Continuous model of conceptus implantation to the maternal endometrium

in Journal of Endocrinology

As placental morphology as well as trophoblast characteristics exhibit wide diversity across mammalian species, underling molecules were also thought to vary greatly. In the majority of cases, however, regardless of the mode of implantation, physiological and biochemical processes in conceptus implantation to the maternal endometrium including the kinds of gene expression and their products are now considered to share many similarities. In fact, recent progress has identified that in addition to the hormones, cytokines, proteases and cell adhesion molecules classically characterized, molecules related to lymphocyte homing and epithelial–mesenchymal transition (EMT) are all required for the progression of conceptus implantation to placentation. In this review, therefore, the newest findings are all incorporated into the molecular and cellular events related to conceptus implantation to the maternal endometrium; primarily from non-invasive bovine placentation and also from invasive human implantation.

Abstract

As placental morphology as well as trophoblast characteristics exhibit wide diversity across mammalian species, underling molecules were also thought to vary greatly. In the majority of cases, however, regardless of the mode of implantation, physiological and biochemical processes in conceptus implantation to the maternal endometrium including the kinds of gene expression and their products are now considered to share many similarities. In fact, recent progress has identified that in addition to the hormones, cytokines, proteases and cell adhesion molecules classically characterized, molecules related to lymphocyte homing and epithelial–mesenchymal transition (EMT) are all required for the progression of conceptus implantation to placentation. In this review, therefore, the newest findings are all incorporated into the molecular and cellular events related to conceptus implantation to the maternal endometrium; primarily from non-invasive bovine placentation and also from invasive human implantation.

Introduction

In the early development of mammalian embryos, fertilized eggs differentiate into an inner cell mass (ICM) and an outer trophectoderm (TE), from which ICM develops into the embryo as well as the amnion, yolk sac and allantois, whereas the TE forms chorionic membrane and later becomes a major part of the conceptus placenta. Because fertilized eggs in most mammalian species lack yolk sac development, the conceptus must form the placenta to receive nutrients and gases from the mother in utero; however, its cell types as well as structures vary considerably among mammalian species (Amoroso 1968). For example, an epitheliochorial placenta is found in several orders of animals including even-toed ungulates, whales and dolphins and lower primates, of which the uterine epithelium is in contact with the chorionic TE cells. An endotheliochorial placenta is generally seen in carnivores; however, it is also found in distantly related elephants (Enders & Carter 2004), in which the endothelium of the maternal capillaries is located close to the TE cells, resulting from stromal thinning and a loss of uterine epithelium. A hemochorial placentation, by contrast, is seen in many rodents and in higher primates including humans, in which maternal blood is directly in touch with the trophoblast, functioning without the capillary endothelium. In this type of placentation, multinucleate TE, syncytiotrophoblast enables efficient nutrient and gas transfer. However, molecular mechanisms by which this type of cell forms have not been definitively elucidated.

Approximately 50% of pregnancy losses occur between blastocyst hatching and embryo attachment to endometrium in cattle (Wolf et al. 2003), during which the establishment of proper maternal–fetal communication and uterine environment is required. Over the past decade, various global analyses were implemented to study the expression of transcripts and proteins in bovine endometria and conceptuses (Spencer et al. 2008, Forde et al. 2009, 2011, 2012, Mansouri-Attia et al. 2009, Carter et al. 2010, Clemente et al. 2011, Sakurai et al. 2013a), identifying many molecules with potential importance in each peri-implantation event. Although data continue to accumulate, the means by which these factors could improve implantation processes and more importantly embryo survival in utero have not been definitively established. Therefore, studies of conceptus implantation to the maternal endometrium require not only identification of molecules functioning in these events but also use of in vitro models to study the significance of single or multiple factors in limited and/or continuous windows into implantation processes.

In our previous studies, we established the in vitro TE–endometrium attachment model using bovine trophoblast CT-1 cells (Talbot et al. 2000) and endometrial epithelial cells (EECs) (Skarzynski et al. 2000, Sakurai et al. 2012). In this co-culture system, treatment of CT-1 and EECs with uterine flushings (UF) obtained from pregnant day 17, 20 or 22 (day 0 = day of estrus, P17, P20, P22, respectively; conceptus attachment to EECs is initiated on days 19–19.5) could mimic the gene expression in utero on days 17, 20 or 22, respectively, indicating that the establishment of conceptus attachment requires not only cell–cell interactions between conceptus and endometrium but also constituents in the UF. Although several global analyses of proteins in bovine UF during early pregnancy have demonstrated changes in protein levels between blastocyst hatching and conceptus attachment (Forde et al. 2013, 2014, 2015, Kusama et al. 2016a), the significance of multiple molecules alone or in conjunction, in regulating TE implantation to the endometrium remains unclear. In this review, new information will be integrated into the discussion of cellular events associated with conceptus implantation to the maternal endometrium.

