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How Cells of the Immune System Prepare the Endometrium for Implantation Ana Teles, PhD1
Ana Claudia Zenclussen, PhD1
1 Experimental Obstetrics and Gynaecology, Medical Faculty, Otto-von-
Guericke University, Magdeburg, Germany Semin Reprod Med 2014;32:358–364
Abstract
Keywords
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endometrium receptivity implantation infertility immune cells
Address for correspondence Ana Teles, PhD, Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Gerhart-Hauptmann-Straße 35, 39108 Magdeburg, Germany (e-mail:
[email protected]).
Characterized by its cyclical regeneration and differentiation, the endometrium is one of the most dynamic tissues of the human body. As a main player during implantation and later development of the embryo it has a unique and extremely important role in the survival of species. This study is a review of the current literature focused on the cyclical restructuring of the endometrium and the morphological and cellular alterations during the different phases of the reproductive cycle. These changes confer specific receptive capabilities for implantation to take place. The mechanism of implantation is addressed as well as possible receptivity obstacles that can influence this process. More specifically, we discuss the involvement of immune cells in the establishment of implantation and its consequences for a successful pregnancy. A deep knowledge of the mechanisms involved in the regulation and transformation of the endometrium and embryo implantation is essential to understand disorders that can influence fertility and women health.
The endometrium is a multilayered and dynamic tissue that undergoes cyclical changes. It has an important biologic role in the implantation and nourishment of the early embryo. It regenerates and differentiates from the basal layer, which is attached to the myometrium, toward the construction of an upper, functional layer.1 This process, known as the menstrual cycle in humans and some primates and as the estrous cycle in non-primates, is regulated by ovarian steroid hormones 2,3 and further influenced by the production of local regulators like growth factors, cytokines and enzymes.4,5
Endometrial Development and Metamorphosis The endometrial tissue is constituted by a luminal epithelium which has an exceptional capacity to regenerate. Tubular glands extend from the functional and basal layer to the endometrial-myometrial junction. Because of their secretory capacity they contribute to nurturing the implanting blastocyst. The stroma is constituted by stromal fibroblastic cells,
Issue Theme Endometrium and Implantation; Guest Editor, Steven L. Young, MD, PhD, FACOG
vascular cells and leukocytes that are also of importance in supporting implantation.6,7 During the three distinct phases (proliferative, secretory and menstrual) of a 28 day menstrual cycle in humans, several architectural changes occur in the endometrium.2 After ovulation, during days 16 to 20, the epithelial glands start showing increased secretory activity, formation of prominent subnuclear vacuoles, and decreased mitotic activity. Globular protrusions in the surface membrane of epithelial cells of the uterine cavity, named pinopodes, typically appear between day 19 and day 21, coinciding with the phase of a receptive endometrium.8 On day 21 the accumulation of fluids is evident in the stroma, which becomes edematous.3,9,10 While menstruation progresses, there is a re-epithelization of the luminal surface which starts at the very beginning of menstruation, the desquamation of the premenstrual endometrium. First, the detachment of the most luminal areas of the endometrium occurs and the glands and vessels are exposed above the cellular stroma of the basalis. Next, the endometrial surface is remodeled and covered by new epithelium, which is created by the differentiation of cells from the endometrial
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DOI http://dx.doi.org/ 10.1055/s-0034-1383735. ISSN 1526-8004.
