Review Article | Open Access
Kameliya Vinketova, Milena Mourdjeva, Tsvetelina Oreshkova, "Human Decidual Stromal Cells as a Component of the Implantation Niche and a Modulator of Maternal Immunity", Journal of Pregnancy, vol. 2016, Article ID 8689436, 17 pages, 2016. https://doi.org/10.1155/2016/8689436
Human Decidual Stromal Cells as a Component of the Implantation Niche and a Modulator of Maternal Immunity
The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa termed endometrium. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs). In the process of decidualization, which is controlled by oestrogen and progesterone, DSCs acquire specific functions related to recognition, selection, and acceptance of the allogeneic embryo, as well as to development of maternal immune tolerance. In this review we discuss the relationship between the decidualization of DSCs and pathological obstetrical and gynaecological conditions. Moreover, the critical influence of DSCs on local immune cells populations as well as their relationship to the onset and maintenance of immune tolerance is described.
1. Human Decidual Development and Structure
(1) Contribution of the Maternal Decidua to Placental Development. The success of human pregnancy strongly depends on embryo quality and the physiological state of the uterine lining—an epithelial tissue layer called endometrium. To prepare the uterus for embryo implantation and pregnancy, the endometrium undergoes a process termed decidualization. During this process, the endometrial epithelium, blood vessels, and stroma are transformed into a specialized tissue, called decidua [1, 2]. The decidualization process initiates during the midsecretory phase of the menstrual cycles as a result of the elevated levels of ovarian hormones—oestrogen and progesterone [3–5]—independent of the presence of an implanting blastocyst (Figure 1). It causes a gradual and profound alteration in gene expression, cellular functions, and tissue remodelling until the complete formation of a placenta during pregnancy. Analyses of gene expression and secretome of the decidua reveal changed profiles of signal messengers/intermediates, transcription factors, hormones/growth factors, cytokines, chemokines, adhesion molecules, ligands/receptors, cytoskeleton organization, composition of extracellular matrix, ion and water transport, cell cycle regulation, cell trafficking, migration and functions, angiogenesis, decidual receptivity, and implantation [6–10]. The reported magnitude of changes in gene expression altogether suggests an important turning point at the start of the decidual transformation. Initially triggered by the oestrogen or/and progesterone, all components of the functional endometrial layer, that is, glandular epithelium, endometrial stromal cells (ESCs), and endothelium, respond by interrelated and simultaneous activation of multiple factors and mediators. Some factors such as the progesterone receptors (PRs) [11, 12] and the angiogenic factors—VEGF [13, 14], FGF , and prokineticin-1 —have oestrogen or progesterone response elements in their promoter region suggesting direct regulation. However, the decidualization-related markers such as tissue factor (TF) [17, 18], insulin-like growth factor binding protein-1 (IGFBP-1) , prolactin (PRL) , and leukemia inhibitory factor (LIF)  do not have hormone response elements in their promoter regions. Nevertheless, their transcription is enhanced by hormones, and this effect is mediated by the activation of signalling pathways, transcription factors, and coactivators (Figure 1).
PR expression also plays a role in the signalling of stimuli maintaining endometrial homeostasis during preparation for pregnancy. PRs are nuclear receptors that exist in two isoforms (PR-A and PR-B) and have different functions [11, 22]. They are stimulated by oestrogen [11, 12] and therefore show the highest levels of expression in the proliferative stage of the menstrual cycle . Furthermore, during the postovulatory rise of progesterone, PRs are gradually downregulated by their ligand (progesterone) even in the presence of oestrogen [12, 22, 23]. In the first trimester of pregnancy, the amount of PR is further decreased with a remaining expression of PR-A predominantly in stromal cells . Nevertheless, PRs are present throughout pregnancy  with prevailing PR-B isoform at term . Altogether, the expression level of PR in the human decidua is the net result of a complex regulation by oestrogen, progesterone, and prostaglandins  and autoregulation of its own promoter region . The physiological significance of the gradual decrease of PR expression in the endometrium as decidualization advances and pregnancy begins [22, 27] might imply intrinsic subsiding of PR signalling, limiting the response to progesterone . PR response elements are found in the promoter regions of a number of factors. Among them are PRL  and IGFBP-1 [29, 30] that experience inhibitory effect, while extracellular matrix component fibronectin  is positively influenced by the signalling via PR response elements. The existing regulation between the steroid hormones and their receptors presumably provides counteracting signals that drive decidual transformation and maintain the mechanisms of endometrial homeostasis.
Experimental data strongly indicates that progesterone alone is a weak inductor of decidualization in human ESC as evaluated by the synthesized PRL  and IGFBP-1 . However, in vivo progesterone exerts endocrine control on the differentiating endometrium and immune cells together with oestrogen . Oestrogen does not induce decidualization on its own [32, 33], but when added to progesterone and incubated for a prolonged period of time (longer than 8 days), it leads to an increase in PRL [34, 35] and IGFBP-1 levels in ESCs . Altogether, progesterone and oestrogen, deprived of decidual environment, are not strong stimulators of decidualization. This implies that other hormones, relaxin [20, 36, 37] and corticotropin-releasing factor (CRF) [38, 39]; decidualization factors, IL-11 [34, 35], activin A (a member from the transforming growth factor beta superfamily) [33, 40], IL-6 , and LIF ; and prostaglandin E2 (PGE2) [37, 41, 42] from the endometrial niche synergistically augment decidual transformation of ESCs as measured by PRL and IGFBP-1.
It is well documented that the ovarian hormones progesterone , estradiol , and relaxin , as well as CRF  and PGE2 [41, 44], induce accumulation of intracellular cAMP. cAMP is synthesized from adenosine triphosphate via the activation of the enzyme adenylate cyclase [43, 44] and signals via the protein kinase A (PKA) pathway . It is a second messenger in the cells and induces the synthesis of essential factors/morphogens, some of them not directly regulated by progesterone. In combination with progesterone and estradiol, cAMP provides synergistic enhancement of decidualization [28, 39] and induces the synthesis of IL-11 , LIF , activin A [33, 46], PRL , IGFBP-1 , and others (Figure 2). These secretory factors, produced in the epithelial and stromal cells of the endometrium, are considered to act in an autocrine and paracrine manner and sequentially activate genes that control the morphological and functional changes associated with decidual differentiation, implantation, trophoblast proliferation/invasion, and recruitment of immune cells.
Prokineticin-1 [16, 48], TF , activin A [50, 51], IL-11 [52, 53], PRL , and IGFBP-1, which are known decidualization factors, increase in the epithelial and stromal cells of the endometrium starting in the secretory phase and usually increasing in the first trimester of pregnancy (Figure 1). The only exception from this group is LIF, which peaks at the midsecretory/luteal phase [32, 53] in accordance with the expected implantation of the blastocyst [48, 54]. Depending on the function of the aforementioned factors, they might either be indispensable for the induction and maintenance of decidualization or be a result of the process. However, abrogation of endometrial differentiation using inhibitors/neutralization binding proteins, antagonists, knock-down approaches, neutralizing antibodies, or signalling inhibitors against activin A [33, 46], LIF , prokineticin-1 , and IL-11 [35, 37] shows the crucial role of each of these factors in the decidualization process. Importantly, successful decidualization is critical for the establishment of pregnancy and it is qualitatively and quantitatively evaluated by the amounts of produced PRL and IGFBP-1 .
All factors and hormones that are upregulated at the onset of decidualization characteristically have pleiotropic function. The interdependence between them reveals simultaneous, alternative, and sequential manner of activation. For example, prokineticin-1, a protein induced by progesterone, oestrogen, and human chorionic gonadotropin (hCG) [16, 48, 57], stops epithelial cell proliferation, potentiates decidualization , and increases angiogenesis and endothelial permeability . Therefore, it is considered that prokineticin-1 contributes to the processes of implantation and placentation during pregnancy . Its action in implantation is mediated by the induction of factors such as cyclooxygenase 2, PGE2, IL-6, IL-11, and LIF [7, 48, 52]. The latter three are members of the IL-6 family of cytokines and share a common signalling chain (gp130) of their receptors . IL-11 and LIF increase the expression of adhesion molecules and the attachment of endometrial epithelial cells to fibronectin and collagen IV . In particular, IL-11 augments the adhesion of endometrial epithelial cells to primary trophoblasts , while LIF upregulates adhesion molecules in trophoblasts  and increases the adhesion of trophoblasts to fibronectin and laminin (components of the extracellular matrix) . Therefore, the increased adherence of trophectoderm (trophoblasts) to the epithelial cells of the decidua facilitates the attachment and implantation of the blastocyst. In further stages of placental development, trophoblast migration and invasion are mediated by IL-11 [62, 63] and LIF .
IL-11 regulation is an excellent example of the complexity of the operational network during decidualization. IL-11 is an important cytokine involved in decidualization , implantation , and placentation . It is stimulated alternatively or by convergence of signalling pathways of prokineticin-1 , activin A , relaxin, and PGE2 , known as early inducers of decidualization. Relaxin and PGE2 stimulate IL-11 via cAMP/PKA  and prokineticin-1 via calcineurin-NFAT signalling pathways . The elevated cAMP/PKA activates IL-11 by the intermediary implication of activin A (Figure 2). This sequence of activation is demonstrated by the usage of activin A receptor inhibitor that downregulates IL-11 production . Activin A, on the other hand, is activated by its own network of factors including progesterone, IL-1β, cAMP, and CRF [46, 64–66]. However, IL-1β is also a downstream target of IL-11  and seems to form an autoregulatory loop via the activation of activin A. IL-1β is secreted in low levels by decidual cells  as well as by human preimplantation embryos  and promotes decidualization and implantation . Altogether the sequential activation of activin A, IL-11, IL-1β, and PRL factors [37, 40, 67] only partially depicts the complex program of decidual transformation, and deficiency in its fulfilment might abrogate or aggravate the state of pregnancy.
(2) Signalling Pathways Controlling Decidualization. The receptors of prokineticin-1, relaxin, PGE2, and CRF, like the chemokines’ receptors, are G-protein coupled receptors characterized by the presence of seven transmembrane spanning domains [52, 56]. They activate adenylate cyclase that consequently forms the second messenger cAMP. cAMP signalling may be conveyed either by direct influence on genes possessing cAMP responsive elements in their promoter regions (e.g., PRL  and IGFBP-1 ) or by the activation of protein kinase A (PKA) [37, 56, 69] (Figure 2). As mentioned earlier, cAMP shortens the time and amplifies the magnitude of the decidualization response of endometrial cells. cAMP acts downstream of progesterone, as antiprogestin treatment inhibits cAMP-induced decidualization . cAMP induces the expression of the transcription factors FOXO1 (forkhead/winged helix protein O1A) , signal transducers and activators of transcription (STATs) , p53, and CCAAT/enhancer-binding protein β (C/EBPβ) and further regulates target genes . Analyses of tissue samples confirm significant upregulation of FOXO1 and C/EBPβ from the midsecretory phase of the cycle [70, 72, 73]. When applied simultaneously with cAMP, progesterone has an additive effect on FOXO1 expression , suggesting that it amplifies the effect of signals from the decidual microenvironment. FOXO1 is the main transcription factor that dominates and controls cell differentiation and represses cell cycle regulation genes during decidualization . It cooperatively interacts with other transcription factors such as C/EBPβ and PR  and regulates the expression of PRL  and IGFBP-1 .