Sequential events associated with implantation

There are five phases of conceptus implantation to the maternal endometrium (Bazer et al. 2009): (1) migration/hatching, the fertilized egg/blastocyst migrates from the oviduct to uterine cavity and sheds zona pellucida (ZP); (2) pre-contact, the blastocyst/conceptus migrates, orients and apposes appropriate regions of the uterine lining; (3) attachment, TE cells of the blastocyst/conceptus attaches to the uterine epithelium; (4) adhesion, TE cells attach firmly to the uterine epithelium; and (5) invasion, the blastocyst/conceptus invades into the uterine endometrium. These processes are followed by placental formation. During phase 1, the fertilized egg/blastocyst enters and migrates within the uterus and may become affixed evenly at any point along the uterine horn in murine and porcine species (Yoshinaga 2013). Hatching allows the expansion of the blastocyst into a sphere or it may migrate and go through changes in its shape from spherical to tubular and filamentous form, as in domestic animals. Phase 2 is a pre-contact period during which the blastocyst/conceptus may still migrate or elongates without definitive contact between the TE cells and endometrial epithelium. This is the period when biochemical communication including micro RNAs (miRNAs) (Ponsuksili et al. 2014) between developing conceptus and maternal endometrium must be established and continued secretion of progesterone (P4) is ensured (Roberts et al. 1992, Bazer et al. 2009). Phase 3 is the attachment period, during which the outer TE cells of embryo/conceptus establish definitive contact with the uterine epithelium. Numerous cell adhesion molecules have been identified on both TEs and uterine epithelial cells and changes in DNA methylation contribute to uterine stromal cell decidualization in murines (Gao et al. 2012). However, current information is not sufficient to fully explain or replicate this event, particularly immunological recognition at the maternal–fetal interface (PrabhuDas et al. 2015). Phase 4 is the time of firm adhesion between the TE cells and uterine epithelium and in some cases, superficial glandular epithelium, during which mononucleate TE cells differentiate into binucleate and/or multinucleate syncytiotrophoblast cells. Much more information is required to mimic or regulate the cellular events occurring during the Phase 4 period (PrabhuDas et al. 2015) because although both cell types require intercellular adhesions, at the same time, the cells require intracellular loosening and movement. Phase 5 is when many mammalian species begin to diverge greatly in their development, in particular, invasive or non-invasive TEs, as invasive TE cells (placental villous trophoblasts) invade the decidua as well as the inner third of the myometrium, followed by uterine artery remodeling (PrabhuDas et al. 2015). In contrast, TE cells in the uterus of ruminants are not invasive, and these cells do not penetrate deep into uterine stroma or spinal arteries. Nevertheless, implantation processes appear fairly similar in cell–cell interactions for the first four phases; however, some differences exist in gene usage such as kinds, degree and/or timing of expression and degree of TE differentiation among mammalian species.

Similar to malignant cells, TE cells possess the ability to invade neighboring cells. Therefore, if left unchecked, TE cells have the potential to damage or destroy uterine structures, and this aggression must be controlled for the protection of the uterine endometrium (PrabhuDas et al. 2015). When the cell cycles of TE cells are restricted, these cells go through endoreduplication, resulting in the formation of giant trophoblast cells as in the murine species. In many mammalian species including murine species, the outermost layer of TE cells go through cell fusion, resulting in the formation of multinucleate cells, syncytiotrophoblasts (Lavialle et al. 2013). The syncytiotrophoblast cells do not go through cell cycles, and thereby their invasiveness is held under control (Huppertz et al. 2002). Unlike in primates and rodents, syncytiotrophoblasts are not formed in TE cells of ruminant ungulates. However, bovine TE cells form binucleate cells (BNCs) as well as trinucleate cells (TNCs) (Wooding & Beckers 1987). Although it has not been definitively determined whether BNCs result from cell fusion or endoreduplication, it is generally accepted, with exception of the new evidence by Seo and coworkers (Seo et al. 2016), that TNCs are products of heterotypic cell fusion between BNCs and uterine epithelial cells (Wooding & Beckers 1987, Dunlap et al. 2006, Baba et al. 2011, Nakaya et al. 2013) and are only localized in the endometrium (Wooding 1992).

