Abstract Contrary to widespread belief, the implantation of an embryo for the initiation of pregnancy is like a battle, in that the embryo uses a variety of coercive tactics to force its acceptance by the endometrium. We propose that embryo implantation involves a three-step process: (1) identification of a receptive endometrium; (2) superimposition of a blastocyst-derived signature onto the receptive endometrium before implantation; and finally (3) breaching by the embryo and trophoblast invasion, culminating in decidualization and placentation. We review here the story that is beginning to emerge, focusing primarily on the cells that are in “combat” during this process. The bond between mother and child is commonly seen as one of the strongest connections in nature, and the extended intrauterine retention of the fetus is regarded as the highest form of self-kill by the mother. Yet pregnancy has many aspects of a battle. The uterus forces the embryo to prove itself adequate or face death; the embryo, at the same time deploys various specialized tactics to ensure its survival. It is increasingly clear that the embryo at the time of implantation in effect has to assault the fortresslike wall of the endometrium, modify the stromal cells, and trick the mother’s potentially lethal immune cells to establish kinship. Here, we attempt to decipher the plot of this “battle.” The Endometrium as a Well-Guarded Fortress The endometrium, the inner lining of the uterus, is composed of epithelial cells, stromal cells (the bulk of the population), immune cells, and the endothelial cells that make up the vasculature. The epithelial cells of the uterus are of two varieties. Luminal epithelial cells face the lumen of the uterus. Others radiate into the endometrial stroma toward the base of the myometrium to form the uterine glands. This entire endometrium cyclically undergoes dynamic remodeling under strict hormonal regulation to replenish its population, thus ensuring its health (1). One of the key functions of the endometrium is to implant the embryo and nourish it to ensure pregnancy. Paradoxically, the endometrium is refractory to embryo implantation throughout the menstrual cycle except for a narrow window. Classic transplantation experiments have revealed that although embryos can implant in and invade almost any tissue, this ease of implantation does not generally hold in the uterus, as an embryo is almost always rejected unless correctly primed by hormones (2–5). However, in the event that the luminal epithelium of the endometrium is damaged, embryos can implant even in the absence of hormonal priming (4–6), suggesting that the endometrial epithelium is a barrier to implantation. The luminal epithelial cells of the endometrium appear to be like a barricade of guards that protects the endometrium from invasion, and the embryo must fight the guards to establish its ability to survive. The Weakest Phase: A Receptive Endometrium In a cycling endometrium, the phase at which the embryo can implant is termed the “window of receptivity.” Achieved after sequential actions of estrogen and progesterone, this window lasts for ∼3 to 5 days in most primates and a few hours in rodents (1, 7).The receptive endometrium is characterized morphologically by the presence of apical protrusions called pinopodes on the cells of the luminal epithelium (8). Beyond the pinopodes, the luminal epithelium is pseudostratified, columnar, and polarized. The glands are large and highly convoluted and secrete a lot of fluid. The endometrial stroma is edematous, and the tissue is highly vascularized. These morphological changes are also mirrored by the distinct molecular signature of the receptive endometrium (9), and this signature is altered in women with recurrent implantation failure (10). The genomic signature of the receptive endometrium exhibits characteristics of an inflammatory response, alterations in the complement pathway, wound repair, immune responses, and regulation of coagulation (10, 11; see note at end of manuscript). In general, similar responses are observed during tissue injury. Because receptivity is achieved just before menstruation and its molecular signature is characteristic of injured tissue, it is plausible that the receptive endometrium is actually a weakened tissue and that the embryo recognizes this weakness to invade. Indeed, poor inflammatory responses and inhibition of complement activation are characteristics of the endometrium of women with infertility and recurrent implantation failure (10), suggesting that a weakened/injured endometrium is a prerequisite for receptivity. Modification of the Luminal Epithelium of the Endometrium by the Embryo Once the endometrium has attained the receptive phase, it is thought to be like a passive tissue that must allow embryo implantation. However, distinct