The synchronization of pregnancy-related tissue development and differentiation implies that cytokines and peptide growth factors and hormones act in a network. The majority of the factors are engaged in transduction signalling via STAT3 or STAT5. STATs are phosphorylated by cytokines receptor-associated Janus kinases (JAK) or by Src family kinases ; they dimerize, translocate to the nucleus, and activate target genes . Suppressors of cytokine signalling (SOCS), which are specifically induced by cytokine stimuli, counteract STATs activation, thus forming a negative feedback regulatory mechanism.
Decidualization stimuli such as oestrogen, progesterone, and cAMP specifically upregulate STAT3 [75, 76] and STAT5  in endometrial stromal cells. In vivo STAT3 is maximally expressed in glandular epithelium during the secretory phase and in decidual cells during late-secretory phase . Phosphorylated STAT3 is the activated form of the bulk STAT3 and is the convergent focus of LIF , IL-11 , and IL-6  cytokine signalling. Moreover, STAT3 is a downstream target of the transcription factor C/EBPβ  demonstrating the crosstalk of signalling pathways in cells (Figure 2).
The engagement of STAT3 in endometrial differentiation is indispensable. This has been demonstrated by pathway inhibition approaches with progesterone receptor antagonists, SOCS3 , and small interfering/silencing RNA (siRNA) . These treatments cause a significant reduction of PRL and IGFBP-1 production leading to defective decidualization. However, other studies show enhancement of PRL and IGFBP-1 expression  via activation of STAT5 signalling . The STAT5 pathway is also an important signal for the decidualization programme of endometrial cells. In summary, STAT3 and STAT5 have been shown to be simultaneously involved into decidual cell differentiation because inhibition of their signalling activity abrogates decidualization.
Altogether, attaining the state of endometrial competence and receptivity is a process regulated by steroid hormones and multiple growth factors. Various signalling pathways are active; they interconnect, converge, diverge, overlap, and amplify to ensure the inherent progress of pregnancy.
(3) The Embryonic Trophectoderm Contributes to Placental Development. The decidualization is a prerequisite for endometrial receptivity. It is essential but not sufficient for the implementation of implantation. Therefore, signalling from the blastocyst is necessary for completing the hormone-driven differentiation of endometrium. A functional crosstalk established via paracrine action of hormones and growth factors synchronizes the development of the preimplantation embryo and endometrial decidualization. Viable early blastocysts secrete hCG [80, 81] starting from day 7 after insemination . At this early stage, the blastocysts are often still in their preimplantation period of development . Investigation of the values of hCG, oestrogen, and progesterone in blood samples from fertile women in conceptive and nonconceptive cycles revealed a correlative enhancement of the ovarian estradiol and progesterone with hCG levels in pregnant women during preimplantation period compared to lower estradiol and progesterone levels in nonpregnant women . After adhesion, the blastocysts significantly augment the secretion of hCG suggesting an important role for trophoblast attachment in differentiation and the establishment of pregnancy . Physiologically, the implantation of the blastocyst into the maternal decidua occurs during a limited time window of 6–10 days after the surge of luteinizing hormone, which marks the ovulation [83, 85]. Thereafter, the embryonic trophectoderm releases hCG in the maternal serum and urine [83, 86], indicating that the embryo has successfully breached the decidual lining and has established contact with the maternal blood. After implantation, during the first 10–12 weeks of prenatal development the embryos secrete increasing amounts of hCG, which subsequently decline in the second and third trimester . This temporal distribution underlines the importance of hCG for the establishment of viable pregnancy and the development of placental tissue. In particular, some of the reported functions of hCG relate to sustaining elevated levels of ovarian hormones , stimulating decidualization factors, and mediating trophoblast invasion as shown in in vitro models . Furthermore, some cellular and molecular mechanisms of the foetal-maternal dialogue are attributed to hCG specifically released by the embryo. This hormone interacts with its receptors on epithelial cells of the maternal endometrium and successively induces the expression of prokineticin-1 and LIF . As mentioned previously, hCG, prokineticin-1, and LIF are members of the intricate network of factors that exert autocrine and/or paracrine stimulation on the epithelial and stromal cells and influence endometrial decidualization and receptivity. Moreover, CRF , prokineticin-1 , IL-11 , activin A , LIF , and IL-1 [92, 93] are also secreted by the trophoblast cells or preimplantation embryos, which highlights the contribution of the embryo to the ongoing process of decidual transformation in the stages before and after implantation. The pleiotropic nature of these hormones and cytokines is further revealed by the observation that they participate in the sequence of events leading to embryo acceptance. These include apposition and adhesion of the blastocyst to the extracellular matrix, breaching of the epithelial basal lamina, and the invasion of the endometrial stroma by the trophectoderm [94, 95]. The interaction of the embryo with the decidua is mediated via the expression of integrins [96, 97]—heterodimeric transmembrane glycoproteins which mediate cell-to-cell or cell-to-substratum adhesion by binding to cellular ligands and proteins from the extracellular matrix . In this manner, the decidua and in particular the stromal cells are primed by decidualization factors and secrete extracellular matrix molecules such as collagens, laminin, and vitronectin [98, 99] that participate in tissue remodelling (Figure 3). Among several integrins regulated during menstrual cycle , the integrin, which is expressed by endometrial epithelial and stromal cells, is defined as a marker for uterine receptivity [85, 93]. In fertile women it is upregulated during the implantation window when the endometrium becomes receptive [97, 100, 101]. Besides steroid hormones , is stimulated by IL-1α and IL-1β secreted by human embryos, showing that embryo can regulate endometrial receptivity . Known ligands of are fibronectin, fibrinogen, vitronectin, von Willebrand, osteopontin, and collagen . Some studies show that trophoblasts are able to secrete collagen , while others demonstrate LIF-mediated enhancement of trophoblast adhesion to fibronectin and laminin . These data suggest the existence of active reciprocal mechanisms for strengthening embryo attachment to the maternal decidua. These mechanisms are controlled by hormones and factors such as hCG, prokineticin-1, and LIF, and their effect is to enhance receptivity and maintain early pregnancy .
(4) Placenta. The collaboration of the endometrium and trophectoderm constitutes the endocrine component of the placenta that maintains the course of pregnancy . Both tissues synthesize the same hormones and factors, such as CRF [89, 104], prokineticin-1 [52, 59], LIF [21, 53, 91], IL-11 [53, 62], and activin A [65, 66, 90] (Figure 3), while at the same time they differentially express the corresponding receptors [48, 59, 62, 89, 105–107]. Crucially, this set of factors attains reciprocal responsiveness, regulation, and synchronization of tissue remodelling during placentation. As a result, in a healthy pregnancy, the placenta develops only after an equilibrated exposure to maternal and foetal factors, cells, and tissues. Crucially, the maternal immune system intervenes in the processes of placentation and ensures the proper implementation of tissue remodelling, trophoblast invasion, and induction of tolerance towards the allogeneic embryo. The two immune cell subsets prevailing in decidua during pregnancy are uNK and monocytes/antigen-presenting cells with characteristic stage-dependent migration and distribution. Their recruitment into the decidua depends on the microenvironmental stimuli for chemoattraction. Characteristically, localized activation of inflammatory cytokines (TNF-α, IL-1, IL-6 , and IFN-γ) secreted by the recruited NK cells and Mo/Mph  occurs in the decidua around the time of embryo implantation. These cytokines influence the decidualization of DSCs and therefore determine the crosstalk between immune and nonimmune cells in the differentiating decidual milieu. Later on, the decidual niche is enriched in anti-inflammatory factors supporting maternal immune tolerance towards the embryo.
(5) Immune Cell Migration into the Placenta. Decidualization of the endometrial cells induces profound changes of their gene expression profiles and the secretion of bioactive mediators (hormones, transcription factors, cytokines, chemokines, selectins, integrins, tissue metalloproteinases, proteins, lipids, etc.) which are operational at every stage of placental remodelling [8, 9]. When stimulated by steroid hormones, the epithelial cells and DSCs produce chemokines (CCL2/MCP1, CXCL8/IL-8, CXCL10/IP-10, CX3CL1/fractalkine , CXCL10, and CXCL11 ) and cytokines (IL-6, IL-8, and IL-15)  and create an immune milieu in the decidua. Chemokines are chemoattractant cytokines that navigate the trafficking of leukocytes into organs in order to perform homeostatic immune surveillance or reach sites of inflammation . Depending on the environmental (external/internal) stimuli, tissues encode combinations of chemokine patterns, which are specifically recognized by receptor expressing immune cells subsets [113, 114]. Cytokines and hormones, independently and in combination, can influence the expression of chemokines [110, 111, 115, 116], chemokine receptors , adhesion molecules, and their ligands  within different cells and tissues, such as leukocytes and the endothelium . For example, LIF is reported to augment chemokine (MCP-1 and CXCL8) and cytokine (IL-6 and IL-15) expression in stromal cells , thus potentiating the effect of progesterone/progesterone and estradiol. Furthermore, TNF-α and IL-1β are shown to induce MCP-1 , whereas IL-1β stimulates expression of the chemokines MCP-1, CXCL8, CCL5/RANTES, CXCL2/MIP-2α, and CXCL3/MIP-2β, which are known to recruit monocytes/macrophages to tissues . However, there might also be chemokines that are not regulated by hormones. An example is the chemokine CXCL12/SDF1, which is exclusively and highly expressed in decidual stromal cells but only scarcely expressed in epithelial cells. CXCL12 expression remains unchanged after progesterone treatment of stromal cells .
The chemokine repertoire of the decidua and placenta define the temporal recruitment of uNK cells  and monocytes  from the peripheral blood (Figure 3). The suggested mechanism implies that the progesterone and estradiol upregulate the chemokines CXCL10 and CXCL11 in the decidua , while progesterone is shown to upregulate their receptor CXCR3 on NK cells . CXCL10 and CXCL11 along with CXCL12 and CX3CL1 create a specific environment in the decidua, which attracts CXCR3 and CXCR4 receptor expressing peripheral blood NK cells, to migrate into the decidua [110, 111]. Recruited locally, the peripheral blood NK cell subsets CD56+CD16+ and are converted into decidual uNK by the tissue-specific microenvironment. The main role in this process is attributed to the decidual stromal cells, which contribute to the maintenance of uNK cells via TGFβ1 signalling, which triggers their differentiation , and IL-15 signalling, which controls their proliferation . Similarly to the factors mentioned before, the expression levels of TGFβ1 and IL-15 in stromal cells are decidualization-dependent  and were found to progressively increase in decidual tissue sections from the secretory phase to the first trimester [118, 119]. Located in the decidua and differentiated accordingly, the uNK cells still express CXCR3  and CXCR4  chemokine receptors. They are chemoattracted to the vicinity of trophoblast cells that have been shown to spontaneously secrete CXCL12  and CCL3/MIP-1α , but not CXCL11, CXCL10, and CXCL9 chemokines . This profile suggests the utilization of CXCR4  and CCR5 chemokine receptors by uNK cells for driving their migration towards trophoblasts invading the spiral arteries . In this way, the uNK cells, which are enriched in the decidua close to the site of embryonic implantation, release factors and control the remodelling of spiral arteries  and trophoblast invasion [123–125].
