

defective. It has been shown that in women

with preeclampsia shallow placental invasion

and inadequate plugging of the spiral artery

affects blood supply into the intervillous space

and alters the consistency of the blood flow.

This can lead to fluctuations in the supply of

oxygen to the placenta (Ji et al., 2013; Saito

and Nakashima, 2014), triggering a maternal

response by increasing blood pressure and

compromising fetal development (Furuya et

al., 2008). Another disorder caused by defects

in trophoblast invasion is intrauterine growth

restriction (IUGR). IUGR arises as a result of

inadequate blood supply and/or inadequate

transport of nutrients across the placenta to the

fetus, resulting in a range of mechanisms

including reduced uteroplacental blood flow,

compromised feto-placental angiogenesis and

subsequent villous development (Gourvas et

al., 2012). It is believed that 'poor placentation'

along with hypoxic micromilieu of

fetoplacental site, shear stress of

uteroplacental blood flow, and aberrantly

secreted proinflammatory substances into

maternal circulation, synergistically

contribute to progression of preeclampsia and

IUGR (Furuya et al., 2008; Gourvas et al.,

2012; Ji et al., 2013; Saito and Nakashima,

2014). Since trophoblast invasion and

placentation are dependent on proper

decidualization, defective embryo-

endometrial cross talk can lead to improper

decidual response thereby causing poor

trophoblast invasion, shallow placentation and

hence preeclampsia. Preliminary evidence

suggests that decidualization defects might

exist in decidua of women with pregnancies

complicated with preeclampsia (Saito and

Nakashima, 2014).

Thus, there is a need for better

understanding of the basic processes of

placentation and mechanisms that go awry in

women with preeclampsia and IUGR for

effective therapeutic approaches to these

common disorders.

CONCLUSIONS

The embryo-endometrial cross talk has

evolved as a delicately poised mechanism to

respond initially to the hormonal trigger to

achieve receptivity and then to amplify the

decision under embryonic signals to permit

pregnancy. During this critical period, the

Biomed Res J 2015;2(1):83-104


receptive endometrium gains the ability for

selectivity, where response of the luminal

epithelium serves to transduce and amplify

signals coming from competent embryos

renders the underlying decidual layer more

receptive to invasion (Fig. 1). This permits

embryo apposition followed by trophoblast

invasion to establish placentation (Fig. 2). In

the event the endometrium experiences

presence of a poor-quality embryo, the

supportive network is not activated, but the

decidua mount a stress response, leading to

withdrawal of receptivity resulting in

menstruation and failure of pregnancy (Fig. 2).

Such a selector mechanism of the decidua is

highly desirous to avoid investing energy in

pregnancy with abnormal fetuses which may

not survive till term or have compromised

survival ability. Once the receptive and the

selective competence of the endometrium are

ensured and the right blastocyst implants, the

decidua creates a local microenvironment that

is conducive for trophoblast invasion and

placentation (Fig. 2).

The significance of such bimodal and

biphasic endometrial response to the

implanting embryo is potentially far reaching.

To date, treatment of recurrent miscarriages

and implantation failure are inefficacious and

highly empirical. The recent understanding of

the dual processes has revealed that recurrent

implantation failure may be caused by defects

in endometrial embryo cross talk. It will be

necessary to unravel the molecular processes

that control the timely transition of the

receptive uterus to a selective decidua which

Figure 2: Biosensor activity of the implantation stage endometruim. A) In presence of a normal good quality embryo

the endometrium undergoes extensive biochemical and molecular transformation allowing the apposition of the embryo

to the luminal epithelium. Consequently, the secretory factors from the decidua promote invasion of trophoblast cells

allowing plancetation. B) In presence of a poor quality embryo the endometrium responds by activating a strong

inflammatory cascade thereby triggering closure of receptivity leading to menstruation.


Biomed Res J 2015;2(1):83-104

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