morphological and molecular changes are observed in the receptive endometrium in response to the embryo even before implantation (Fig. 1). In histological analyses of monkey and baboon uteri collected on the day of (or a day before) embryo apposition or those infused with embryo-derived molecules such as chorionic gonadotropin (CG), the endometrial epithelium undergoes endoreduplication (replication of the nuclear genome without cell division), resulting in an “epithelial plaque reaction” (12–18) (Fig. 1). The functional significance of the plaque response is presently unclear, but it is thought to stimulate the precocious development of the maternal vasculature below the epithelium (18). Another characteristic feature of implantation-stage epithelium is a loss of cell polarity and cell flattening (Fig. 1). This is more clearly described in the mouse, in which the single-layer luminal epithelium becomes flattened and the cells lose polarity (19). Figure 1. View largeDownload slide Embryo-induced morphological changes in the luminal epithelium at the time of implantation. Embryo-luminal epithelium interactions with a range of ligands and receptors permit its rolling and apposition. At the same time, polarized epithelial cells at the site of embryo apposition undergo flattening, and the epithelial barrier is weakened. The foci of epithelial cells undergo endoreduplication to form epithelial plaque. There is an increase in vascularization. At the beginning of the invasion, the embryo undergoes apoptosis and entosis, paving the way for it to implant. Figure 1. View largeDownload slide Embryo-induced morphological changes in the luminal epithelium at the time of implantation. Embryo-luminal epithelium interactions with a range of ligands and receptors permit its rolling and apposition. At the same time, polarized epithelial cells at the site of embryo apposition undergo flattening, and the epithelial barrier is weakened. The foci of epithelial cells undergo endoreduplication to form epithelial plaque. There is an increase in vascularization. At the beginning of the invasion, the embryo undergoes apoptosis and entosis, paving the way for it to implant. In addition, the edematous stroma of the receptive endometrium undergoes extensive compaction in response to the embryo, and there is increased vascularity (12–17, 20, 21). The morphological changes observed in the endometrium are accompanied by extensive changes in gene expression profiles. In response to embryonic signals, the uterine cells change their expression of several genes, including transcription factors; alter the distribution of glycans; and sort integrins differently (15, 22–25). Global gene profiling of the baboon endometrium treated with CG with or without interleukin-1β (IL-1β) in a manner that mimics embryo apposition has further revealed activation in inflammatory and complement pathways (17, 26). A similar activation of genes involved in immune responses is observed in human endometrial cells cocultured with trophoblast cells (27). These observations clearly indicate that the receptive endometrium is modified by the embryo at the time of implantation, and the process seems to involve further activation of inflammation. This could be expected to lead to further tissue damage. The embryo-mediated changes in the endometrium can be compared with strafing (here, the repeated use of small arms) in which the embryos secrete factors, mainly CG and IL-1β, that play the part of missiles and grenades. However, the contribution of other factors yet to be identified cannot be ruled out. This strafing seems to be essential, as intrauterine infusion of CG in medically assisted reproductive cycles significantly improves the ability of the embryo to implant and enhances the success rate in assisted reproduction (28). Trojan Horses: The Embryonic Extracellular Vesicles and MicroRNAs In this battle for implantation, the embryo seems to make use of “deceptive” entities that parallel the Trojan horse of Greek mythology. These are the embryo-derived extracellular vesicles (EVs) and microRNAs (miRNAs). EVs are small membrane-bound structures that are secreted by most cells and carry and deliver important biomolecules such as lipids, proteins, DNA, and messenger RNA (mRNA) (including miRNA) to other cells (29). miRNAs are small noncoding RNA molecules that bind target mRNA and regulate gene expression (30). The miRNAs can work intracellularly or can be secreted in free or EV-bound forms that can be taken up by target cells, where they control gene expression (29–31). EVs and secreted miRNAs have been isolated from embryo-conditioned media as well as from cultured trophoblasts (32–35). The embryo/trophoblastic EVs contain a variety of RNA and miRNA species that have diverse targets on both epithelial and stromal cells (29–31, 34). The target genes of these miRNAs are predicted to mediate cellular activities such as adhesion and migration, suggesting that embryos could potentially modify the endometrial genome so that it improves trophoblast adhesion. Thus, embryonic EVs and miRNAs can be viewed as Trojan horses that, after reaching their target, seize the machinery and take over its functioning. Interestingly, the endometrium also appears to be a smart enemy that cannot be easily coaxed. It has been shown that the profiles of secreted miRNA differ significantly between developmentally and/or implantation-competent and -incompetent blastocysts. One such miRNA is MiR-166, which is specifically secreted by implantation-incompetent blastocysts. In vitro experiments have demonstrated that transfection of miR-166 in cultured human endometrial epithelial cells decreases the adhesion of trophoblasts onto the epithelium (35). This indicates that the embryo secretes only the desirable kinds of signals that will alter the luminal epithelium to support apposition. Adhesion of the Embryo to the Luminal Epithelium: Making Friends With the Foe After strafing, the embryo must adhere and then firmly anchor to the uterine lumen to initiate apposition. The embryo must recognize an appropriate site, which has to be firm enough to oppose but eventually allow anchoring and breaching. For this, the embryo must initially survey the wall of the uterine lumen, perhaps to find its weak points. The embryo does so by rolling itself over the uterine lumen and determining an appropriate implantation site. This rolling seems to be a function of the embryo-uterine glycocalyx. The apical cell surfaces of epithelia contain numerous microvilli, which are covered by a thick layer of glycocalyx; the embryo contains several complementary receptors and/or ligands, and these receptor-ligand interactions aid in initial adhesion (Fig. 1). The uterine glycocalyx and its regulation and involvement in receptivity and implantation have been extensively reviewed (36–38). Amongst the glycocalyx molecules, interaction of l-selectin on human blastocysts and its oligosaccharide ligands on endometrial epithelia has been shown to interact and is involved in embryo adhesion (38, 39). However, this interaction is weak, as trophoblastic spheroids bound to the l-selectin ligand sialyl detach at a force of 2.74 × 10−3 dyne and 7.5 × 10−5 dyne-cm of torque (40), suggesting that such interactions may aid in embryo rolling, though they are possibly too weak to support firm attachment. During the course of embryo rolling, the attachment-detachment reactions of the endometrial epithelium and the embryo have very localized effects. For example, MUC1 levels are reduced in the apical portion of the luminal epithelium juxtaposed to the opposing embryo (attachment pole) but not at the opposite pole (15, 41). In contrast, the levels of both αV and β3 integrin subunits are increased in the luminal epithelial cells at the site of apposition compared with the nonapposing region (15). Reduced expression of HOXA10 has also been noted in luminal epithelium at the time of apposition (42, 43). The fact that these changes in the luminal epithelial cells are highly localized implies that the embryo is not always successful, but it keeps trying at several places to find one that ultimately allows its docking. We do not yet completely understand how the embryo manages this focal action to allow initial apposition. The process does not seem to be driven by soluble factors of the embryo, as CG and IL-1β bring about the changes uniformly across the entire lumen rather than creating specialized foci (16, 17). Furthermore, both loss of MUC1 and gain of integrin subunit expression along with its appropriate membrane sorting occur uniformly in in vitro‒cultured epithelial cells treated with embryo culture fluid (15). It is possible that these changes are a consequence of more direct attacks by the embryo and that mechanical forces also play a role in this event. In summary, it is most likely that the embryo physically brushes off the glycocalyx using trophoblastic protease to pave the way for anchorage. Weakening of the Epithelium Once the embryo adheres itself, it anchors and breaches the luminal epithelium to gain entry. However, the luminal epithelial cells tightly adhere to each other, and adhesion molecules along the lateral plasma membrane of the uterine epithelium are a barrier to invasion. Thus, the embryo first needs to physically weaken this wall to eventually gain entry into the endometrium. Diffusion of apical and lateral gap junctions in the luminal epithelium is observed in implantation-stage endometrium (44); there is also a reduction in cell polarity (45–47). A recent study in marsupials reported that in nonpregnant uteri, the adherence junction protein