Monocytes are another subset of immune cells that plays a role during pregnancy. They are sensitised to the combinatorial profile of chemokines expressed by DSCs that recruits them from the blood flow into the decidua. Thereafter, they interact with CXCL16 , MIP-1α , and chemokines released from trophoblasts and relocate to the proximity of foetal placental cells. Locally, monocytes are exposed to the placental environment (decidua and trophoblasts) and differentiate into antigen-presenting cells (APCs)—macrophages  or dendritic cells  with tolerogenic phenotype and function [129, 130]. APCs in the decidua demonstrate reduced allogeneic reactivity  and produce many immune factors, such as IL-10, IL-15 , and the chemokine MCP-1 , which play a role in immune suppression, differentiation, and recruitment of cell subsets. Altogether, the synchronized contact of immune, decidual, and trophoblast cells prompts their own temporal and cell-specific distribution, differentiation, and function, thus facilitating proper placental development and overall tissue homeostasis.
2. Immune Modulatory Properties of DSCs
The acceptance of a semiallogeneic embryo and the maintenance of immune tolerance during pregnancy alter leukocyte distribution and function in the maternal decidua. However, pregnancy hormones, the decidualization process, and the interactions of decidual and trophoblast cells with immune cells help to establish pregnancy-related immune homeostasis. This highlights the importance of intercellular communications in the implantation niche for the physiology of pregnancy in health and disease. DSCs might be the main operational immune modulators in placenta able to change lymphocyte function and suppress immune responses. Recent application of DSCs in clinical trials for treatment of steroid-resistant graft-versus-host disease shows the strong immune suppressive ability of DSCs .
2.1. DSCs and NK Cells
NK cells belong to the innate immunity and divide into noncytotoxic NK cells () and cytotoxic NK cells () . The cytotoxic NK cells lyse the virus-infected and tumour cells by secreting Granzyme A and Perforin. NK cells circulate in peripheral blood and through the secondary lymphoid organs but are also residing in tissues and organs such as the skin, lung, liver, and uterus [132, 133]. In the uterus NK (uNK) cells are the predominant immune population and represent approximately 70% of all leukocytes . uNK cells are noncytotoxic  and have nonimmune functions during the first trimester of pregnancy, including tissue remodelling, neoangiogenesis, and control of trophoblast invasion . Two mechanisms of uNK cell enrichment have been suggested [136, 137]. As previously described, NK cells migrate from the peripheral circulation to the decidua where they undergo a modification of their function. In addition, NK cells might appear as a result of differentiation of tissue resident haematopoietic CD34+ precursor cells . The presence of haematopoietic precursor cells (CD45+CD34+) that give rise to uNK cells was first described by the group of Vacca . These precursor cells are found to express membrane receptors specific for NK cell mitogen IL-15-CD122 and mIL-15 as well as NK specific transcription factors E4PB4 and ID2. Therefore, CD34+ cells in decidua are considered to be NK lineage restricted. Their commitment is demonstrated by in vitro experiments in which stimulation of CD34+ cells with a combination of stem cell factor, FMS-like tyrosine kinase ligands, IL-7, IL-15, and IL-21, leads to their differentiation into mature NK cells . Moreover, coculturing with DSCs causes CD34+ cells to differentiate into mature NK cells that secrete IL-8 . It has been shown that DSCs can suppress the proliferation of IL-15 activated NK cells  and can inhibit their Granzyme A and Perforin synthesis. As a result, the NK cell cytotoxicity has been impaired and decreased lysis of erythroleukemia (К562) and melanoma (FO1) target cells has been observed . This inhibition on NK cell proliferation and cytotoxicity is mediated by the immune suppressive factors PGE2 and indoleamine 2,3-dioxygenase (IDO), which are secreted by DSCs. However, a bidirectional interaction between DSCs and NK cells is necessary for the induction of tissue-specific cell functions. For example, Croxatto et al. point out that interferon γ (IFNγ) produced by NK cells is necessary for the activation of ido transcription in DSCs . Altogether, the summarized literature suggests that the cells from the decidual niche create specific microenvironment that modulates cell functions.
2.2. DSCs and Antigen-Presenting Cell Populations
Various APCs are observed in the human decidua during pregnancy. The majority of these are macrophages (Mph), while the number of mature dendritic cells (DCs) is much smaller . Besides APCs with a classical profile, there are also cells simultaneously expressing markers characteristic of Mph and DCs . This DC/Mph phenotype suggests either that these cells are in intermediate differentiation stages or that they constitute a separate APC subpopulation. In the decidua, these DC/Mph phenotype cells are found in the vicinity of the spiral arteries and are often clustered with uNK cells . In contrast, the mature DCs are located close to lymphatic vessels and in contact with T lymphocytes. Although decidual APCs are in contact with different immune cells, their function is not completely elucidated. It has been hypothesised that they do not act as classical APCs to activate allospecific effector cells. Still, the function of DCs, and in particular whether they act as immune activators or suppressors, is unclear. In vitro experiments demonstrate that DC/Mph phenotype cells isolated from the decidua activate allogeneic lymphocytes to a twofold lesser extent in comparison to mature DCs .
The state of maturity of DCs is a major control mechanism regulating the antigen-specific immune responses. Croxatto et al. showed that DSCs modulate the DC maturation process . In the presence of DSCs, the differentiation of blood monocytes to immature DCs (CD14+CD1a+) via IL-4 and GM-CSF cytokines is inhibited by 50–96%. Although phenotyped as fully differentiated, the rest of the cells remain weak activators or, probably, inhibitors of allogeneic T lymphocytes proliferation . In addition, DSCs inhibit the differentiation of immature DCs into mature DCs via the secretion of MIC-1 (Macrophage Inhibitory Cytokine-1) by DSCs. Furthermore, DSCs block the expression of CD25, CD83, and CD86 receptors, which could explain the observed weaker activation potential of DCs . Altogether, these observations demonstrate that DSCs support decidua-specific microenvironment and modify the functions of infiltrating APCs.
3. DSC Involvement in Reproductive Pathological Conditions
The implantation of the blastocyst is the critical event in human pregnancy and is strongly dependent on the physiological state of the blastocyst as well as the uterine lining [142, 143]. Evolution has endowed the endometrium with the ability to evaluate embryo quality . Either the implantation of a low-quality embryo does not occur or the embryo is rejected soon after implantation . Apart from this natural protective mechanism, the pathology-related implantation failure occurs also due to an inappropriately differentiated endometrium (Figure 4). Therefore, any disturbance in the decidualization programme and/or maternal-foetal crosstalk could cause pregnancy complications such as implantation failure, pregnancy loss, or development of a chromosomally abnormal embryo. The adequacy of endometrial functionality for pregnancy progression can be estimated by the fraction of abnormal embryos from miscarried pregnancies. While women with sporadic spontaneous abortions miscarry chromosomally normal embryos in 40–50% of the cases , this percentage is almost twice higher among women with recurrent pregnancy loss . The higher rate of normal embryos loss, together with the lower rate of live births in consequent pregnancies in the patients with recurrent pregnancy loss, strongly suggests that endometrial dysfunction is the more probable cause for abortion in these cohorts .
In this sense, the precise coordination and synchronization of the factors related to decidualization are critical for the success of pregnancy. The change in expression and/or function of one particular factor might affect the whole network of factors, abrogate tissue homeostasis, and cause reproductive disorders. Indeed, studies of the endometrium of women with reproductive disorders have demonstrated dysregulation of gene [146, 147] and protein [148, 149] expression profiles. However, the number of the dysregulated genes varies among different studies depending on the applied statistical methods , on the investigated phase of the menstrual cycle , and the type of reproductive disorder [146, 147]. Moreover, for a given pathology, no clear relationship between the gene and protein expression profiles has been observed . This suggests that the effect of the pathology occurs at the level of posttranscriptional modifications. This is consistent with investigations of miRNA expression, which reveal changed profiles in some pathological conditions [151, 152].
Investigations of whole endometrial biopsies also demonstrate dysregulation in gene and protein expression but do not reveal what are the affected cell subtypes. The analyses of signal transduction pathway components have demonstrated a relationship between the reproductive disorders and the impairment of progesterone signalling in the endometrium [148, 150, 153], which implies stromal cell dysfunctions. In addition, the involvement of other signalling pathways tightly connected to decidualization has also been suggested to contribute to pathological conditions. These pathway components include Dickkopf homolog1, FOXO1A, and TGFβ2 and the receptors for PGE2, IL-1, LIF, and gp130 [150, 153]. Indeed, a growing number of reports attribute DSC dysfunction to a variety of reproductive diseases and pregnancy complications. Notably, decidual stromal cells isolated from patients with reproductive disorders demonstrate an aberrant in vitro decidualization as evaluated by lower PRL and/or IGFBP-1 expression levels in comparison to healthy controls. Impaired differentiation of stromal cells has been observed in pathologies with different aetiology, namely, endometriosis (EOS) [154, 155], recurrent pregnancy loss (RPL) , and antiphospholipid syndrome (APLS). EOS is defined as an oestrogen-dependent, progesterone-resistant gynaecological condition, manifested by endometrial lesions developing in the peritoneal cavity . RPL is characterized by three or more consecutive abortions , while APLS is marked by the levels of circulating antiphospholipid autoantibodies and symptoms of vascular thrombosis and thrombocytopenia. However, despite these differences between the pathologies, all of them are accompanied by high infertility rate and reproductive complications, possibly predefined by the described impairment in the decidualization of DSCs. The case of APLS strongly supports this hypothesis. It has been accepted that the thrombotic events in the maternal as well as foetal-maternal circulation are the main cause for pregnancy complications in APLS. But an impairment of decidualization, as well as vasculature development in the implantation niche, has also been suspected . The assumption is confirmed by the observation that the antiphospholipid autoantibody 2-glycoprotein-I decreases the expression of PRL and IGFBP-1 by ESC isolated from women with APLS in response to in vitro decidualization . This finding is confirmed in vivo as well by the observation that the levels of PRL and IGFBP-1 transcripts in endometrial biopsies of RPL patients with an accompanying APLS are decreased and correlated to an increased rate of miscarriages in the group compared to the cohort of RPL without APLS . The altered timing and amplitude of the decidualization response developed by the impaired stromal cells function or pathology-related environmental factors, such as circulating autoantibodies, reveal their correlation to the clinical manifestation of the investigated diseases. For example, in EOS, the level of estradiol, as well as enzymes involved in its synthesis, is found to be increased in ESCs [155, 160]. The ability of stromal cells to autonomously synthesize oestrogen , in addition to their progesterone resistance [162, 163], impairs decidualization. While in the endometriotic patients the decidualization process is incomplete, in RPL patients the endometrial transformation is significantly delayed [156, 164]. The molecular basis of decidual dysfunction in RPL lies in the impaired dynamics and expression of proinflammatory and implantation factor, such as IL-33  and prokineticin-1 . IL-33 regulates the decidual receptivity factors during the implantation window, while prokineticin-1 is involved in angiogenesis and control of decidualization and implantation processes. Both factors show delayed expression in in vitro decidualized DSCs; hence the resulting in vivo outcome is a prolonged implantation window, increased decidual receptivity, and impaired selective functions of decidua in RPL patients.