How Cells of the Immune System Prepare the Endometrium for Implantation stroma. The shedding process occurs in zones, meaning that some areas are actively shedding while others have not yet begun to shed, some areas are in the process of repair while some others are already completely re-epithelialized with a new surface.11–13 The growth of the glandular and stromal tissues starts when the re-epithelialization is completed.14
The Mouse Endometrium Despite the inexistence of a basal layer and the lack of menstruation in mice, the organization of the mouse endometrium is, to some extent, similar to that in the human as it contains highly similar glands and supportive stroma. The murine endometrium undergoes cycles of cellular proliferation and apoptosis lasting 4–5 days named oestrus cycle and divided in four different phases. On days 1–2, proestrus takes place with the development of the follicles and the proliferation of the endometrium. Estrus occurs with ovulation, generally on days 2–3. In this phase, the endometrial epithelial cells reach their maximum development allowing the receptivity of the endometrium. On days 3–4, vacuolar degeneration and the loss of the definite organization of the endometrial epithelium characterize metestrus. Finally, the desquamation of the endometrium and the collapse of endometrial glands on days 4–5 set the beginning of the regeneration of the endometrium during diestrus.15–17
Endometrial Stem Cells The presence of stem cells in the human endometrium has long been speculated6,18 but it was only in the past decade that the presence of small populations of epithelial and stromal cells with stem cell-like properties in the endometrium was reported.19,20 More recently, the presence of multipotent stromal stem cells in the human menstrual blood was demonstrated21 which has potential in the future of cell therapy.22
Cellular Markers of Receptivity Several morphological and cellular changes occur in the endometrium during the reproductive cycle. Some of them seem to be associated with an ideal receptive phase.
Pinopodes Pinopodes were first described as micrometer smooth mushroom or balloon-like membrane projections originated from the fusion of the hairy-like apical surface of the luminal epithelium of the endometrium in rodents and humans.23,24 The appearance of these structures in rodents is a clear marker of the window of receptivity with an abundance peak on day 5, the day at which embryo implantation takes place and declining immediately after that.24,25 In humans, pinopodes were previously associated with the endometrial receptivity26 but their clinical utility for the success of implantation is still under discussion.27
Glycocalyx As in mucosal epithelia, the endometrium is covered with a glycocalyx, a thick layer constituted by secreted and cell
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membrane-intercalated glycoproteins. The most common glycoprotein forming the glycocalyx of the endometrium is the membrane-intercalated mucin, MUC-1.28 In humans, embryo implantation seems to depend on the encounter of the blastocyst with the epithelial glycocalyx, MUC-1.29–31 In contrast, the murine homologue, Muc-1, is down-regulated at the time of implantation and it is thought that its reduction has a role during the onset of a “receptive window” but not in the post-implantation phase.32
Epithelial Tight Junction The epithelial cells of the endometrium are in direct contact with each other through tight junctions. In humans, while the tight junctions of the basal layer show no major alterations during the menstrual cycle, some remarkable changes can be observed in the tight junctions of the functionalis layer during different phases of this cycle and in a hormonal dependent manner.33 In the early proliferative phase these junctions are smaller and in lower number suggesting a role in implantation by reducing the integrity of the epithelial barrier and facilitating the invasion of the epithelium by the embryo.34,35 It has been suggested that murine endometrial differentiation and function is regulated by E-cadherin (Cdh1), which has an important role in the formation of tight junctions. The lack of Cdh1 caused defects in the endometrial glands leading to implantation and decidualization failure.36
Apoptosis Apoptosis in human endometrium fluctuates with the menstrual cycle, with peak levels seen during the late secretory and menstrual phases.37–41 Endometrial apoptosis occurs predominately in the epithelium and is regulated, at least in part, by Bcl-2 and Bax via both death-receptor and mitochondrial pathways.38,42–44 Given the cyclic nature of endometrial apoptosis, it has been hypothesized that it is involved in the maintenance of cellular homeostasis by promoting the elimination of senescent cells from the functional layer of the endometrium during the late secretory and menstrual phase of the cycle.41 Some reports suggest that endometrial apoptosis regulation is also crucial for successful implantation in mice.45 Interestingly, murine endometrial apoptosis can be observed in the stroma, luminal and glandular epithelium during all oestrus cycle phases except in the stroma during the receptive phase of estrus, suggesting a role in regulating embryo implantation.46
Implantation During implantation, trophoblast cells anchor in the endometrial stroma and the blastocyst becomes dependent on the maternal environment to further development. The general aspects of the implantation process are similar in humans and rodents47 and its success depends on a proper stage of embryo development and the receptivity of the endometrium during the implantation window.48 In mice this takes place around 4–4.5 days after fertilization49,50 and is finished at day 5, and in humans it occurs between day 19 and day 24 of a Seminars in Reproductive Medicine
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How Cells of the Immune System Prepare the Endometrium for Implantation normal 28 day cycle.51 The uterine receptivity is the result of an adequate exposure to progesterone and estrogen.52 In both species, implantation occurs in three main phases: apposition, attachment and penetration.
