Decidualization: A preparation for pregnancy
Pregnancy triggers an intricate array of active changes that allows
close approximation of genetically dissonant embryonic and maternal
tissues [116]. The accomplishment of human pregnancy robustly relies
on the quality of the embryo in addition to the physiological condition
of the uterine lining termed endometrium. The endometrium undergoes
decidualization so that the uterus is prepared for the embryo
implantation and pregnancy. During the process of decidualization the
endometrial epithelium, blood vessels along with stroma are changed into
a special tissue termed decidua (Fig 1) [117-119]. The
process of decidualization begins in the midsecretory period of
menstrual cycle independently of blastocyst implant due to the raised
concentration of ovarian hormones such as estrogen and progesterone
[119-122]. During the reproductive cycle in normal women CD4+ T
cells are significantly altered (Table 4) and show a considerable
difference in their densities between early luteal and mid-luteal phase.
They exhibit lower levels during mid-luteal and late luteal phases as
compared to early follicular phase [33]. Decidualization process
plays a key part in the regulation of invasion of trophoblasts,
protection against oxidative stress and modulation of specialized uNK
cells (CD56 bright and CD16 dim) [118] uNK cellular entities on the
other hand regulate angiogenesis, remodeling of vessels and inflammation
through IL11 and 1L15 [130-133].
During the process of decidualization, stromal cells of human
endometrium are modified into decidual cells [134-137] via severe
inflammatory responses with subsequent anti-inflammatory condition as a
result of retinoid and corticosteroid signaling pathway reprogramming.
The inflammatory responses orchestrate the implantation window
[134]. The decidualization of endometrial stromal cells is essential
for the implantation of embryo [138]. The implantation of embryo is
important for normal pregnancy [136]. Decidualization has been
recognized as a vital event for facilitating embryo implantation and
successful pregnancy establishment [135-137]. Decidualization
depends on progesterone which acts via nuclear-progesterone-receptor
(PR) [137]. A wider range of factors (Table 5) contribute for the
successful decidualization. Any impairment in the decidualization
process causes failure of implantation, pregnancy loss and other
pregnancy related abnormalities in later trimesters [138]. Recently,
basal decidua of RPL patients has been found containing more vasculature
(veins, lymph vessels, and arteries) compared to fertile women
[154]. Conversely, the secretory endometrium of non-pregnant RPL
patients has reported highly dense blood vasculature [131]. Various
pathological conditions that reduce reproductive potential, such as
polycystic ovarian syndrome, endometriosis, antiphospholipid syndrome,
and RPL have been found showing error in the timing and state of
decidual cell differentiation [155]. During pregnancy the
decidualization brings about slow but sure and intense change in gene
expression, cellular physiology as well as modification of tissue until
the total development of the placental tissue. The examination of
decidual secretome and study of expression of genes reveal the details
of the changes that occur in the signaling messengers or intermediate
molecules, factors of transcription, chemokines molecules, factors of
growth/hormones, cyto-skeletal organization, cytokine molecules,
contents of extracellular matrix, molecules of adhesion,
receptors/ligands, water and ion transportation, mechanism of cell cycle
regulation, trafficking within the cell, migratory process and actions,
formation of blood vessels, decidual receptiveness and the process of
implantation [119, 156-160].
The decidua is an ephemeral, however, a vital uterine podium that
develops from the differentiation of stromal cells of endometrium,
freshly formed motherly blood and vascular cells in the interior and
exterior of the vessels. Decidual development is a strong tissue
remodeling wherein the residential and employed cells of immune system
undergo humoral as well as physical modifications subsequent to
blastocyst attachment on the uterine wall [9]. During the course of
decidualization mushroom like endometrial projections termed pinopods
connect with the blastocyst via tight junctions for the communication
and employment of cells of immune system. The cells of maternal immune
system may communicate with the cells of embryo right through the
syncytiotrophoblast which covers up the placental villi and the
implantation site where the deciduas is invaded by extra villous
trophoblasts [161]. The decidua has been recognized as a vital
maternal uterine tissue that guards the embryo from maternal immune cell
attack as well as gives dietetic support for the budding embryo
preceding to the formation of the placenta [9]. Adaptive immunity is
believed to be modulated by decidual macrophages and uterine dendritic
cells (DCs) by means of cytokine balancing and promoting the production
of Treg cells. The remodeling of uterine tissue and blood vessels during
the process of decidualization provides physical and nutritional support
to the growing embryo [9]. The various signaling networks are
triggered between the mother and the embryo at the time of implantation
due to the release of an array of cytokine and chemokine molecules from
the cells of embryo as well as the cells of decidua [9], which are
extremely large polygonal cells with pale-staining nuclei and
eosinophilic granular cytoplasm (Fig 2) [162]. A huge
figure of maternal decidual immune cells is believed to establish
equilibrium between antipathogenic resistance and tolerance of embryo.