In addition to the dysregulated factors mentioned above, a number of mitogens and chemoattractants for immune cells are also affected. For example, DSCs isolated from women with polycystic ovary syndrome have increased expression of IL-6 and IL-8 in response to decidualization in comparison to DSCs from healthy individuals. Conditioned medium from these cells correspondingly increases the chemoattraction of CD14+ monocytes and CD4+T cells . Conversely, IL-11 production is lower in ESCs from infertile compared to fertile women when their ESCs are subjected to in vitro decidualization . This suggests that the deficiency of this cytokine in the case of infertility might be a sign of improper or abrogated decidual differentiation.
In reproductive disorders, it has been observed that chemoattracting molecules are overexpressed in DSCs. These elevated levels are often induced and promoted by the immune cells that are recruited in the decidua . Thus the feedback of interactions between factors released by the decidual and immune cells is impaired, which disrupts the temporal and spatial distribution of immune cells and pregnancy homeostasis.
The significance of the cytokines, chemokines, and their receptors expressed at the foetal-maternal interface for the success of pregnancy is confirmed by studies of endometrial biopsies from patients with reproductive disorders. The results reveal a reduction in LIF, its receptor LIFR, and the signal transducing chain gp130 in patients with unexplained infertility , endometriosis [169–171], and recurrent implantation failure . By contrast, in preeclampsia, LIF is increased . However, signalling downstream of LIF is abrogated, because the corresponding transcription factor STAT3 and its phosphorylated, active form are reduced [174, 175]. Collectively, loss of LIF signalling has been established in patients with variable pathologies, such as preeclampsia, unexplained infertility, endometriosis, and recurrent implantation failure, indicating its importance for the maintenance of reproductive functions.
Other pregnancy factors, related to leukocyte homing to the foetal-maternal interface, are also dysregulated in patients with different reproductive pathologies. Briefly, impaired expression of CXCR4  and enhancement of IL-15 in women with implantation failure  and augmented expression of CXCL13, IL-8, MCP-1, and in endometriosis [176–179] as well as increased expression of the intercellular adhesion molecule-1 (ICAM-1) in the placenta of foetal growth restricted pregnancies  have been observed. These data suggest that the foetal-maternal interface in complicated pregnancies is enriched in chemoattracting molecules and their corresponding receptors, which is likely to be accompanied by an abnormal influx of immune cells into the decidua.
The relationship between the impairment of molecules regulating immune cell migration and the presence of immune cells in the endometrium has been shown in women with recurrent implantation failure. A significantly higher number of CD56+ uNK cells in the midsecretory endometrium are observed in the diseased group , which correlates with a significantly higher IL-15 expression in the endometrial stroma  in comparison to healthy controls. An enrichment of uNK cells in the decidua is also observed in other reproductive disorders [182, 183]. Interestingly, Kuroda et al.  found a reverse dependency between the number of CD56+ cells accumulating in the subluminal decidua and the ability of primary ESC cultures to decidualize in vitro. The results show that the more the NK cells are present in the tissue, the weaker the decidualization evaluated by the expression of PRL and IGFBP1 in stromal cells is. The authors observed decreased mRNA levels of the enzyme 11βHSD1 in ESC decidualized in vitro, which is consistent with the increased presence of CD56+ cells in the corresponding tissue. This enzyme is involved in the synthesis of cortisol, a potent inhibitor of uNK cell cytotoxicity . Hence, it is possible that cortisol deprivation caused by 11βHSD1 insufficiency in the stromal cells leads to the enrichment of activated NK cells, linked to low fertility status of the patients. Support for this hypothesis is given by the group of Giuliani et al. . The authors investigated the distribution of the CD56 expressing uNK subpopulations and their activation status by the evaluation of the expression of CD16 and the activation marker NKp46. Contrary to the previous report, in this study a significant difference of the number of CD56+ cells was not found. However, the authors  found a correlation between the increased number of activated uNK and the investigated pathologies (unexplained infertility, unexplained RPL, and endometriosis) . Altogether, further investigations will be needed to confirm a connection between the number/activation of uNK cells and endometrial dysfunctions.
The APCs are the second most prevalent immune cell population in the uterine lining, involved in embryo recognition and tolerance. Tolerogenic cells (DC-SIGN+DC and CD163+Mph), mature CD83+DC, and APCs with a DC/Mph phenotype have been described [134, 139, 140, 185]. The maintenance of a specific phenotype, distribution, and functional status among the APC populations is essentially dependent on the microenvironment. In many pregnancy complications, abnormal APC activation and distribution are suggested. The Mph, defined as CD14+ cells, in third-trimester decidua of women with preeclampsia were found to be decreased using immunohistochemical analysis , although this observation was not confirmed in another study where a bigger cohort was analyzed by FACS analysis . In addition, no difference in CD68+CD14− and CD68+CD14+ Mph density and distribution was observed in the decidua of patients with preterm birth with or without preeclampsia . Furthermore, another study elucidates a general change of CD14+/CD163+ or DC-SING/CD163+ (CD14+ and CD163+) Mph in the decidua basalis of women with preterm birth and preeclampsia in comparison with patients without preeclampsia . In conclusion, more investigations will be required to reach a consensus on the role of APCs in directing the immune response to tolerance or activation in pregnancy complications.
Hormonally controlled differentiation of ESCs into DSCs is decisive for transforming the uterine mucosa/decidua into a receptive implantation site, for performing selection, and for achieving immune acceptance of the allogeneic foetus. The summarized literature emphasizes the important contribution of decidual stromal cells to the microenvironment and their direct or indirect influence on immune cell recruitment, distribution, and function, on tissue remodelling, and on placenta formation. This clarifies the association between impairment in the timing and the state of differentiation of DSCs with the occurrence of severe pathological conditions, such as endometriosis, RPL, and APLS, all of which are with poor prognosis for human reproduction.
The authors declare that they have no competing interests.
The authors are very grateful to Professor Anna Kicheva for her critical discussion and helpful comments. The authors were supported by Grant no. BG051PO001-3.3.06-0059.
- J. J. Brosens, R. Pijnenborg, and I. A. Brosens, “The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literature,” American Journal of Obstetrics and Gynecology, vol. 187, no. 5, pp. 1416–1423, 2002.
- B. Gellersen and J. J. Brosens, “Cyclic decidualization of the human endometrium in reproductive health and failure,” Endocrine Reviews, vol. 35, no. 6, pp. 851–905, 2014.
- J. J. Brosens and B. Gellersen, “Death or survival—progesterone-dependent cell fate decisions in the human endometrial stroma,” Journal of Molecular Endocrinology, vol. 36, no. 3, pp. 389–398, 2006.
- D. Maldonado-Pérez, J. Evans, F. Denison, R. P. Millar, and H. N. Jabbour, “Potential roles of the prokineticins in reproduction,” Trends in Endocrinology and Metabolism, vol. 18, no. 2, pp. 66–72, 2007.
- A. Schumacher, S.-D. Costa, and A. C. Zenclussen, “Endocrine factors modulating immune responses in pregnancy,” Frontiers in Immunology, vol. 5, article 196, 2014.
- A. K. Brar, S. Handwerger, C. A. Kessler, and B. J. Aronow, “Gene induction and categorical reprogramming during in vitro human endometrial fibroblast decidualization,” Physiol Genomics, vol. 7, no. 2, pp. 135–148, 2001.
- J. Evans, R. D. Catalano, K. Morgan, H. O. D. Critchley, R. P. Millar, and H. N. Jabbour, “Prokineticin 1 signaling and gene regulation in early human pregnancy,” Endocrinology, vol. 149, no. 6, pp. 2877–2887, 2008.
- M. Takano, Z. Lu, T. Goto et al., “Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells,” Molecular Endocrinology, vol. 21, no. 10, pp. 2334–2349, 2007.
- T. Garrido-Gomez, F. Dominguez, J. A. Lopez et al., “Modeling human endometrial decidualization from the interaction between proteome and secretome,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 3, pp. 706–716, 2011.
- R. M. Popovici, L.-C. Kao, and L. C. Giudice, “Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology,” Endocrinology, vol. 141, no. 9, pp. 3510–3513, 2000.
- P. Kastner, A. Krust, B. Turcotte et al., “Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B,” The EMBO Journal, vol. 9, no. 5, pp. 1603–1614, 1990.
- J. F. Savouret, A. Bailly, M. Misrahi et al., “Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene,” The EMBO Journal, vol. 10, no. 7, pp. 1875–1883, 1991.
- M. D. Mueller, J.-L. Vigne, E. A. Pritts, V. Chao, E. Dreher, and R. N. Taylor, “Progestins activate vascular endothelial growth factor gene transcription in endometrial adenocarcinoma cells,” Fertility and Sterility, vol. 79, no. 2, pp. 386–392, 2003.
- M. Perrot-Applanat, M. Ancelin, H. Buteau-Lozano, G. Meduri, and P. Bausero, “Ovarian steroids in endometrial angiogenesis,” Steroids, vol. 65, no. 10-11, pp. 599–603, 2000.
- S. M. Hyder and G. M. Stancel, “Regulation of angiogenic growth factors in the female reproductive tract by estrogens and progestins,” Molecular Endocrinology, vol. 13, no. 6, pp. 806–811, 1999.
- S. Battersby, H. O. D. Critchley, K. Morgan, R. P. Millar, and H. N. Jabbour, “Expression and regulation of the prokineticins (endocrine gland-derived vascular endothelial growth factor and Bv8) and their receptors in the human endometrium across the menstrual cycle,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 5, pp. 2463–2469, 2004.
- F. Schatz, G. Krikun, R. Caze, M. Rahman, and C. J. Lockwood, “Progestin-regulated expression of tissue factor in decidual cells: implications in endometrial hemostasis, menstruation and angiogenesis,” Steroids, vol. 68, pp. 849–860, 2003.
- C. J. Lockwood, G. Krikun, R. Runic, L. B. Schwartz, A. F. Mesia, and F. Schatz, “Progestin-epidermal growth factor regulation of tissue factor expression during decidualization of human endometrial stromal cells,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 1, pp. 297–301, 2000.