Apposition During apposition, the first structural interaction between embryo and mother is established. The accumulation of fluid in the stromal cells causes the closure of the uterine lumen (in the mouse) and increases the contact between microvilli on the surface of the trophectoderm and uterine epithelial cells. Some surface epithelial cells lose the microvilli and develop protrusions, the pinopodes, which development is dependent on progesterone but is inhibited by estradiol.24,53–55
Attachment The communication between the blastocyst and the endometrium becomes stronger and the non-adhesive apical surface of the trophectoderm becomes adhesive. Attachment starts controlled by an adhesive-signaling system of several glycoproteins and carbohydrate ligands and receptors expressed by both blastocyst and endometrium. Together, cytokines, integrins, selectins, galectins, proteoglycans, glycosaminoglycans, laminin and collagen help in the transformation of the endometrial tissue which, resembling an inflammatory response, experiences an increase in its blood vessels permeability and the recruitment of inflammatory cells producing pro-inflammatory cytokines.15,56
Invasion In rodents, the trophoblast cells invade the surface epithelium by displacement penetration.57 In this way, surface epithelial cells are displaced from their basal membrane and from each other and they die by autolysis being phagocytized by trophoblast cells. The trophoblast cells are then exposed to the bare basal membrane and attach to the endometrial epithelium which also starts a decidualization process. During this process the endometrial fibroblastic stromal cells are transformed into the decidua, characterized by changes in cellular shape, organization and metabolism and by establishment of tight junctions with neighbor cells.48,50 In humans, extravillous cytotrophoblasts from anchoring villi tips invade the uterus and migrate near the spiral arteries promoting their transformation into low resistance large vessels.58
Involvement of the Immune System on Implantation Success Lack of tolerance from the maternal immune system toward the fetus might result in pregnancy complications and its termination. Around 70% of all pregnancies fail to generate a viable infant and of these, 50–70% are lost during the first month and therefore are often unnoticed.59 Causes of pregnancy loss, including endometritis, endometriosis, inflammatory pelvic diseases and fallopian tube blockage result from inflammatory processes that change the tissues of the reproductive tract.60–62 Seminars in Reproductive Medicine
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Endometritis Usually caused by infections such as chlamydia, gonorrhea, tuberculosis, or bacteria existing on the vaginal environment, chronic endometritis is often correlated with lower implantation rates after in vitro fertilization.63 Its incidence can be predicted by the quantification of menstrual inflammatory cytokines IL-6 and TNF-α.64
Endometriosis Being an inflammatory and estrogen-dependent disease, endometriosis occurs when viable endometrial tissue establishes itself outside the uterine cavity.65 The endometrium of women with endometriosis shows a diminished apoptotic response compared with the endometrium of healthy women. It was therefore suggested that this apoptotic impairment could be the leading cause of endometriosis by allowing the survival and repopulation of refluxed endometrial cells in the peritoneal cavity.41,66,67 Immune cells are important players in the normal development of reproductive cycles. Whether by production of cytokines, cell-cell interaction mechanisms with the endometrium, or by participating in tissue remodeling, bone marrow derived immune cells are required for normal implantation of the blastocyst and contribute to normal fertility. Immune cells have hormone receptors and can therefore react to hormonal changes during the menstrual or oestrus cycle and can function to support the generation of an embryofriendly environment.