The key cellular population includes the cells of innate immunity, for
instance, uNK cells and macrophages [9]. The decidual cells
subsequent to the initiation of their proliferation and differentiation
go on to the process of multinuclearization, i.e. duplication of DNA
molecule without cell cleavage (endo-reduplication) that permits
multiple gene expression and the discharge of synthesized proteins with
the expenditure of smaller amount of energy and this course of action is
deemed as an essential hallmark for the maturation of decidua in human
beings and rodents [9, 163, 164].
IL11 is a vital cytokine associate with decidualization [119, 165]
implantation [119, 166] as well as placentation [119, 167]. It
is activated either alternatively or by the convergence of signaling
pathways of prokineticin-1 [119, 168] activin A [119, 169]
relaxin and PGE2 (Postaglandin E2) [119, 170] which are recognized
as early inducers of decidualization. IL11 is stimulated by relaxin and
PGE2 via cAMP/PKA signaling pathway [119, 170] whereas
prokineticin-1 triggers it via calcineurin-NFAT signaling pathway
[119, 168]. Any perturbation in the decidualization process causes
the breakdown of materno-embryonic interface and pregnancy loss
[171].
Studies on knockout mouse for IL11Rα have shown that lack of IL11
signaling (mediated via IL11Rα−/−) is responsible for impaired
decidualization and decreased proliferation of uterine stromal cells
[9, 172, 173] as well as causes disrupted expression of protease
inhibitors [174, 175] and also interrupts invasion of trophoblasts
leading to its anarchic proliferation and finally pregnancy loss
[176] and resorption of embryo [177]. IL11 signaling is vital
for enough decidualization in mouse and promoting decidualization in
human [178]. The expression of IL11 has been reported crucial for
decidualization of human stromal cells and the irregularity in its
production in endometrium might be related with several infertility
types [177]. The vital role played by IL11 in in-vitro stromal cell
decidualization in human endometrium supports the fact that IL11 serves
as a key factor for correct process of decidualization in human beings
like in mice [177]. The endometrial stromal cells obtained from
women affected by primary infertility show defective decidualization in
comparison to cells isolated from normal women, depicting compromised
IL11 production in former women [177]. The aberrant IL11 and IL11Rα
production in decidual and placental tissue of women with an-embryonic
pregnancies emphasizes the potential significance of IL11 signaling in
early placentation [179]. Nevertheless, similar IL11Rα expression
has been observed in the decidualized stromal cells of fertile and
infertile women, supporting the significance of expressional modulation
of IL11 and not that of IL11Rα in regulating human endometrial
decidualization [177]. In addition, IL11 signaling plays a crucial
and complex role in endometrial preparation for embryo implantation,
invasion of early trophoblasts and decidualization of stromal cells in
primates and abnormal IL11signaling or action blockade may result in
diminished fertility [178]. The signaling defects of IL11 in
endometrium may well be utilized as one of potential targets for
developing therapeutic approaches in upcoming years for infertility
treatment [177]. The course of preparation for implantation and
pregnancy and the possible pregnancy outcome depending on predominant
cytokine milieu in uterus is briefly depicted in Fig 3 . The
imperfect development of decidua during early pregnancy may well result
in infertility or afterward produce complications such as pre-term
birth, preeclampsia and RPL [9, 99, 180, 181]. However, the
pregnancy outcome both in spontaneous conception or conception
subsequent to in-vitro fertilization may be improved via approaches
developed after understanding different molecular signaling networks
responsible for coordinating strategies for successful implantation and
decidualization [180]. IL15 has been observed to play a particular
role in the development of NK cells in IL15γR knockout mouse that lacks
NK cells [182]. IL15 is considered as a key factor for stimulating
in-vivo proliferation of uNK cells [183] given that IL15 exists in
glands as well as stroma [184].