E-cadherin is expressed laterally; however, during pregnancy, the expression of E-cadherin is cytoplasmic and diffused (46). Interestingly, even in the mouse on the evening of day 4, when the embryo has opposed and is berthing to prepare for an invasion, E-cadherin expression, which is strong at the apicolateral borders in the luminal epithelium of interimplantation sites, is reduced at the implantation sites. Expression in general is reduced and even lost from many cells in the lateral borders (Fig. 2), indicating that the adhered embryo weakens the epithelial barrier to facilitate its further invasion. Figure 2. View largeDownload slide Expression of E-cadherin in the luminal epithelium of pregnant mice. Paraffin-embedded mouse uterine sections on Day 4 (2100 hours) were stained using rabbit polyclonal E-cadherin primary antibody (catalog no. ab15148; Abcam) and anti-rabbit secondary antibody conjugated with Alexa Fluor 568 (catalog no. A10042; Life Technologies). Note the intense apicolateral staining of E-cadherin at the interimplantation site, which is lost at the implantation site. Sections were imaged using the DMi8 fluorescence microscope and processed using LAS-X software (Leica Microsystems, Germany). Red staining is for E-cadherin and blue staining is for nuclei. Scale bar = 50 µm The asterisk depicts the position of the embryo. LE, luminal epithelium; S, stroma. Figure 2. View largeDownload slide Expression of E-cadherin in the luminal epithelium of pregnant mice. Paraffin-embedded mouse uterine sections on Day 4 (2100 hours) were stained using rabbit polyclonal E-cadherin primary antibody (catalog no. ab15148; Abcam) and anti-rabbit secondary antibody conjugated with Alexa Fluor 568 (catalog no. A10042; Life Technologies). Note the intense apicolateral staining of E-cadherin at the interimplantation site, which is lost at the implantation site. Sections were imaged using the DMi8 fluorescence microscope and processed using LAS-X software (Leica Microsystems, Germany). Red staining is for E-cadherin and blue staining is for nuclei. Scale bar = 50 µm The asterisk depicts the position of the embryo. LE, luminal epithelium; S, stroma. Currently, the molecular players in epithelial weakening are unknown. Several proteases are produced by the trophoblast cells of postimplantation-stage embryos, which aid in tissue degradation and weakening of the decidua after invasion (48, 49). Whether the trophoblast cells of the apposed blastocyst produce enough proteases to degrade the junction proteins needs to be investigated. However, a mechanism akin to tactical deception plays a role in this process. Lysophosphatidic acid (LPA) is a lipid mediator synthesized from lysophospholipids, such as lysophosphatidylcholine (LPC), by a secretory enzyme autotaxin. It has been shown that embryos most likely produce LPC in the course of implantation, whereas the endometrial luminal epithelium expresses autotaxin and also the LPA receptor LPAR3. Mouse knockouts for LPAR3 or those treated with an autotaxin inhibitor do not support implantation, and there is the abundant epithelium-expressed E-cadherin (50). Thus, the embryonic LPC is like a double agent; first, it deceives the endometrial epithelium to convert it into LPA, which then leads to epithelial barrier weakening. Carnage of the Guardians: Apoptosis, Entosis, and More Elegant transplantation experiments have demonstrated that only the hormonally primed endometrium allows embryo invasion. However, when the luminal epithelium is physically damaged, the embryo can invade the endometrium even in the absence of hormonal priming. Thus, the embryo, which until this point has been trying to weaken the epithelial wall and anchor itself, now has to literally break the wall to gain entry into the underlying stroma (Fig. 1). In the mouse, this process takes about 20 to 24 hours after apposition, and this battle seems to be the longest and perhaps the fiercest (but the least understood) phenomenon in implantation biology. The trophoblast cells of the embryo can logically breach the luminal epithelial cells by several mechanisms. They can physically remove them, coalesce with them, or trespass through them and invade. In rodents, electron microscopic studies have demonstrated apoptosis of luminal epithelial cells at the site of implantation (51), which could be viewed as death of the guards by the embryonic signals. However, this view has been challenged recently, as apoptotic and autophagy markers were not observed at the site of implantation in the mouse (52). Instead, the authors propose entosis as an alternative mechanism for epithelial breaching. Entosis is a cannibalismlike process in which healthy cells are eaten up by another cell without apoptosis and necrosis of the target cells. In vitro experiments have indeed demonstrated