Mechanisms associated with continuation of progesterone secretion

In mammalian species, the continued P4 secretion is a prerequisite for the establishment and continuation of pregnancy. It has been well studied that P4 is involved directly and/or indirectly in various gene expressions in utero, which regulate numerous uterine functions through endometrial secretions, alteration of blood flow at implantation sites and promotion of physiological and/or immune environments suitable for normal embryonic development (Psychoyos 1973). Despite similar requirement, the biochemical as well as molecular mechanisms by which corpus luteum (CL) is maintained for continued P4 production differs from species to species. In higher primates including humans, CL is maintained by a luteotrophic factor, chorionic gonadotropin (CG), produced by the TE cells as they face and invade the uterine epithelium, in the process required for implantation (Hearn et al. 1991). In rodents, CL is prolonged through the release of copulation-induced pituitary prolactin surges (Soares et al. 1991). Whatever the molecules associated with the maintenance of CL life span, they must be produced long before CL regression begins, and the period during which CL is protected from a luteolytic signal is known as the period of maternal recognition of pregnancy (Short 1969). During such period, trophoblast and uterine endometrium under the influence of P4 must biochemically and possibly physically communicate with each other, resulting in the establishment of proper uterine environments necessary for conceptus survival, implantation and subsequent placental formation. It should be noted, however, that CG in humans (hCG) may not be the only factor maintaining P4 production because the administration of hCG alone does not prevent CL regression in non-pregnant women (Quagliarello et al. 1980). Evidence accumulated suggests that endocrine as well as immune systems control CL function in humans and possibly other mammalian species (Fujiwara et al. 2016).

In ruminant ungulates including cows, sheep and goats, interferon tau (IFNT), a major cytokine produced by mononucleate TE cells during the peri-implantation period, is the anti-luteolytic factor essential for the prolongation of CL life span (Godkin et al. 1982, Imakawa et al. 1987, Stewart et al. 1987, Charpigny et al. 1988, Roberts et al. 1992). IFNT exhibits not only structural similarities to those of type I IFNs such as IFNA and IFNB (Imakawa et al. 1989) but also functional ones such as antiviral and anti-proliferative activities, although IFNT shows much less cytotoxic activity than do IFNA or IFNB (Pestka et al. 1987, Niwano et al. 1989, Roberts et al. 1989, Pontzer et al. 1991, 1997). Type I IFNs bind to a common receptor complex with two polypeptide subunits (IFNAR1 and IFNAR2) (Pestka et al. 2004), both of which are present in ovine uterine epithelial cells (Rosenfeld et al. 2002). It has been thought that the luminal epithelium of the uterine endometrium is the primary target for IFNT (Roberts et al. 1992, Imakawa et al. 2002), but the observations in which the receptor or receptor subunits is identified suggest that IFNT can reach the stroma and even the uterine myometrium (Ott et al. 1998, Johnson et al. 1999, Hicks et al. 2003). Upon binding to the receptor, type I IFNs activate the JAK-STAT–IRF (janus kinase-signal transducer and activator of transcription–interferon regulatory factor) signaling pathway (Stark et al. 1998, Kim et al. 2003), causing the induction of a group of interferon-stimulated genes (ISGs) expression (Chen et al. 2007, Spencer et al. 2008).

It was demonstrated that IFNT inhibits endometrial pulsatile release of prostaglandin (PG) F2α through the prevention of ESR1 and OXTR transcription (Spencer et al. 2004). A study with the use of PG synthase (PTGS) inhibitor, meloxicam (MEL), revealed that MEL treatment decreases the expression of a number of P4-induced ovine endometrial genes such as IGFBP1 (insulin-like growth factor binding protein 1) and HSD11B1 (hydroxysteroid 11-β dehydrogenase 1) as well as IFNT-stimulated endometrial genes such as FGF2, ISG15, RSAD2, CST3, CTSL, GRP, LGALS15 and SLC2A1, the latter of which are important regulators of conceptus elongation (Dorniak et al. 2011). In the same study (Dorniak et al. 2011), IFNT was found to increase endometrial PTGS activity and amounts of PGs in the uterine lumen. IFNT is also known to increase endometrial PGE2 receptors EP2 and EP4 (Lee et al. 2012). Data from recent studies indicate that luteal PG synthesis is selectively directed toward PGF2α at the time of luteolysis, but luteal PG synthesis is directed toward PGE2 at the time of establishment of pregnancy in sheep (Lee et al. 2012, Arosh et al. 2016). In addition, endometrial PGE2 is transported from the uterus to the CL through the utero-ovarian plexus, which protects CL from luteolysis through the increase in intraluteal biosynthesis and signaling of PGE2 (Lee et al. 2012, Arosh et al. 2016). The effect of PGE2 on CL rescue was demonstrated through the use of intrauterine co-administration of IFNT and PGE2 synthase 1 (PGES-1) inhibitor, which reestablishes endometrial PGF2α pulses and regresses the CL while intrauterine co-administration of IFNT and PGES-1 inhibitor along with intraovarian administration of PGE2 rescues the CL (Lee et al. 2012). Furthermore, uterine infusion of PF915275 (a selective inhibitor of HSD11B1) prevented conceptus elongation, whereas IFNT rescued conceptus elongation in PF915275-infused ewes (Dorniak et al. 2013). These results suggest that IFNT, PGs and cortisol coordinately regulate endometrial functions necessary for the rescue of CL from its regression and conceptus elongation during early pregnancy in sheep and possibly other ruminants.