Immune Cells in the Uterus during Implantation Uterine Natural Killer Cells (uNKs) Probably originating from bone marrow derived leucocytes, uNKs constitute a great majority of lymphocytes (65–70%) in the pregnant uterus in both humans and mice. In mice, they proliferate and grow from day 5 to day 10 of pregnancy by an estrogen and progesterone regulated mechanism. Further, uNK cells acquire cytoplasmic granules while producing IFNγ, which induces vascular modifications and contributes to the uNK maturation and senescence. After day 10 of pregnancy apoptotic events lead to a substantial decrease in the uNK population that is no longer active at day 12. In the human endometrium, uNK cells may regulate angiogenesis.68 Additionally, they have a role on promoting trophoblast migration and invasion and development of spiral arteries and placentation, therefore helping in the establishment of a successful pregnancy outcome.69–73
Mast Cells (MCs) Known for their role in allergic diseases, MCs have been recently described as important mediators of implantation. The migration of MCs from the periphery to the uterus and their subsequent maturation and degranulation was shown to be modulated by estradiol and progesterone in both humans and mice.74 Cyclical changes in the population of mast cells in the endometrium during the menstrual cycle was described in healthy humans but these changes were
How Cells of the Immune System Prepare the Endometrium for Implantation absent in the endometrium of patients with dysfunctional uterine bleeding (DUB).75 These variations were also observed during the estrus cycle in mice, where the uterine abundance of MCs seems cyclic, with a peak during the estrus phase.76 Animals devoid of MCs have impaired implantation, likely involving dysregulated TGF-β and CtGF expression. In those mice that achieved pregnancy, despite a lack of MCs, many demonstrated a defective remodeling of spiral arteries that provoked intrauterine growth restriction. Reconstitution of C57/BL6J-KitW-sh/W-sh mice with bone marrow-derived MCs (BMMCs) restored both implantation and pregnancy. It seems that MC-secreted Galectin-1 is of critical importance herein as the transfer of Lgals-1 knockout could not rescue pregnancy as wild type BMMCs did.76 Thus, MCs emerge as novel cellular regulators of implantation and pregnancy.77
Polymorphonuclear Neutrophils (PMNs) PMNs are involved in tissue remodeling in several stages in the reproductive cycle in mammals and implicated on the receptivity of the endometrium.78,79 Their depletion in mouse resulted in the blocking of the cycle in diestrus.80 In human endometrium an extensive population of PMNs with different phenotypes has been reported on day 28, just before the beginning of menstruation.81 It was also suggested that these cells might have a significant role in the inflammatory responses occurring after mating82 and some studies suggest that they might sustain angiogenesis in the early stage of endometriosis83 or promote the development of endometritis through the production of defensins after infection by sexually transmitted diseases.84
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and B and FasL. However, the expression of IL-10 and TGF-β also confers them immunomodulatory capacities92,93 that may be of importance for later pregnancy periods.
Dendritic Cells (DCs) DCs seem to have an important role for pregnancy establishment. They are very abundant in the uterus and form clusters at defined areas, which are most probably the future implantation niches.94 Similar to what was observed for MCs, their depletion resulted in aberrant implantation and abnormal placental development supporting the requirement of these cells in the establishment of a successful pregnancy. This is thought to depend on the ability to produce sFlt1 and TGF-β1 which are important regulators of tissue remodeling and angiogenesis.95 Later these cells are important as “toll controllers” as they are in first line involved in the process of paternal antigens96 and the modulation of their phenotype defines pregnancy outcome.97 A report suggested that in human pregnancies, immature dendritic cells (iDCs), together with NK cells, are recruited by the influence of extravillous cytotrophoblast cells at the implantation site influencing the success of pregnancy through cytokine production.98
Th17 Cells There is a lack of studies on the frequency of Th17 cells in the endometrium during the different phases of menstrual cycle and only few studies reported a correlation of populations of Th17 cells in the peripheral blood and decidua of women with unexplained recurrent pregnancy loss99 and results from a recent study suggest that these cells are involved in the development of endometriosis.100
Macrophages (M) After natural killer cells, macrophages are the second largest decidual leukocyte population (10–20%) and accumulate close to the implantation site.85,86 In the mouse endometrium macrophages were found to be mostly associated with glandular and vascular tissue and its number increased after implantation takes place.87 In humans, the population of Macrophages in the endometrium increases in the late secretory phase as compared with the proliferative phase. These cells seem to be also responsible for the elimination of pathogens in the endometrium.88 Decidual macrophages were classified as having a M2 phenotype because of their ability to produce IL-10 and IDO that confers them an immunosuppressive role. Contrasting with this view, Houser et al89 described two unique macrophage populations in the first trimester human decidual tissue which, by producing both pro-inflammatory and anti-inflammatory cytokines, cannot fit into the classical M1/ M2 classification.