that trophoblastic cells can engulf endometrial epithelial cells, suggesting that entosis could be another possible mechanism facilitating the invasion. Along with apoptosis and entosis, trophoblast cells can intrude between epithelial cells or fuse with them (25) to ultimately embed the embryo in the uterine stroma. Thus, the battle apparently involves sabotage, suicide, active killing, and cannibalism of the maternal cells to breach the epithelium and ensure invasion. What might govern this control of breaching of the weakened epithelium is not yet clear. Although the role of biomolecules in this process cannot be doubted, mechanical cues might contribute. In the mouse, by evening of day 4, the embryo is well apposed in the implantation chamber; it has the shape of a bowl, which elongates to the shape of a cylinder within the next 6 to 12 hours (Fig. 3). Quantitative estimates suggest that a 1.8-fold increase in embryonic length is possible without affecting its transversal length (53). It is conceivable that this expansion of the embryo in one direction exerts a mechanical force on the epithelium, pulling it along its anterior-posterior axis, thereby creating gaps to aid in the invasion (Fig. 3). Although this hypothesis needs formal investigation, it is possible that, along with killing, the embryo might physically push the guard cells away, thus paving its way into the endometrium. Figure 3. View largeDownload slide Mechanical perspective on epithelial weakening at the time of embryo implantation. At the time of apposition (Day 4, 2100 hours), the embryo is round and in the implantation chamber surrounded by the epithelial layer. In the next 12 to 24 hours, the embryo elongates at least by 1.8-fold, establishing an anterior-posterior axis with the lateral length kept constant. This creates a mechanical stretch on the luminal epithelial cells in the anterior-posterior axis, thereby causing it to weaken and creating a space between the epithelial cells that promotes embryo invasion. Figure 3. View largeDownload slide Mechanical perspective on epithelial weakening at the time of embryo implantation. At the time of apposition (Day 4, 2100 hours), the embryo is round and in the implantation chamber surrounded by the epithelial layer. In the next 12 to 24 hours, the embryo elongates at least by 1.8-fold, establishing an anterior-posterior axis with the lateral length kept constant. This creates a mechanical stretch on the luminal epithelial cells in the anterior-posterior axis, thereby causing it to weaken and creating a space between the epithelial cells that promotes embryo invasion. Decidualization The postinvasion embryo seems to secure its new domain. Once the embryo has breached the luminal epithelium, the uterus transforms itself completely into a decidua by a process called decidualization. The decidua is a remodeled endometrium that includes secretory transformation of the uterine stroma, an influx of specialized uterine natural killer (NK) cells, the exclusion of maternal T and B cells, and finally vascular remodeling (1, 54). Thus, decidualization is a prerequisite for embryo implantation; mouse knockouts that lack molecules known to inhibit this transformation are sterile (55, 56). The decidua is an environment created to house the embryo and provide nourishment to it. The first morphological change observed in the endometrium at the time of implantation is transformation of the stromal cells into decidual cells. In its strictest sense, decidualization is the morphological and biochemical reprogramming of the endometrial stromal cells to become secretory epithelial cells (1). The biochemical and molecular processes of stroma-to-decidua transformation are the subjects of intense investigation and have been exquisitely reviewed (1, 57–59). In brief, to decidualize, the stromal cells lose their primary stromal identity, gain an epithelial functionality, synthesize and secrete molecules that they have never made before, and even create permanent changes in their genome in the form of epigenetic modifications (1). Such dramatic change in the cellular machinery does not occur anywhere else in the body, indicating that the embryo indeed appears to be a very dominant force that manages to utterly change the cells of its host. Like most tissues, the uterus also has its own set of immune cells, which carry out standard surveillance and prevent any untoward attacks. However, the pregnant uterus has a dampened immunological repertoire that resists inflammatory and oxidative insults from the fetal cells. In the decidua, the NK cells, which are generally cytotoxic to major histocompatibilty complex (MHC)–null target cells, switch to a molecular phenotype that is less cytotoxic (60–62), and the numbers of T and B cells are kept to a minimum in the decidua to prevent inflammation