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].