In addition to ISGs, galactoside-binding soluble 15 (LGALS15) gene expression is found in the ovine uterus, which is induced by P4 and further stimulated by IFNT (Gray et al. 2004). In mice, expression of wingless-type MMTV integration site family (WNTs) is found in the uterus and its expression at luminal epithelium depends on the presence of blastocysts (Mohamed et al. 2005). It is increasingly evident that chemokines are involved in intracellular communication and signal transduction at the maternal–fetal interface (Du et al. 2014). For example, chemokine ligand CXCL12, expressed by cytotrophoblasts, binds to CXCR4, CXCR7 and syndecan-4 receptors, mediating cell migration, directed invasion, proliferation and survival (Schanz et al. 2011). In ruminants, IFNT induces several chemokines in endometrial tissues including chemokine ligand 10 (CXCL10) and CXCL9 (Nagaoka et al. 2003a, Imakawa et al. 2006). Endometrial CXCL10 in turn attracts immune cells, particularly NK cells, to the caruncular regions of the endometrium (Nagaoka et al. 2003a, Imakawa et al. 2005) and by acting through the CXCL10 receptor, CXCR3, this chemokine regulates TE cell migration and integrin (ITGs) expressions (Nagaoka et al. 2003b). Together with maternal P4, trophoblast IFNT and/or the presence of blastocysts regulates endometrial gene expression (Spencer et al. 2008), and changes resulted from blastocyst–endometrial interactions allow blastocyst attachment to the uterine epithelial cells in mammals including ruminant species (Nagaoka et al. 2003b).

It was often suspected that IFNT could reach the circulatory system. However, due to the limitations of previous methods for detection, it had only been found to be in the uterus. However, it was demonstrated from studies detecting upregulated ISGs in PBMCs during pregnancy that IFNT likely reaches circulating immune cells (Han et al. 2006, Gifford et al. 2007, Oliveira & Hansen 2008) as well as the ovaries (Shirasuna et al. 2012). Previously, endocrine delivery of IFNT was found to protect the CL from PGF2α-induced luteolysis in ewes, resulting from mechanisms that involve the upregulation of ISGs and stabilization of cell survival genes in the CL (Antoniazzi et al. 2013). Recent evidence indicates that IFNT is present in the uterine vein serum on days 15–16 of ovine pregnancy (Romero et al. 2015). These data now affirm that like hCG in humans, IFNT can reach the circulation and thus can affect endocrine responses. This is also supported by the previous study from more than a decade ago, in which the presence of type I IFN receptor with high affinity was found in ovine CL and conceptus (Imakawa et al. 2002). Together, these results support the recent findings suggesting that in addition to the indirect effect of IFNT and direct effect of PGE2 on CL, circulatory IFNT could also protect CL and thereby continued P4 secretion is ensured for the establishment and continuation of pregnancy (Fig. 1).

Figure 1
Figure 1

Hormone levels and events occurring during peri-implantation period in the bovine species. Upper: As the corpus luteum is rescued and serum progesterone (P4) level is maintained, conceptus elongation is initiated on days 14–15 of pregnancy, concurrent with the increase in interferon tau (IFNT) production by mononucleate trophectoderms. Binucleate cells form as the conceptus elongation proceeds, and trinucleate cell formation begins, after conceptus attachment to the uterine epithelium and downregulation of IFNT. Lower: Illustration of binucleate cell formation of trophectoderms, one of which shows a trinucleate cell formation.

Citation: Journal of Endocrinology 233, 1; 10.1530/JOE-16-0490

Use of lymphocyte homing molecules in conceptus attachment

Cell–cell interactions between the conceptus and endometrium have also been documented to be critical for successful implantation in humans and murine species (Aplin et al. 1998, Armant 2005), in which the extracellular domain of ITGs acts as a receptor for extracellular matrix components (ECMs) such as fibronectin, vitronectin, laminin, collagen-type IV and osteopontin (SPP) (Akiyama 1996, MacIntyre et al. 2002). In goats, sheep, and cattle, constituents of uterine histotroph such as CXCL10, LGALS15 and IGFBP1 have been characterized to activate ITGs through their RGD domain during the period of TE cell attachment to the uterine epithelium (Akiyama 1996, Aplin et al. 1998, Nagaoka et al. 2003b). In particular, the expression of ITGs has been characterized at the uteroplacental interface during the periods of bovine TE attachment (MacIntyre et al. 2002, Pfarrer et al. 2003) and placentation (Pfarrer 2006). ITGs characterized in the stages of bovine TE binucleate cell migration and heterotypic fusion with the uterine epithelial cells consist of five α subunits (ITGA2B, ITGA3, ITGA5, ITGA8 and ITGAV) and two β subunits (ITGB1 and ITGB3) (MacIntyre et al. 2002, Pfarrer et al. 2003, Yamakoshi et al. 2012). In the previous investigation (Yamakoshi et al. 2012), we also found that integrin subunits α (ITGAV and ITGA5) and β (ITGB1, ITGB3 and ITGB5) are constitutively expressed in bovine peri-attachment TE cells, whereas the expression of ITGA4 and ITGA8 is induced after attachment of TE cells to uterine epithelial cells is initiated.