- J.-G. Gao, J. Mazella, and L. Tseng, “Activation of the human IGFBP-1 gene promoter by progestin and relaxin in primary culture of human endometrial stromal cells,” Molecular and Cellular Endocrinology, vol. 104, no. 1, pp. 39–46, 1994.
- L. Tseng, J.-G. Gao, R. Chen, H. H. Zhu, J. Mazella, and D. R. Powell, “Effect of progestin, antiprogestin, and relaxin on the accumulation of prolactin and insulin-like growth factor-binding protein-1 messenger ribonucleic acid in human endometrial stromal cells,” Biology of Reproduction, vol. 47, no. 3, pp. 441–450, 1992.
- K. Sawai, N. Matsuzaki, T. Okada et al., “Human decidual cell biosynthesis of leukemia inhibitory factor: regulation by decidual cytokines and steroid hormones,” Biology of Reproduction, vol. 56, no. 5, pp. 1274–1280, 1997.
- H. Wang, H. O. D. Critchley, R. W. Kelly, D. Shen, and D. T. Baird, “Progesterone receptor subtype B is differentially regulated in human endometrial stroma,” Molecular Human Reproduction, vol. 4, no. 4, pp. 407–412, 1998.
- J.-F. Savouret, M. Rauch, G. Redeuilh et al., “Interplay between estrogens, progestins, retinoic acid and AP-1 on a single regulatory site in the progesterone receptor gene,” Journal of Biological Chemistry, vol. 269, no. 46, pp. 28955–28962, 1994.
- S. Mesiano, Y. Wang, and E. R. Norwitz, “Progesterone receptors in the human pregnancy uterus: do they hold the key to birth timing?” Reproductive Sciences, vol. 18, no. 1, pp. 6–19, 2011.
- S. Goldman, A. Weiss, I. Almalah, and E. Shalev, “Progesterone receptor expression in human decidua and fetal membranes before and after contractions: possible mechanism for functional progesterone withdrawal,” Molecular Human Reproduction, vol. 11, no. 4, pp. 269–277, 2005.
- M. Tang, J. Mazella, J. Gao, and L. Tseng, “Progesterone receptor activates its promoter activity in human endometrial stromal cells,” Molecular and Cellular Endocrinology, vol. 192, no. 1-2, pp. 45–53, 2002.
- J.-D. Wang, J.-B. Zhu, Y. Fu et al., “Progesterone receptor immunoreactivity at the maternofetal interface of first trimester pregnancy: a study of the trophoblast population,” Human Reproduction, vol. 11, no. 2, pp. 413–419, 1996.
- J. J. Brosens, N. Hayashi, and J. O. White, “Progesterone receptor regulates decidual prolactin expression in differentiating human endometrial stromal cells,” Endocrinology, vol. 140, no. 10, pp. 4809–4820, 1999.
- J. Gao and L. Tseng, “Progesterone receptor (PR) inhibits expression of insulin-like growth factor-binding protein-1 (IGFBP-1) in human endometrial cell line HEC-1B: characterization of the inhibitory effect of PR on the distal promoter region of the IGFBP-1 gene,” Molecular Endocrinology, vol. 11, no. 7, pp. 973–979, 1997.
- J. J. Kim, O. L. Buzzio, S. Li, and Z. Lu, “Role of FOXO1A in the regulation of insulin-like growth factor-binding protein-1 in human endometrial cells: interaction with progesterone receptor,” Biology of Reproduction, vol. 73, no. 4, pp. 833–839, 2005.
- L. Tseng, M. Tang, Z. Wang, and J. Mazella, “Progesterone receptor (hPR) upregulates the fibronectin promoter activity in human decidual fibroblasts,” DNA and Cell Biology, vol. 22, no. 10, pp. 633–640, 2003.
- L. L. Shuya, E. M. Menkhorst, J. Yap, P. Li, N. Lane, and E. Dimitriadis, “Leukemia inhibitory factor enhances endometrial stromal cell decidualization in humans and mice,” PLoS ONE, vol. 6, no. 9, Article ID e25288, 2011.
- R. L. Jones, L. A. Salamonsen, and J. K. Findlay, “Activin A promotes human endometrial stromal cell decidualization in vitro,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 8, pp. 4001–4004, 2002.
- C. A. White, E. Dimitriadis, A. M. Sharkey, and L. A. Salamonsen, “Interleukin-11 inhibits expression of insulin-like growth factor binding protein-5 mRNA in decidualizing human endometrial stromal cells,” Molecular Human Reproduction, vol. 11, no. 9, pp. 649–658, 2005.
- E. Dimitriadis, L. Robb, and L. A. Salamonsen, “Interleukin 11 advances progesterone-induced decidualization of human endometrial stromal cells,” Molecular Human Reproduction, vol. 8, no. 7, pp. 636–643, 2002.
- R. Telgmann, E. Maronde, K. Taskén, and B. Gellersen, “Activated protein kinase A is required for differentiation-dependent transcription of the decidual prolactin gene in human endometrial stromal cells,” Endocrinology, vol. 138, no. 3, pp. 929–937, 1997.
- E. Dimitriadis, C. Stoikos, M. Baca, W. D. Fairlie, J. E. McCoubrie, and L. A. Salamonsen, “Relaxin and prostaglandin E2 regulate interleukin 11 during human endometrial stromal cell decidualization,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 6, pp. 3458–3465, 2005.
- E. Zoumakis, A. N. Margioris, C. Stournaras et al., “Corticotrophin-Releasing Hormone (CRH) interacts with inflammatory prostaglandins and interleukins and affects the decidualization of human endometrial stroma,” Molecular Human Reproduction, vol. 6, no. 4, pp. 344–351, 2000.
- A. Ferrari, F. Petraglia, and E. Gurpide, “Corticotropin releasing factor decidualizes human endometrial stromal cells in vitro. Interaction with progestin,” Journal of Steroid Biochemistry and Molecular Biology, vol. 54, no. 5-6, pp. 251–255, 1995.
- E. Menkhorst, L. A. Salamonsen, J. Zhang, C. A. Harrison, J. Gu, and E. Dimitriadis, “Interleukin 11 and activin A synergise to regulate progesterone-induced but not cAMP-induced decidualization,” Journal of Reproductive Immunology, vol. 84, no. 2, pp. 124–132, 2010.
- A. K. Brar, G. R. Frank, C. A. Kessler, M. I. Cedars, and S. Handwerger, “Progesterone-dependent decidualization of the human endometrium is mediated by cAMP,” Endocrine, vol. 6, no. 3, pp. 301–307, 1997.
- G. R. Frank, A. K. Brar, M. I. Cedars, and S. Handwerger, “Prostaglandin E2 enhances human endometrial stromal cell differentiation,” Endocrinology, vol. 134, no. 1, pp. 258–263, 1994.
- S. M. Aronica, W. L. Kraus, and B. S. Katzenellenbogen, “Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and camp-regulated gene transcription,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 18, pp. 8517–8521, 1994.
- N. Tanaka, K. Miyazaki, H. Tashiro, H. Mizutani, and H. Okamura, “Changes in adenylyl cyclase activity in human endometrium during the menstrual cycle and in human decidua during pregnancy,” Journal of Reproduction and Fertility, vol. 98, no. 1, pp. 33–39, 1993.
- B. S. Skalhegg and K. Tasken, “Specificity in the cAMP/PKA signaling pathway. Differential expression,regulation, and subcellular localization of subunits of PKA,” Frontiers in Bioscience, vol. 5, pp. D678–D693, 2000.
- E. P. Tierney and L. C. Giudice, “Role of activin A as a mediator of in vitro endometrial stromal cell decidualization via the cyclic adenosine monophosphate pathway,” Fertility and Sterility, vol. 81, supplement 1, pp. 899–903, 2004.
- I. Tamura, H. Asada, R. Maekawa et al., “Induction of IGFBP-1 expression by cAMP is associated with histone acetylation status of the promoter region in human endometrial stromal cells,” Endocrinology, vol. 153, no. 11, pp. 5612–5621, 2012.
- J. Evans, R. D. Catalano, P. Brown et al., “Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor,” The FASEB Journal, vol. 23, no. 7, pp. 2165–2175, 2009.
- C. J. Lockwood, G. Krikun, C. Papp et al., “The role of progestationally regulated stromal cell tissue factor and type-1 plasminogen activator inhibitor (PAI-1) in endometrial hemostasis and menstruation,” Annals of the New York Academy of Sciences, vol. 734, pp. 57–79, 1994.
- R. L. Jones, J. K. Findlay, P. G. Farnworth, D. M. Robertson, E. Wallace, and L. A. Salamonsen, “Activin A and inhibin a differentially regulate human uterine matrix metalloproteinases: potential interactions during decidualization and trophoblast invasion,” Endocrinology, vol. 147, no. 2, pp. 724–732, 2006.
- R. L. Jones, L. A. Salamonsen, and J. K. Findlay, “Potential roles for endometrial inhibins, activins and follistatin during human embryo implantation and early pregnancy,” Trends in Endocrinology and Metabolism, vol. 13, no. 4, pp. 144–150, 2002.
- I. H. Cook, J. Evans, D. Maldonado-Pérez, H. O. Critchley, K. J. Sales, and H. N. Jabbour, “Prokineticin-1 (PROK1) modulates interleukin (IL)-11 expression via prokineticin receptor 1 (PROKR1) and the calcineurin/NFAT signalling pathway,” Molecular Human Reproduction, vol. 16, no. 3, pp. 158–169, 2009.
- E. Dimitriadis, L. A. Salamonsen, and L. Robb, “Expression of interleukin-11 during the human menstrual cycle: coincidence with stromal cell decidualization and relationship to leukaemia inhibitory factor and prolactin,” Molecular Human Reproduction, vol. 6, no. 10, pp. 907–914, 2000.
- M. Marwood, K. Visser, L. A. Salamonsen, and E. Dimitriadis, “Interleukin-11 and leukemia inhibitory factor regulate the adhesion of endometrial epithelial cells: implications in fertility regulation,” Endocrinology, vol. 150, no. 6, pp. 2915–2923, 2009.
- L. J. Macdonald, K. J. Sales, V. Grant, P. Brown, H. N. Jabbour, and R. D. Catalano, “Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium,” Molecular Human Reproduction, vol. 17, no. 10, pp. 626–636, 2011.
- B. Gellersen and J. Brosens, “Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair,” Journal of Endocrinology, vol. 178, no. 3, pp. 357–372, 2003.
- E. S. W. Ngan, K. Y. Lee, W. S. B. Yeung, H. Y. S. Ngan, E. H. Y. Ng, and P. C. Ho, “Endocrine gland-derived vascular endothelial growth factor is expressed in human peri-implantation endometrium, but not in endometrial carcinoma,” Endocrinology, vol. 147, no. 1, pp. 88–95, 2006.