γδ T Cells Two populations of γδT cells were described in the murine decidua: an early population producing Th1 cytokines, and a later Th2/3 cell subset.90 These cells have also been described in the peripheral blood of healthy pregnant women.91 Decidual γδTCRþ cells are mostly CD4-CD8-T cells with cytolytic properties through the expression of perforin, granzyme A
CD8 Cells CD8 T cells were shown to proliferate in the uterus of mice depleted from regulatory T cells and this was associated with a pro-inflammatory environment and the development of uterine fibrosis.101 In addition, CD8þ cells isolated from the endometrium during the secretory phase of the menstrual cycle in humans were unable to mediate a cytotoxic Tlymphocyte activity after being stimulated with interleukin-2 (IL-2) suggesting that the response of these cells is differentially controlled during different phase of the reproductive cycle.102
Regulatory T Cells (Treg) Although Treg are cells of the adaptive immune system in charge of preventing autoimmunity, their role in pregnancy was widely demonstrated. They are involved not only in tolerance to the fetal semiallograft but also at the initial stages of pregnancy. Cyclic accumulation of Treg seems to occur in the murine uterus during the estrus phase of the oestrus cycle as a result of estrogen induced expression of chemokines which receptors are expressed by Treg.103 We observed a cyclic expansion of Treg in the vaginal lumen of mice during the oestrus cycle, peaking during the receptive phase. This expansion is also coincident with the accumulation of Treg at specific sites along the uterus at the fertile period, just before conception can occur.101 A similar process Seminars in Reproductive Medicine
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How Cells of the Immune System Prepare the Endometrium for Implantation was suggested to occur during the menstrual cycle of women.104 Primary unexplained infertility has been related to a lower expression of the Treg specific marker FOXP3 mRNA in endometrial tissue of women.105 As soon as pregnancy establishes, Treg seem to be attracted by the luteinizing hormone/coriogonadotropin (LH/ CG).106 Mouse experiments confirmed this and also showed that hCG has a central role in modulating tolerance to the growing fetus.107 Thymic derived Treg seem to be involved in the implantation process and additionally, immediately after implantation takes place, an expanded population of Foxp3þ Treg was observed in the periphery in a Rag-1(/) model of cell transfer.108 Most importantly, Foxp3.DTR specific depletion of Treg prior to mating caused an impaired implantation and the infiltration of activated T effector cells. Treg depletion was associated with uterine inflammation and fibrosis in both allogeneic and syngeneic mating combinations after the depletion of Treg and this confirms that these cells play a critical role in embryo implantation by preventing the development of a hostile uterine microenvironment.101 A diminished population of peripheral Treg was associated with endometriosis and infertility in mice, while their augmentation in the ectopic endometrium was associated with the development of the endometrial lesions after the onset of endometriosis.61
6 Padykula HA. Regeneration in the primate uterus: the role of stem
cells. Ann N Y Acad Sci 1991;622:47–56 7 Uduwela AS, Perera MA, Aiqing L, Fraser IS. Endometrial-myo-
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The endometrium is remodeled though the menstrual cycle in humans or oestrus cycle in mice and it has a short period of receptivity known as the implantation window. The process of implantation is only possible if the arrival of the blastocyst to the endometrium occurs in synchrony with its receptivity. Cells of the immune system contribute to the establishment of an optimal microenvironment for the blastocyst to attach and the embryo to grow. A deeper understanding of the morphological changes and cellular and immune mediated mechanisms occurring before implantation are crucial to improve the success of pregnancy establishment in both natural and assisted reproduction techniques.
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