and fetal rejection (61). Thus, along with other cells, the “police force” of the uterus is also co-opted by the embryo. Decidual Control of the Trophoblast Invasion After breaching, the trophectodermal cells of the embryo start extensively proliferating and invade the endometrial bed. This invasion is a highly active process in which the trophoblast cells secrete large amounts of proteases to cleave the extracellular matrix of the decidua and pave the way for a deeper invasion. In addition, they also switch their integrin expression to suit the ligands present in the decidual bed, thus obtaining firmer and better anchorage. Although the trophectodermal cells have an inherently high invasive potential (63), several molecular players aid the trophoblasts in gaining more proliferative, adhesive, and invasive properties. The biochemical, molecular, and epigenetic control of trophoblast invasion has been extensively reviewed elsewhere (64–66). In the present review, we focus on how the different cell types in the decidual bed control trophoblast physiology (Fig. 4;Table 1). Figure 4. View largeDownload slide Factors controlling trophoblast physiology at the time of implantation. Once the embryo breaches and initiates the invasion, several factors aid in this process. Decidualized endometrial stromal cells secrete factors, which promote trophoblast invasion. Peripheral NK (pNK) cells, which differentiate into uterine/decidual NK cells (u/dNK), also secrete factors promoting trophoblast invasion. EVs from the decidua and epithelial cells are taken up by trophoblast cells, promoting trophoblast physiology. EVs from the pluripotent stem cells (inner cell mass) also promote trophoblast adhesion/invasion. Dashed arrows indicate cell differentiation. Arrows with triple arrowheads indicate effects of secretions from these cells on tropoblast invasion. Figure 4. View largeDownload slide Factors controlling trophoblast physiology at the time of implantation. Once the embryo breaches and initiates the invasion, several factors aid in this process. Decidualized endometrial stromal cells secrete factors, which promote trophoblast invasion. Peripheral NK (pNK) cells, which differentiate into uterine/decidual NK cells (u/dNK), also secrete factors promoting trophoblast invasion. EVs from the decidua and epithelial cells are taken up by trophoblast cells, promoting trophoblast physiology. EVs from the pluripotent stem cells (inner cell mass) also promote trophoblast adhesion/invasion. Dashed arrows indicate cell differentiation. Arrows with triple arrowheads indicate effects of secretions from these cells on tropoblast invasion. Table 1. Control of Trophoblast Invasion by Different Cell Types in Implantation-Stage Decidua Cell Population Trophoblast Cells Effect on Trophoblast Invasion Reference Decidual cells First-trimester human decidual tissue First-trimester primary EVTs Decreases (74) First-trimester human decidual tissue B6Tert Increases (68) In vitro decidualized endometrial stromal cell JEG-3 and ACH-3P cells Increases (69) NK cells First-trimester human decidual tissue First-trimester primary EVTs Inhibition (72) First-trimester human decidual tissue First-trimester primary EVTs Increases (73) First-trimester human decidual tissue First-trimester primary EVTs Increases (71) First-trimester human decidual tissue First-trimester primary EVTs Increases (70) Inner cell mass Mouse embryonic stem cell Trophectoderm Increases (67) Cell Population Trophoblast Cells Effect on Trophoblast Invasion Reference Decidual cells First-trimester human decidual tissue First-trimester primary EVTs Decreases (74) First-trimester human decidual tissue B6Tert Increases (68) In vitro decidualized endometrial stromal cell JEG-3 and ACH-3P cells Increases (69) NK cells First-trimester human decidual tissue First-trimester primary EVTs Inhibition (72) First-trimester human decidual tissue First-trimester primary EVTs Increases (73) First-trimester human decidual tissue First-trimester primary EVTs Increases (71) First-trimester human decidual tissue First-trimester primary EVTs Increases (70) Inner cell mass Mouse embryonic stem cell Trophectoderm Increases (67) Data are compiled from the literature, and references are mentioned. Abbreviations: ACH-3P, hybrid cell from the fusion of primary human first-trimester trophoblasts with a human choriocarcinoma cell line (AC1-1); B6Tert, an immortalized normal human cytotrophoblast cell line transfected with the htert gene; EVT, human primary extravillous trophoblast; JEG cell, human choriocarcinoma cell line. View Large Chronologically, one of the earliest promoters of trophoblast invasions seems to be the inner cell mass of the embryo itself (Fig. 4). It has been observed that EVs produced by the embryonic stem cell of the inner cell mass can trigger