- J. LeCouter, J. Kowalski, J. Foster et al., “Identification of an angiogenic mitogen selective for endocrine gland endothelium,” Nature, vol. 412, no. 6850, pp. 877–884, 2001.
- P. Hoffmann, J.-J. Feige, and N. Alfaidy, “Expression and oxygen regulation of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 and its receptors in human placenta during early pregnancy,” Endocrinology, vol. 147, no. 4, pp. 1675–1684, 2006.
- P. C. Heinrich, I. Behrmann, G. Müller-Newen, F. Schaper, and L. Graeve, “Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway,” Biochemical Journal, vol. 334, no. 2, pp. 297–314, 1998.
- P. Suman, N. Shembekar, and S. K. Gupta, “Leukemia inhibitory factor increases the invasiveness of trophoblastic cells through integrated increase in the expression of adhesion molecules and pappalysin 1 with a concomitant decrease in the expression of tissue inhibitor of matrix metalloproteinases,” Fertility and Sterility, vol. 99, no. 2, pp. 533–542, 2013.
- P. Paiva, L. A. Salamonsen, U. Manuelpillai et al., “Interleukin-11 promotes migration, but not proliferation, of human trophoblast cells, implying a role in placentation,” Endocrinology, vol. 148, no. 11, pp. 5566–5572, 2007.
- P. Suman, T. G. Poehlmann, G. J. Prakash, U. R. Markert, and S. K. Gupta, “Interleukin-11 increases invasiveness of JEG-3 choriocarcinoma cells by modulating STAT3 expression,” Journal of Reproductive Immunology, vol. 82, no. 1, pp. 1–11, 2009.
- P. Florio, M. Rossi, M. Sigurdardottir et al., “Paracrine regulation of endometrial function: interaction between progesterone and corticotropin-releasing factor (CRF) and activin A,” Steroids, vol. 68, no. 10-13, pp. 801–807, 2003.
- P. Florio, M. Rossi, P. Viganò et al., “Interleukin 1β and progesterone stimulate activin A expression and secretion from cultured human endometrial stromal cells,” Reproductive Sciences, vol. 14, no. 1, pp. 29–36, 2007.
- F. M. Reis, S. Luisi, P. Florio, A. Degrassi, and F. Petraglia, “Corticotropin-releasing factor, urocortin and endothelian-1 stimulate activin A release from cultured human placental cells,” Placenta, vol. 23, no. 6, pp. 522–525, 2002.
- C. A. White, E. Dimitriadis, A. M. Sharkey, C. J. Stoikos, and L. A. Salamonsen, “Interleukin 1 beta is induced by interleukin 11 during decidualization of human endometrial stromal cells, but is not released in a bioactive form,” Journal of Reproductive Immunology, vol. 73, no. 1, pp. 28–38, 2007.
- J.-S. Krüssel, P. Bielfeld, M. L. Polan, and C. Simón, “Regulation of embryonic implantation,” European Journal of Obstetrics & Gynecology and Reproductive Biology, vol. 110, supplement 1, pp. S2–S9, 2003.
- E. P. Tierney, S. Tulac, S.-T. J. Huang, and L. C. Giudice, “Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation,” Physiological Genomics, vol. 16, pp. 47–66, 2004.
- M. Christian, X. Zhang, T. Schneider-Merck et al., “Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein β in differentiating human endometrial stromal cells,” The Journal of Biological Chemistry, vol. 277, no. 23, pp. 20825–20832, 2002.
- I. Y. H. Mak, J. J. Brosens, M. Christian et al., “Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 6, pp. 2581–2588, 2002.
- S. Labied, T. Kajihara, P. A. Madureira et al., “Progestins regulate the expression and activity of the Forkhead transcription factor FOXO1 in differentiating human endometrium,” Molecular Endocrinology, vol. 20, no. 1, pp. 35–44, 2006.
- B. J. Plante, A. Kannan, M. K. Bagchi, L. Yuan, and S. L. Young, “Cyclic regulation of transcription factor C/EBP beta in human endometrium,” Reproductive Biology and Endocrinology, vol. 7, article 15, 2009.
- S. S. Jatiani, S. J. Baker, L. R. Silverman, and E. Premkumar Reddy, “JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies,” Genes and Cancer, vol. 1, no. 10, pp. 979–993, 2010.
- Y. Jiang, Y. Liao, H. He et al., “FoxM1 directs STAT3 expression essential for human endometrial stromal decidualization,” Scientific Reports, vol. 5, Article ID 13735, 2015.
- E. Dimitriadis, C. Stoikos, Y.-L. Tan, and L. A. Salamonsen, “Interleukin 11 signaling components signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) regulate human endometrial stromal cell differentiation,” Endocrinology, vol. 147, no. 8, pp. 3809–3817, 2006.
- Y. S. Devi, M. DeVine, J. DeKuiper, S. Ferguson, and A. T. Fazleabas, “Inhibition of IL-6 signaling pathway by curcumin in uterine decidual cells,” PLoS ONE, vol. 10, no. 5, Article ID e0125627, 2015.
- W. Wang, R. N. Taylor, I. C. Bagchi, and M. K. Bagchi, “Regulation of human endometrial stromal proliferation and differentiation by C/EBPβ involves cyclin E-cdk2 and STAT3,” Molecular Endocrinology, vol. 26, no. 12, pp. 2016–2030, 2012.
- T. Nagashima, T. Maruyama, H. Uchida et al., “Activation of SRC kinase and phosphorylation of signal transducer and activator of transcription-5 are required for decidual transformation of human endometrial stromal cells,” Endocrinology, vol. 149, no. 3, pp. 1227–1234, 2008.
- A. Lopata, K. Oliva, P. G. Stanton, and D. M. Robertson, “Analysis of chorionic gonadotrophin secreted by cultured human blastocysts,” Molecular Human Reproduction, vol. 3, no. 6, pp. 517–521, 1997.
- E. A. Lenton, L. M. Neal, and R. Sulaiman, “Plasma concentrations of human chorionic gonadotropin from the time of implantation until the second week of pregnancy,” Fertility and Sterility, vol. 37, no. 6, pp. 773–778, 1982.
- D. Lachlan-Hay and A. Lopata, “Chorionic gonadotropin secretion by human embryos in vitro,” Journal of Clinical Endocrinology and Metabolism, vol. 67, no. 6, pp. 1322–1324, 1988.
- A. J. Wilcox, D. D. Baird, and C. R. Weinberg, “Time of implantation of the conceptus and loss of pregnancy,” The New England Journal of Medicine, vol. 340, no. 23, pp. 1796–1799, 1999.
- D. R. Stewart, J. W. Overstreet, S. T. Nakajima, and B. L. Lasley, “Enhanced ovarian steroid secretion before implantation in early human pregnancy,” Journal of Clinical Endocrinology and Metabolism, vol. 76, no. 6, pp. 1470–1476, 1993.
- K. Sueoka, N. Kuji, S. Shiokawa, M. Tanaka, T. Miyazaki, and Y. Yoshimura, “Integrins and reproductive physiology: expression and modulation in fertilization, embryogenesis, and implantation,” Fertility and Sterility, vol. 67, no. 5, pp. 799–811, 1997.
- P. N. Lohstroh, J. W. Overstreet, D. R. Stewart et al., “Secretion and excretion of human chorionic gonadotropin during early pregnancy,” Fertility and Sterility, vol. 83, no. 4, pp. 1000–1011, 2005.
- S. Meuris, A. M. Nagy, J. Delogne-Desnoeck, D. Jurkovic, and E. Jauniaux, “Temporal relationship between the human chorionic gonadotrophin peak and the establishment of intervillous blood flow in early pregnancy,” Human Reproduction, vol. 10, pp. 947–950, 1995.
- M. Zygmunt, D. Hahn, K. Münstedt, P. Bischof, and U. Lang, “Invasion of cytotrophoblastic JEG-3 cells is stimulated by hCG in vitro,” Placenta, vol. 19, no. 8, pp. 587–593, 1998.
- S. N. Kalantaridou, E. Zoumakis, A. Makrigiannakis, H. Godoy, and G. P. Chrousos, “The role of corticotropin-releasing hormone in blastocyst implantation and early fetal immunotolerance,” Hormone and Metabolic Research, vol. 39, no. 6, pp. 474–477, 2007.
- C. Bearfield, E. Jauniaux, N. Groome, I. L. Sargent, and S. Muttukrishna, “The secretion and effect of inhibin A, activin A and follistatin on first-trimester trophoblasts in vitro,” European Journal of Endocrinology, vol. 152, no. 6, pp. 909–916, 2005.
- H.-F. Chen, K.-H. Chao, J.-Y. Shew, Y.-S. Yang, and H.-N. Ho, “Expression of leukemia inhibitory factor and its receptor is not altered in the decidua and chorionic villi of human anembryonic pregnancy,” Human Reproduction, vol. 19, no. 7, pp. 1647–1654, 2004.
- M. J. De los Santos, A. Mercader, A. Francés et al., “Role of endometrial factors in regulating secretion of components of the immunoreactive human embryonic interleukin-1 system during embryonic development,” Biology of Reproduction, vol. 54, no. 3, pp. 563–574, 1996.
- C. Simón, M. J. Gimeno, A. Mercader et al., “Embryonic regulation of integrins β3, α4, and in human endometrial epithelial cells in vitro,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 8, pp. 2607–2616, 1997.
- G. A. Thouas, F. Dominguez, M. P. Green, F. Vilella, C. Simon, and D. K. Gardner, “Soluble ligands and their receptors in human embryo development and implantation,” Endocrine Reviews, vol. 36, no. 1, pp. 92–130, 2015.
- E. R. Norwitz, D. J. Schust, and S. J. Fisher, “Implantation and the survival of early pregnancy,” New England Journal of Medicine, vol. 345, no. 19, pp. 1400–1408, 2001.
- S. Quenby, M. Anim-Somuah, C. Kalumbi, R. Farquharson, and J. D. Aplin, “Different types of recurrent miscarriage are associated with varying patterns of adhesion molecule expression in endometriu,” Reproductive BioMedicine Online, vol. 14, no. 2, article 2542, pp. 224–234, 2007.
- R. R. Gonzalez, A. Palomino, A. Boric, M. Vega, and L. Devoto, “A quantitative evaluation of α1, α4, αV and β3 endometrial integrins of fertile and unexplained infertile women during the menstrual cycle. A flow cytometric appraisal,” Human Reproduction, vol. 14, no. 10, pp. 2485–2492, 1999.
- M. Iwahashi, Y. Muragaki, A. Ooshima, M. Yamoto, and R. Nakano, “Alterations in distribution and composition of the extracellular matrix during decidualization of the human endometrium,” Journal of Reproduction and Fertility, vol. 108, no. 1, pp. 147–155, 1996.
- J. D. Aplin, A. K. Charlton, and S. Ayad, “An immunohistochemical study of human endometrial extracellular matrix during the menstrual cycle and first trimester of pregnancy,” Cell and Tissue Research, vol. 253, no. 1, pp. 231–240, 1988.