It has been determined that cell adhesion molecule, L-selectin (SELL), is required for processes of lymphocyte homing (Tedder et al. 1990). In the human placenta, SELL adhesion system is identified to be essential for forming and maintaining cell columns during early stages of placenta development and mediating cytotrophoblast migration (Prakobphol et al. 2006). In our study (Bai et al. 2015), SELL expression was detected in bovine endometrial epithelia, not in trophoblasts, and its ligands, P-selectin glycoprotein ligand (SELPLG) and podocalyxin (PODXL), were found in both conceptus and endometrium. Although endometrial epithelial SELL expression is not orthologous to that in humans (Prakobphol et al. 2006), cessation of conceptus movement and/or apposition through SELL and PODXL expression is required for the implantation processes in humans as well as bovine species.

In addition to SELL, vascular cell adhesion molecule (VCAM-1), a trans-membrane glycoprotein member of the immunoglobulin gene superfamily (Osborn et al. 1989), functions in lymphocyte homing (May et al. 1993), angiogenesis (Ding et al. 2003) and allantoic membrane fusion to the chorion (Gurtner et al. 1995). In VCAM-1 gene ablation study (Gurtner et al. 1995), the allantois fails to fuse with the chorion, resulting in abnormal placental development and embryonic losses at 9.5–11.5 days of gestation, whereas a minority of VCAM-1-deficient mice survives although allantoic mesoderm is distributed over the chorionic surface. In humans, VCAM-1 is present on the endometrial side, specifically localized on decidual stromal cells in the areas where migrating TE cells are present, but not on vascular endothelial cells in decidua parietalis. Endometrial expression of VCAM-1 at the peri-implantation stage of patients with unexplained infertility was significantly lower than that in control patients (Konac et al. 2009), suggesting that the expression of VCAM-1 might be essential for the preparation of the endometrium for invasive mode of implantation. In the study of early pregnancy in sheep, VCAM-1 is first found in endothelial cells on days 17–19 in both caruncular and intercaruncular areas of the endometrium and becomes strongly induced in endothelial cells on days 26–27 (Rahman et al. 2004).

VCAM-1, induced by various cytokines in different tissues or organs in mice (Henninger et al. 1997) functions through integrin α4β1 (ITGA4/ITGB1), also known as very late antigen-4 (VLA4) (Denucci et al. 2009). Homozygous loss of ITGB1 expression in mice was lethal during early post-implantation period, resulting from failure in inner cell mass development (Stephens et al. 1995). It was also identified that homozygous ITGA4 null knockout mice fail to complete fusion of the allantois with the chorionic membrane during placentation period (Yang et al. 1995), the cellular event similar to that of VCAM-1 gene ablation. In our previous investigations, EECs’ VCAM-1 expression was enhanced with the addition of IFNT (Bai et al. 2014) and elevated ITGA4 mRNA in bovine conceptuses was found on day 22, 2–3 days after the initiation of trophoblast attachment to the endometrial epithelium (Yamakoshi et al. 2012, Bai et al. 2014). We also found that changes in TE cells’ gene expression including ITGs were seen when bovine CT-1 cells were cocultured with EECs, which was further enhanced with the addition of uterine flushings from pregnant animals (Sakurai et al. 2012, Bai et al. 2014). These results suggest that TEs–EECs interactions as well as constituents of uterine flushings/histotroph including ECMs and/or various cytokines are important in the progression of conceptus attachment to the uterine epithelium in the bovine and other mammalian species.

Changes in gene expression similar to epithelial–mesenchymal transition

The outer layer TE cells possesses apicobasal cell polarity, lateral junctions with neighboring cells and basal contact with the basement membrane proteins, all of which are typical of epithelial characteristics (Biggers et al. 1988, Kang et al. 1990, Fleming et al. 2000). Despite the fact that the apical plasma membranes of simple epithelia normally lack adhesive properties, TE cells still manage to adhere to the uterine epithelium through its apical domains as part of the peri-implantation process. Thus, the adhesion between TE cells and uterine epithelial cells has long been considered a cell biological paradox (Denker 1993). With the exception of rodents, in which the conceptus enters a receptive uterus and attaches immediately to the uterine epithelium, primates and most domestic animals have a prereceptive phase during which the conceptus does not physically interact with the uterine epithelium (phase 2 of implantation processes). In the bovine species, attachment between TE cells and endometrial epithelium is first seen on day 20 of gestation, and subsequent stable adhesion occurs between days 20 and 22 (Wathes & Wooding 1980).