trophoblast invasion. In vitro, EVs from embryonic stem cells enhance the migration and invasion of trophoblast cells (67). Transplantation of microvesicle (MV)-injected blastocysts have higher implantation and invasion ability (67), suggesting that the inner cell mass initially directs trophoblast invasion and migration. Once the embryo has managed to invade the maternal territory, the decidua now seems to aid in this process. Several lines of experimental evidence seem to support the notion that secretions from decidual cells alter trophoblast and NK cells’ physiology (68–75). Initial studies using crude cell preparations from late first-trimester decidual cells had shown an inhibitory effect of decidua on trophoblast invasion (Table 1); however, secretions from highly purified decidualized but not nondecidualized endometrial stromal cells promote invasion (68, 69, 75). The decidual secretions also alter the expression of cell adhesion molecules and integrins on trophoblast cells so that they aid in its firm anchoring to the decidual matrix (27, 75). This effect seems to be due to the ability to secrete large numbers of invasion-promoting growth factors, cytokines, and chemokines (75). A list of factors secreted by the decidua and their effects on trophoblast invasion is provided in Supplemental Table 1. Beyond secretory molecules, the endometrial cells also secrete abundant amounts of EVs that contain several molecules, including mRNA and miRNA (76–78). It has been demonstrated that these EVs are internalized in trophoblast cells and increase their adhesiveness (76–78), indicating that endometrial-derived EVs have a positive effect on implantation of trophoblast cells. To achieve the potential to serve the embryo maximally, the endometrial stromal cells seem to intriguingly switch loyalty and become, as it were, the embryo’s servants. HOXA10 is an endometrial transcription factor that is essential for normal endometrial functions and is highly expressed in endometrial stroma (42, 79). It is often considered an identifier/marker of endometrium. However, once the stromal cells have transformed into decidual cells, they actually switch off HOXA10 (80). This switching-off releases a burst of cytokines from the decidua, creating a local milieu that is proinvasive in nature and which, in a paracrine manner, phosphorylates STAT3 in trophoblast cells to increase protease production and invasion (80). The molecules from trophoblasts that signal the switching-off of HOXA10 in the decidua are still unknown, but it is evident that the embryo not only gains control over the endometrial machinery but also turns it in its favor. However, it is intriguing that the downregulation of HOXA10 is not generic but is localized to the implantation site (80). This mechanism perhaps prevents overinvasion. Beyond the decidual cells, the NK cells of the decidua also increase trophoblast invasion (Fig. 4), which has been a subject of recent reviews (70–73) (Table 1). This seems to occur by virtue of their ability to secrete several proinvasive cytokines and chemokines (81). From these studies, it is clear that once the embryo initiates invasion and induces decidualization, the entire system starts working for it to aid in invasion. Keeping a Check on the Immune System For survival of the semi-allogeneic blastocyst, the decidua transforms its innate and adaptive immune system to prevent any sort of immunological reaction to the conceptus. The NK cells, which are usually cytolytic in nature, are transformed in the decidua into a less cytolytic type and fail to recognize paternal antigens expressed by trophoblasts (82). This transformation seems to be a function of the decidua, as secretions from decidual cells aid in the transformation of peripheral NK cells to decidual NK cells, and mice that have defective decidualization have failed peripheral NK‒to‒decidual NK transformation (61, 82–84). Beyond NK cells, the decidua also seems to keep the numbers of T and B cells in check, and this also seems to be controlled by the decidualized stromal cells. The decidualized stroma has a methylation signature that leads to silencing of several chemokines that prevent homing of the T cells near invading trophoblasts. Also, mice with defective decidualization experience pregnancy failure and have a high number of activated T cells (85). Beyond these, the decidua also controls macrophage polarization and dendritic cell physiology and also has a regulated cross talk (61). From these studies, it is evident that the decidua actively creates an environment that protects the invader. Denouement The fundamental role of the endometrium is to implant the embryo and nourish it to ensure pregnancy. However, the endometrium appears to be not only an organ that is unfavorable for pregnancy but also one that the embryo has to