- A. Germeyer, R. F. Savaris, J. Jauckus, and B. Lessey, “Endometrial beta3 integrin profile reflects endometrial receptivity defects in women with unexplained recurrent pregnancy loss,” Reproductive Biology and Endocrinology, vol. 12, article 53, 2014.
- B. A. Lessey, A. J. Castelbaum, S. W. Sawin, and J. Sun, “Integrins as markers of uterine receptivity in women with primary unexplained infertility,” Fertility and Sterility, vol. 63, no. 3, pp. 535–542, 1995.
- B. A. Lessey, I. Yeh, A. J. Castelbaum et al., “Endometrial progesterone receptors and markers of uterine receptivity in the window of implantation,” Fertility and Sterility, vol. 65, no. 3, pp. 477–483, 1996.
- C. M. Oefner, A. Sharkey, L. Gardner, H. Critchley, M. Oyen, and A. Moffett, “Collagen type IV at the fetal-maternal interface,” Placenta, vol. 36, no. 1, pp. 59–68, 2015.
- F. Petraglia, S. Tabanelli, M. C. Galassi et al., “Human decidua and in vitro decidualized endometrial stromal cells at term contain immunoreactive corticotropin-releasing factor (CRF) and CRF messenger ribonucleic acid,” Journal of Clinical Endocrinology and Metabolism, vol. 74, no. 6, pp. 1427–1431, 1992.
- P. Florio, A. Franchini, F. M. Reis, I. Pezzani, E. Ottaviani, and F. Petraglia, “Human placenta, chorion, amnion and decidua express different variants of corticotropin-releasing factor receptor messenger RNA,” Placenta, vol. 21, no. 1, pp. 32–37, 2000.
- R. L. Jones, L. A. Salamonsen, Y. C. Zhao, J.-F. Ethier, A. E. Drummond, and J. K. Findlay, “Expression of activin receptors, follistatin and betaglycan by human endometrial stromal cells; consistent with a role for activins during decidualization,” Molecular Human Reproduction, vol. 8, no. 4, pp. 363–374, 2002.
- K. Kojima, H. Kanzaki, M. Iwai et al., “Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts,” Human Reproduction, vol. 10, no. 7, pp. 1907–1911, 1995.
- M. S. M. van Mourik, N. S. Macklon, and C. J. Heijnen, “Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment,” Journal of Leukocyte Biology, vol. 85, no. 1, pp. 4–19, 2009.
- C. J. Lockwood, S. J. Huang, C.-P. Chen et al., “Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia,” The American Journal of Pathology, vol. 183, no. 3, pp. 841–856, 2013.
- C. Carlino, H. Stabile, S. Morrone et al., “Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy,” Blood, vol. 111, no. 6, pp. 3108–3115, 2008.
- C. L. Sentman, S. K. Meadows, C. R. Wira, and M. Eriksson, “Recruitment of uterine NK cells: induction of CXC chemokine ligands 10 and 11 in human endometrium by estradiol and progesterone,” The Journal of Immunology, vol. 173, no. 11, pp. 6760–6766, 2004.
- B. Johnston and E. C. Butcher, “Chemokines in rapid leukocyte adhesion triggering and migration,” Seminars in Immunology, vol. 14, no. 2, pp. 83–92, 2002.
- E. J. Kunkel and E. C. Butcher, “Chemokines and the tissue-specific migration of lymphocytes,” Immunity, vol. 16, no. 1, pp. 1–4, 2002.
- D.-W. Park and K.-M. Yang, “Hormonal regulation of uterine chemokines and immune cells,” Clinical and Experimental Reproductive Medicine, vol. 38, no. 4, pp. 179–185, 2011.
- S. J. Huang, F. Schatz, R. Masch et al., “Regulation of chemokine production in response to pro-inflammatory cytokines in first trimester decidual cells,” Journal of Reproductive Immunology, vol. 72, no. 1-2, pp. 60–73, 2006.
- C. J. Lockwood, P. Matta, G. Krikun et al., “Regulation of monocyte chemoattractant protein-1 expression by tumor necrosis factor-α and interleukin-1β in first trimester human decidual cells: implications for preeclampsia,” The American Journal of Pathology, vol. 168, no. 2, pp. 445–452, 2006.
- D. B. Keskin, D. S. J. Allan, B. Rybalov et al., “TGFβ promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 9, pp. 3378–3383, 2007.
- K. Kitaya, J. Yasuda, I. Yagi, Y. Tada, S. Fushiki, and H. Honjo, “IL-15 expression at human endometrium and decidua,” Biology of Reproduction, vol. 63, no. 3, pp. 683–687, 2000.
- C. J. Stoikos, C. A. Harrison, L. A. Salamonsen, and E. Dimitriadis, “A distinct cohort of the TGFβ superfamily members expressed in human endometrium regulate decidualization,” Human Reproduction, vol. 23, no. 6, pp. 1447–1456, 2008.
- X. Wu, L.-P. Jin, M.-M. Yuan, Y. Zhu, M.-Y. Wang, and D.-J. Li, “Human first-trimester trophoblast cells recruit CD56 brightCD16- NK cells into decidua by way of expressing and secreting of CXCL12/stromal cell-derived factor 1,” Journal of Immunology, vol. 175, no. 1, pp. 61–68, 2005.
- P. M. Drake, M. D. Gunn, I. F. Charo et al., “Human placental cytotrophoblasts attract monocytes and CD56(bright) natural killer cells via the actions of monocyte inflammatory protein 1alpha,” The Journal of Experimental Medicine, vol. 193, no. 10, pp. 1199–1212, 2001.
- A. Robson, L. K. Harris, B. A. Innes et al., “Uterine natural killer cells initiate spiral artery remodeling in human pregnancy,” The FASEB Journal, vol. 26, no. 12, pp. 4876–4885, 2012.
- J. Tabiasco, M. Rabot, M. Aguerre-Girr et al., “Human decidual NK cells: unique phenotype and functional properties—a review,” Placenta, vol. 27, supplement, pp. 34–39, 2006.
- G. E. Lash, H. A. Otun, B. A. Innes et al., “Regulation of extravillous trophoblast invasion by uterine natural killer cells is dependent on gestational age,” Human Reproduction, vol. 25, no. 5, pp. 1137–1145, 2010.
- J. Hanna, D. Goldman-Wohl, Y. Hamani et al., “Decidual NK cells regulate key developmental processes at the human fetal-maternal interface,” Nature Medicine, vol. 12, no. 9, pp. 1065–1074, 2006.
- Y. Huang, X.-Y. Zhu, M.-R. Du, and D.-J. Li, “Human trophoblasts recruited T lymphocytes and monocytes into decidua by secretion of chemokine CXCL16 and interaction with CXCR6 in the first-trimester pregnancy,” Journal of Immunology, vol. 180, no. 4, pp. 2367–2375, 2008.
- R. H. McIntire, K. G. Ganacias, and J. S. Hunt, “Programming of human monocytes by the uteroplacental environment,” Reproductive Sciences, vol. 15, no. 5, pp. 437–447, 2008.
- L. Zhao, Q. Shao, Y. Zhang et al., “Human monocytes undergo functional re-programming during differentiation to dendritic cell mediated by human extravillous trophoblasts,” Scientific Reports, vol. 6, Article ID 20409, 2016.
- M. H. Abumaree, M. A. Al Jumah, B. Kalionis et al., “Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages,” Stem Cell Reviews and Reports, vol. 9, no. 5, pp. 620–641, 2013.
- F. M. Abomaray, M. A. Al Jumah, B. Kalionis et al., “Human chorionic villous mesenchymal stem cells modify the functions of human dendritic cells, and induce an anti-inflammatory phenotype in CD1+ dendritic cells,” Stem Cell Reviews and Reports, vol. 11, no. 3, pp. 423–441, 2015.
- T. Erkers, H. Kaipe, S. Nava et al., “Treatment of severe chronic graft-versus-host disease with decidual stromal cells and tracing with 111indium radiolabeling,” Stem Cells and Development, vol. 24, no. 2, pp. 253–263, 2015.
- P. Carrega and G. Ferlazzo, “Natural killer cell distribution and trafficking in human tissues,” Frontiers in Immunology, vol. 3, article 347, 2012.
- H. Sun, C. Sun, Z. Tian, and W. Xiao, “NK cells in immunotolerant organs,” Cellular and Molecular Immunology, vol. 10, no. 3, pp. 202–212, 2013.
- C. Bartmann, S. E. Segerer, L. Rieger, M. Kapp, M. Sütterlin, and U. Kämmerer, “Quantification of the predominant immune cell populations in decidua throughout human pregnancy,” American Journal of Reproductive Immunology, vol. 71, no. 2, pp. 109–119, 2014.
- P. Vacca, M. C. Mingari, and L. Moretta, “Natural killer cells in human pregnancy,” Journal of Reproductive Immunology, vol. 97, no. 1, pp. 14–19, 2013.
- J. Hanna, O. Wald, D. Goldman-Wohl et al., “CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells,” Blood, vol. 102, no. 5, pp. 1569–1577, 2003.
- P. Vacca, C. Vitale, E. Montaldo et al., “CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 6, pp. 2402–2407, 2011.
- D. Croxatto, P. Vacca, F. Canegallo et al., “Stromal cells from human decidua exert a strong inhibitory effect on NK cell function and dendritic cell differentiation,” PLoS ONE, vol. 9, no. 2, Article ID e89006, 2014.
- U. Kammerer, M. Schoppet, A. D. McLellan et al., “Human decidua contains potent immunostimulatory CD83+ dendritic cells,” American Journal of Pathology, vol. 157, no. 1, pp. 159–169, 2000.
- U. Kämmerer, A. O. Eggert, M. Kapp et al., “Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy,” The American Journal of Pathology, vol. 162, no. 3, pp. 887–896, 2003.
- S. E. Segerer, L. Rieger, M. Kapp et al., “MIC-1 (a multifunctional modulator of dendritic cell phenotype and function) is produced by decidual stromal cells and trophoblasts,” Human Reproduction, vol. 27, no. 1, pp. 200–209, 2012.
- R. G. Edwards, “Human implantation: the last barrier in assisted reproduction technologies?” Reproductive BioMedicine Online, vol. 13, no. 6, pp. 887–904, 2006.
- N. Dekel, Y. Gnainsky, I. Granot, K. Racicot, and G. Mor, “The role of inflammation for a successful implantation,” American Journal of Reproductive Immunology, vol. 72, no. 2, pp. 141–147, 2014.
- J. J. Brosens, M. S. Salker, G. Teklenburg et al., “Uterine selection of human embryos at implantation,” Scientific Reports, vol. 4, article 3894, 2014.
- H. Carp, V. Toder, A. Aviram, M. Daniely, S. Mashiach, and G. Barkai, “Karyotype of the abortus in recurrent miscarriage,” Fertility and Sterility, vol. 75, no. 4, pp. 678–682, 2001.