Another surprising finding was that changes in gene expression associated with epithelial–mesenchymal transition (EMT) occurred not before attachment, but rather on day 22. EMT is known as the process characterized by downregulation of apicobasal polarity, loss of cell–cell adhesion, reorganization of the cytoskeleton, expression of matrix metalloproteinases (MMP) and enhanced migratory potential, all of which are present in metastasis of cancer cells, gastrulation and possibly trophoblast invasion (Jordan et al. 2011, Lim & Thiery 2012, Lamouille et al. 2014). In humans and mice, subsequent to the blastocyst adhesion to the uterine wall, the trophoblast undergoes EMT and invades into the endometrial matrix, suggesting that the trophoblast switches from epithelial phenotype to mesenchymal phenotype after blastocyst adhesion (Sutherland 2003, Kokkinos et al. 2010, Jordan et al. 2011). These observations also indicate that loss of cell polarity and gain of cell movement in TEs while TEs and EECs are in close proximity is required for conceptus implantation to proceed and support that the process of conceptus implantation to the uterine endometrium is highly coordinated and their associated gene expression is tightly controlled. Therefore, insufficient production of one or more molecules or uncoordinated timing of events and/or gene expression results in a uterine environment unable to fully support conceptus growth and/or implantation to the uterine endometrium.

In the bovine species, positive signals for both the epithelial marker cytokeratin and the mesenchymal marker vimentin were seen in TE cells of elongated conceptuses on day 22 (Yamakoshi et al. 2012). Although epithelial E-cadherin (CDH1) was downregulated, mesenchymal N-cadherin (CDH2), vimentin (VIM), MMP2 and MMP9 were upregulated in day 22 bovine conceptuses. These observations indicate that after the conceptus-endometrium attachment, EMT-related transcripts as well as cytokeratin are present in the bovine TE and suggest that in addition to extracellular matrix expression, EMT-related molecule expression is required for the proper adhesion of elongated conceptus to the maternal endometrium. In that study, we also identified that transcription factors SNAI2, ZEB1, ZEB2, TWIST1, TWIST2 and KLF8 transcripts were upregulated concurrent with cytokeratin expression in the TE cells (Yamakoshi et al. 2012). It has been characterized that SNAIL, ZEB and KLF8 factors bind to and repress CDH1 promoter activity (Peinado et al. 2007, Wang et al. 2007), whereas TWIST1 and TWIST2 repress CDH1 transcription indirectly (Yang & Weinberg 2008). In addition, SNAIL and ZEB factors are known to induce the expression of MMPs that can degrade basement membrane, thereby favoring invasion (Thiery et al. 2009). Although the bovine conceptus does not penetrate into the endometrium, the confirmation that MMP2 and MMP9 transcripts are upregulated not only suggests that they play a role in non-invasive trophoblasts but also confirms further the similarity between invasive and non-invasive modes of implantation.

Despite the fact that IFNT is absolutely required for the maintenance of CL function in ruminant ungulates, downregulation of IFNT occurs shortly after conceptus attachment to the uterine epithelial cells is initiated (Sakurai et al. 2013b, Kusama et al. 2016a). It should be noted that this decline of IFNT after conceptus attachment to the uterine epithelium was originally observed nearly three decades ago (Guillomot et al. 1990), but the significance of IFNT’s downregulation has still not been well characterized (Sakurai et al. 2013b). Data continue to accumulate that when IFNT is further downregulated on day 22 (Kusama et al. 2016a), expression of cell adhesion molecules and EMT-related factors is upregulated (Yamakoshi et al. 2012, Bai et al. 2014, 2015).

Regulation of EMT-related molecule expression during the peri-attachment period

Data accumulated in this laboratory indicate that SELL-PODXL is highly expressed on days 17 and 20, whereas VCAM-ITGA4 is upregulated on day 22 of gestation, 2–3 days after the conceptus attachment to the uterine epithelium is initiated. This was also the day EMT-related molecule expression was found in the bovine uterus, in which non-invasive bovine TE has upregulated mesenchymal markers CDH2, VIM, MMP2 and EMT-related transcription factors SNAI2, ZEB1 and TWIST1 (Yamakoshi et al. 2012, Kusama et al. 2016b). In addition, the inhibition of PODXL expression has been demonstrated to prevent the TGF-β-induced EMT in human lung adenocarcinoma A549 cells, strongly suggesting that upregulation of PODXL is necessary for EMT to occur (Meng et al. 2011). These data indicated that lymphocyte homing-related cell adhesion and EMT-related molecule expressions are happening on the same day of bovine gestation.