endure and fight to win. The story, with some imagination, casts the endometrium as a ruthless entity and the embryo as a deceitful and treacherous enemy who desires to establish its empire. On the basis of the existing literature, it appears that the embryo-endometrial confrontation is a three-step process that involves (1) endowment of receptivity in the endometrium (a weak phase in the cycle of the target), (2) superimposition of a blastocyst-derived signature onto the receptive endometrium (strafing of the target), and (3) embryo implantation (invasion into the target). In this war, the result seems always to favor the mother, as the rate of natural conception is less than 30%, and this number intriguingly remains almost constant even in assisted reproduction (86). Thus, not to achieve pregnancy appears to be the default process of the uterus. In the light of evolution, such an energetically demanding process is not favorable and should be selected against. Why does such a system exist? There are as yet no direct answers to the question. We can only speculate that in this clash, the ultimate aim is to decide the next heir. This heir not only has to be fit but also must be capable of surviving, against all odds, the ferocious strategy designed by the mother. Perhaps only those embryos that can win should, in an evolutionary sense, be allowed to continue the genetic legacy. What can happen if one of the combatants is weak? Infertility is one situation in which the embryo is always on the losing end. The endometrium is reported to have a very sensitive sensing mechanism that is constantly judging the weak points of the embryo. It has been demonstrated that when it encounters a morphologically or genetically weak embryo, the endometrium terminates its receptivity (20, 21, 87–89), hence winning the war. Conversely, recurrent pregnancy losses could be a case of a weak endometrium that is incapable of sensing a weak enemy (such as a genetically or developmentally incompetent embryo), allowing its implantation and invasion. As development proceeds, the incompetent embryo is unable to maintain itself, leading to its death. Indeed, women with recurrent pregnancy losses have defective endometrial programming in preparation for pregnancy, which is characterized by impaired decidualization of stromal cells, prolonged endometrial receptivity, and a deregulated maternal response to embryonic signals (90). Not all wars end in a clear-cut victory. This could be the case in preeclampsia and/or intrauterine growth restriction, in which the decidua has been found to have compromised functions that disallow adequate trophoblast invasion and lead to shallow placentation (91). It is plausible that the decidua actually has many insurgents that act independently of the embryo, limiting its power in space and time, perhaps to deprive it of nutrition and curb its growth. Much of the plot of this epic is yet undiscovered. The parts that are best understood are the attainment of receptivity in the endometrium and the molecular factors that govern the process. Further, we are just beginning to understand the existence of a new phase in receptivity in which a signal from the embryo drives further changes in the endometrium. However, the factors from the embryo that prime the endometrium and their molecular signature are an enigma. Least understood are how the embryo manages to breach the luminal epithelium and the embryo-endometrial molecular factors that govern this process. We need to focus on this area, as clinical observations have clearly indicated that achievement of the receptive state of the endometrium alone is not sufficient to ensure pregnancy. Perhaps failure to achieve implantation and invasion is the bottleneck limiting the success of assisted reproduction. We believe that expanding our understanding of these mechanisms will improve the clinician’s ability to treat disorders such as infertility, early pregnancy loss, and preeclampsia. Conversely, this information can be useful for the development of anti-implantation strategies for contraception. Note added in proof: The inflammatory nature of receptivity and implantation is a general phenomenon to all eutherians and is ancestrally derived. A recent study has shown extensive uterine inflammation even in marsupial (opossum) endometrium during embryo attachment reaction (92). Abbreviations: CG chorionic gonadotropin EV extracellular vesicle IL-1β interleukin-1β LPA lysophosphatidic acid LPC lysophosphatidylcholine miRNA microRNA mRNA messenger RNA NK natural killer. Acknowledgments Financial Support: D.M.’s laboratory is supported by grants from the Indian Council of Medical Research, Department of Science and Technology, and the Department of Biotechnology, Government of India. 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