- A. Tapia, L. M. Gangi, F. Zegers-Hochschild et al., “Differences in the endometrial transcript profile during the receptive period between women who were refractory to implantation and those who achieved pregnancy,” Human Reproduction, vol. 23, no. 2, pp. 340–351, 2008.
- L. C. Kao, A. Germeyer, S. Tulac et al., “Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease. Based implantation failure and infertility,” Endocrinology, vol. 144, no. 7, pp. 2870–2881, 2003.
- A. N. Stephens, N. J. Hannan, A. Rainczuk et al., “Post-translational modifications and protein-specific isoforms in endometriosis revealed by 2D DIGE,” Journal of Proteome Research, vol. 9, no. 5, pp. 2438–2449, 2010.
- M. Manohar, H. Khan, V. K. Sirohi et al., “Alteration in endometrial proteins during early-and mid-secretory phases of the cycle in women with unexplained infertility,” PLoS ONE, vol. 9, no. 11, Article ID e111687, 2014.
- R. O. Burney, S. Talbi, A. E. Hamilton et al., “Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis,” Endocrinology, vol. 148, no. 8, pp. 3814–3826, 2007.
- J. Chen, L. Gu, J. Ni, P. Hu, K. Hu, and Y.-L. Shi, “MIR-183 regulates ITGB1P expression and promotes invasion of endometrial stromal cells,” BioMed Research International, vol. 2015, Article ID 340218, 10 pages, 2015.
- X.-Y. Shi, L. Gu, J. Chen, X.-R. Guo, and Y.-L. Shi, “Downregulation of miR-183 inhibits apoptosis and enhances the invasive potential of endometrial stromal cells in endometriosis,” International Journal of Molecular Medicine, vol. 33, no. 1, pp. 59–67, 2014.
- A. Tapia-Pizarro, P. Figueroa, J. Brito, J. C. Marín, D. J. Munroe, and H. B. Croxatto, “Endometrial gene expression reveals compromised progesterone signaling in women refractory to embryo implantation,” Reproductive Biology and Endocrinology, vol. 12, article 92, 2014.
- P. A. B. Klemmt, J. G. Carver, S. H. Kennedy, P. R. Koninckx, and H. J. Mardon, “Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity,” Fertility and Sterility, vol. 85, no. 3, pp. 564–572, 2006.
- L. Aghajanova, A. Hamilton, J. Kwintkiewicz, K. C. Vo, L. C. Giudice, and R. B. Jaffe, “Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis,” Biology of Reproduction, vol. 80, no. 1, pp. 105–114, 2009.
- M. Salker, G. Teklenburg, M. Molokhia et al., “Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss,” PLoS ONE, vol. 5, no. 4, Article ID e10287, 2010.
- S. Ozkan, W. Murk, and A. Arici, “Endometriosis and infertility: epidemiology and evidence-based treatments,” Annals of the New York Academy of Sciences, vol. 1127, pp. 92–100, 2008.
- K. D. Beaman, E. Ntrivalas, T. M. Mallers, M. K. Jaiswal, J. Kwak-Kim, and A. Gilman-Sachs, “Immune etiology of recurrent pregnancy loss and its diagnosis,” American Journal of Reproductive Immunology, vol. 67, no. 4, pp. 319–325, 2012.
- J. Francis, R. Rai, N. J. Sebire et al., “Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome,” Molecular Human Reproduction, vol. 12, no. 7, pp. 435–442, 2006.
- E. Attar, H. Tokunaga, G. Imir et al., “Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 2, pp. 623–631, 2009.
- P. A. B. Klemmt, J. G. Carver, P. Koninckx, E. J. McVeigh, and H. J. Mardon, “Endometrial cells from women with endometriosis have increased adhesion and proliferative capacity in response to extracellular matrix components: towards a mechanistic model for endometriosis progression,” Human Reproduction, vol. 22, no. 12, pp. 3139–3147, 2007.
- R. Shao, S. Cao, X. Wang, Y. Feng, and H. Billig, “The elusive and controversial roles of estrogen and progesterone receptors in human endometriosis,” American Journal of Translational Research, vol. 6, no. 2, pp. 104–113, 2014.
- S. E. Bulun, Y.-H. Cheng, M. E. Pavone et al., “Estrogen receptor-β, estrogen receptor-α, and progesterone resistance in endometriosis,” Seminars in Reproductive Medicine, vol. 28, no. 1, pp. 36–43, 2010.
- M. S. Salker, J. Nautiyal, J. H. Steel et al., “Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss,” PLoS ONE, vol. 7, no. 12, Article ID e52252, 2012.
- T. T. Piltonen, J. C. Chen, M. Khatun et al., “Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro,” Human Reproduction, vol. 30, no. 5, pp. 1203–1215, 2015.
- N. Karpovich, P. Klemmt, J. H. Hwang et al., “The production of interleukin-11 and decidualization are compromised in endometrial stromal cells derived from patients with infertility,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 3, pp. 1607–1612, 2005.
- G. E. Lash and J. Ernerudh, “Decidual cytokines and pregnancy complications: focus on spontaneous miscarriage,” Journal of Reproductive Immunology, vol. 108, pp. 83–89, 2015.
- L. Aghajanova, S. Altmäe, K. Bjuresten, O. Hovatta, B.-M. Landgren, and A. Stavreus-Evers, “Disturbances in the LIF pathway in the endometrium among women with unexplained infertility,” Fertility and Sterility, vol. 91, no. 6, pp. 2602–2610, 2009.
- E. Dimitriadis, C. Stoikos, M. Stafford-Bell et al., “Interleukin-11, IL-11 receptorα and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window,” Journal of Reproductive Immunology, vol. 69, no. 1, pp. 53–64, 2006.
- C. Moberg, V. Bourlev, N. Ilyasova, and M. Olovsson, “Endometrial expression of LIF and its receptor and peritoneal fluid levels of IL-1α and IL-6 in women with endometriosis are associated with the probability of pregnancy,” Archives of Gynecology and Obstetrics, vol. 292, no. 2, pp. 429–437, 2015.
- Z. Alizadeh, N. Shokrzadeh, M. Saidijam, and M. F. Sanoee, “Semi-quantitative analysis of HOXA11, leukemia inhibitory factor and basic transcriptional element binding protein 1 mRNA expression in the mid-secretory endometrium of patients with endometriosis,” Iranian Biomedical Journal, vol. 15, no. 3, pp. 66–72, 2011.
- N. Mariee, T. C. Li, and S. M. Laird, “Expression of leukaemia inhibitory factor and interleukin 15 in endometrium of women with recurrent implantation failure after IVF; correlation with the number of endometrial natural killer cells,” Human Reproduction, vol. 27, no. 7, pp. 1946–1954, 2012.
- A. Benian, H. Uzun, S. Aydin, M. Albayrak, S. Uludağ, and R. Madazli, “Placental stem cell markers in pre-eclampsia,” International Journal of Gynecology and Obstetrics, vol. 100, no. 3, pp. 228–233, 2008.
- M. Weber, C. Kuhn, S. Schulz et al., “Expression of signal transducer and activator of transcription 3 (STAT3) and its activated forms is negatively altered in trophoblast and decidual stroma cells derived from preeclampsia placentae,” Histopathology, vol. 60, no. 4, pp. 657–662, 2012.
- Z. Zhang, X. Yang, L. Zhang et al., “Decreased expression and activation of Stat3 in severe preeclampsia,” Journal of Molecular Histology, vol. 46, no. 2, pp. 205–219, 2015.
- J. M. Franasiak, K. A. Burns, O. Slayden et al., “Endometrial CXCL13 expression is cycle regulated in humans and aberrantly expressed in humans and rhesus macaques with endometriosis,” Reproductive Sciences, vol. 22, no. 4, pp. 442–451, 2015.
- M. Ulukus, E. C. Ulukus, E. N. Tavmergen Goker, E. Tavmergen, W. Zheng, and A. Arici, “Expression of interleukin-8 and monocyte chemotactic protein 1 in women with endometriosis,” Fertility and Sterility, vol. 91, no. 3, pp. 687–693, 2009.
- C. Jolicoeur, M. Boutouil, R. Drouin, I. Paradis, A. Lemay, and A. Akoum, “Increased expression of monocyte chemotactic protein-1 in the endometrium of women with endometriosis,” The American Journal of Pathology, vol. 152, no. 1, pp. 125–133, 1998.
- L. L. Hii and P. A. Rogers, “Endometrial vascular and glandular expression of integrin α(v)β3 in women with and without endometriosis,” Human Reproduction, vol. 13, no. 4, pp. 1030–1035, 1998.
- R. Madazli, A. Benian, S. Ilvan, and Z. Calay, “Placental apoptosis and adhesion molecules expression in the placenta and the maternal placental bed of pregnancies complicated by fetal growth restriction with and without pre-eclampsia,” Journal of Obstetrics and Gynaecology, vol. 26, no. 1, pp. 5–10, 2006.
- E. Tuckerman, N. Mariee, A. Prakash, T. C. Li, and S. Laird, “Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF,” Journal of Reproductive Immunology, vol. 87, no. 1-2, pp. 60–66, 2010.
- E. Giuliani, K. L. Parkin, B. A. Lessey, S. L. Young, and A. T. Fazleabas, “Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis,” American Journal of Reproductive Immunology, vol. 72, no. 3, pp. 262–269, 2014.
- K. Kuroda, R. Venkatakrishnan, S. James et al., “Elevated periimplantation uterine natural killer cell density in human endometrium is associated with impaired corticosteroid signaling in decidualizing stromal cells,” Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 11, pp. 4429–4437, 2013.
- Y. Chen, Y. Wang, Y. Zhuang, F. Zhou, and L. Huang, “Mifepristone increases the cytotoxicity of uterine natural killer cells by acting as a glucocorticoid antagonist via ERK activation,” PLoS ONE, vol. 7, no. 5, Article ID e36413, 2012.
- D. Schonkeren, M.-L. Van Der Hoorn, P. Khedoe et al., “Differential distribution and phenotype of decidual macrophages in preeclamptic versus control pregnancies,” American Journal of Pathology, vol. 178, no. 2, pp. 709–717, 2011.
- P. J. Williams, J. N. Bulmer, R. F. Searle, B. A. Innes, and S. C. Robson, “Altered decidual leucocyte populations in the placental bed in pre-eclampsia and foetal growth restriction: a comparison with late normal pregnancy,” Reproduction, vol. 138, no. 1, pp. 177–184, 2009.
- L. Rieger, S. Segerer, T. Bernar et al., “Specific subsets of immune cells in human decidua differ between normal pregnancy and preeclampsia—a prospective observational study,” Reproductive Biology and Endocrinology, vol. 7, article 132, 2009.
- J.-S. Kim, R. Romero, E. Cushenberry et al., “Distribution of CD14+ and CD68+ macrophages in the placental bed and basal plate of women with preeclampsia and preterm labor,” Placenta, vol. 28, no. 5-6, pp. 571–576, 2007.
Copyright © 2016 Kameliya Vinketova et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.