Follistatin (FST), an inhibitor of activin A and other TGF-β superfamily members, increased in uterine flushing media (UF) obtained from day 20 of gestation (P20), but FST decreased in P22 UF, whereas elevated activin A was found in P22 UF (Kusama et al. 2016b). Among SMAD2, SMAD3 and SMAD4 expression, phosphorylated SMAD2 increased in day 22 conceptuses. In our TE (CT-1) and EEC co-culture system, the treatment with P22 UF or activin A upregulated EMT marker expressions, which were inhibited by FST in bovine trophoblast cells (Kusama et al. 2016b). These results suggest that EMT-related molecule expression in day 22 bovine conceptuses could be induced by activin A secreted from the endometrium to the uterine lumen.

In the co-culture of CT-1 cells and EECs with P22 UF or activin A, SNAI2, ZEB1 and TWIST1 expression was also upregulated (Kusama et al. 2016b). Mesenchymal CDH2 had been expressed in the co-culture of CT-1 and EECs, but not in the mono-culture of CT-1 cells alone (Sakurai et al. 2012), indicating that TE (CT-1) cells with EECs were altered to the mesenchymal phenotype from the epithelial phenotype. It is reported that EMT is induced by NOTCH signaling, an intracellular signaling pathway induced by cell attachment (Gonzalez & Medici 2014). On blastocyst implantation, NOTCH signaling is achieved via cell–cell interaction, in which NOTCH receptors expressed on the surface of endometrium interact with ligands present on the surface of blastocysts in humans and mice (Cuman et al. 2014). Activin A or TGF-β upregulates several transcription factors such as SNAI2, ZEB1 or TWIST1 mediated by phosphorylated SMAD2 or SMAD3 (Lamouille et al. 2014, Li et al. 2015). NOTCH signaling upregulates the SMAD3 expression, which enhances TGF-β-induced EMT markers expression (Niessen et al. 2008, Fu et al. 2009, Chen et al. 2014). These findings suggest that attachment of TE (CT-1) cells to EECs could activate the NOTCH signaling, which enhances activin A-induced EMT marker expression via SMAD2, SMAD3 and/or SMAD4.

Despite the upregulation of activin A on day 20, the treatment with P20 UF did not alter the EMT marker expression in TE (CT-1) cell mono-cultures, which was consistent with our previous in vivo study (Yamakoshi et al. 2012). We identified that FST increased in P20 UF, concurrent with transiently upregulated FST in day 20 conceptuses. In addition, the expression of EMT markers induced by P22 UF or activin A was inhibited by FST in the co-culture system (Kusama et al. 2016b). It was reported that TGF-β1, TGF-β2 or TGF-β3 expression in ovine conceptuses and endometrium increase during the peri-attachment period (Doré et al. 1996, Imakawa et al. 1998). We also found that TGF-β1, TGF-β2 and TGF-β3, known to induce EMT, were upregulated on day 20 (unpublished data). These findings indicated that FST could have played a role in the inhibition of activin A- or TGF-βs-induced conceptus EMT-related molecule expression on day 20 and suggest that the regulation of spatiotemporal expression of these factors is crucial for conceptus attachment to the uterine epithelium (Fig. 2).

Figure 2
Figure 2

Successive gene expression leading to epithelial–mesenchymal transition-like events in the bovine species. On day 17 of pregnancy, IFNT is actively produced by the trophoblast (far left panel). On day 20 of pregnancy, initial attachment between the conceptus and the endometrial epithelium begins through EGF/FGF-stimulated SELL-SELPLG, whereas conceptus production of FST inhibits activin A/TGFβ effect (middle panel). As FST production declines on day 22, activin A/TGFβ induces epithelial–mesenchymal transition (EMT). Through the SELL-PODXL and VCAM-ITGA4 adhesion systems, two cell types are held in a close proximity, whereas intracellular cell loosening and enhanced mobility of the trophectoderm cells are occurring through EMT.

Citation: Journal of Endocrinology 233, 1; 10.1530/JOE-16-0490

How lymphocyte homing molecule expression and EMT enable implantation

In humans and mice, trophoblasts undergo EMT and invade the endometrial matrix, which is subsequent to blastocyst adhesion to the endometrial epithelium (Sutherland 2003, Kokkinos et al. 2010, Jordan et al. 2011). In our studies, although timing of events was not determined precisely, both cell–cell adhesion and EMT-like cell loosening/movement occurred on day 22 of bovine gestation (Yamakoshi et al. 2012, Bai et al. 2015, Kusama et al. 2016b). The treatment with activin A or P22 UF in cocultured CT-1 cells induced characteristics similar to those of EMT (Kusama et al. 2016b), which involves downregulation of apicobasal polarity, loss of cell–cell adhesion and expression of MMPs (Moustakas & Heldin 2014). These results agree with the previous observation, in which bovine TE cells exhibit a mesenchymal-like phenotype without cell polarization (Pfarrer 2006). Unique to ruminant ungulates, BNCs fuse heterotypically with uterine epithelial cells, resulting in TNC formation, which requires close apposition between conceptus cells and uterine epithelia (Wooding & Beckers 1987). As EMT-related molecule expression occurs concurrent with the expression of cell adhesion molecules, TE cells themselves and/or BNCs become more flexible in their orientation as well as their movement (Pfarrer et al. 2006, Kusama et al. 2016b), allowing for the close proximity required for BNCs and uterine epithelial cell fusion. Quite recently, however, Seo and coworkers (Seo et al. 2016) presented the evidence that rather than heterotypic cell fusions between TEs and uterine epithelial cells, ovine TE cells went through homotypic cell fusion and formed syncytiotrophoblast-like fused cells. At this point in time, whether multinucleate cells with more than two nuclei found in TE or endometrial compartments are due to heterotypic and/or homotypic cell fusion could not be definitively resolved. Nevertheless, available data indicate that bovine BNCs undergo a limited invasion, enabling the formation of TNCs with uterine epithelial cells, which are localized in the uterine endometrium (Wooding & Beckers 1987, Lavialle et al. 2013, Nakaya et al. 2013). It is possible that the formation of TNCs through heterotypic cell fusion may strengthen the adhesion between fetal and maternal tissues in the non-invasive mode of implantation in ruminants. Therefore, the degree and timing of cell adhesion as well as EMT must be tightly controlled for normal progression of implantation processes to placental formation. Further experimentation is clearly required to determine the degree and timing of cell adhesion and EMT-related molecule expression during the peri-implantation period.

Conclusion

In depth studies of extracellular matrices, cell adhesion molecules, cytokines and/or proteinases and their inhibitor expression have been undertaken in an effort to explain processes of conceptus implantation to the maternal endometrium. What recent progress suggests, however, is that implantation processes should be analyzed as a whole as well as by individual cellular process. Each process and/or their associated gene expression must then be integrated into the flow of continuous events. In particular, the implantation study must include hormones, cytokines, proteases, cell adhesion-related genes and their specific expression as well as other factors such as lymphocyte homing and EMT-related molecules. Furthermore, more and more molecules have recently been identified: microRNA, lncRNA and exosomes, to name a few. They could also be involved in the regulation of sequential events associated with conceptus implantation to the maternal endometrium, and our current understanding of implantation may be far from finalized. We must then treat these processes as a work still in progress, and, therefore, prepare for more work ahead in the elucidation of molecular mechanisms associated with implantation and placentation, all of which result in reproductive advantages in mammalian evolution.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by Grants-in-aid for Scientific Research (16H02584) from Japan Society for the Promotion of Science, by Livestock Promotional Funds of Japan Racing Association (JRA) and by Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry.

Acknowledgements

The authors would like to acknowledge their valuable contribution to the program: Dr K Nagaoka, Tokyo University of Agriculture and Technology, Dr T Sakurai, Tokyo University of Science, Dr H Bai, Hokkaido University and K Nakamura, The University of Tokyo. They would like to thank Mr Robert Moriarty for his editorial assistance throughout the manuscript preparation.

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    Hormone levels and events occurring during peri-implantation period in the bovine species. Upper: As the corpus luteum is rescued and serum progesterone (P4) level is maintained, conceptus elongation is initiated on days 14–15 of pregnancy, concurrent with the increase in interferon tau (IFNT) production by mononucleate trophectoderms. Binucleate cells form as the conceptus elongation proceeds, and trinucleate cell formation begins, after conceptus attachment to the uterine epithelium and downregulation of IFNT. Lower: Illustration of binucleate cell formation of trophectoderms, one of which shows a trinucleate cell formation.

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    Successive gene expression leading to epithelial–mesenchymal transition-like events in the bovine species. On day 17 of pregnancy, IFNT is actively produced by the trophoblast (far left panel). On day 20 of pregnancy, initial attachment between the conceptus and the endometrial epithelium begins through EGF/FGF-stimulated SELL-SELPLG, whereas conceptus production of FST inhibits activin A/TGFβ effect (middle panel). As FST production declines on day 22, activin A/TGFβ induces epithelial–mesenchymal transition (EMT). Through the SELL-PODXL and VCAM-ITGA4 adhesion systems, two cell types are held in a close proximity, whereas intracellular cell loosening and enhanced mobility of the trophectoderm cells are occurring through EMT.

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