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The rat as an animal model for fetoplacental development: a reappraisal of the post-implantation period
Vol. 12, No. 2
97
REVIEW
The rat as an animal model for fetoplacental development: a reappraisal of the post-implantation period Bruno M. Fonseca, Georgina Correia-da-Silva, Natércia A. Teixeira1 Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto and Institute for Molecular and Cell Biology (IBMC), Porto, Portugal
Received: 5 August 2011; accepted: 25 March 2012
SUMMARY Following implantation in rodents, the uterine stromal broblasts differentiate into densely packed decidual cells. This process, called decidualization, is wellorchestrated and progresses both antimesometrially and mesometrially, creating two regions with distinctive cellular morphologies. In addition, subsequent placental development is dependent on the invasion of the trophoblast, the process intimately linked to the endometrial tissue remodelling and depending largely on the environment created by the decidua; this phenomenon is crucial for the establishment and maintenance of pregnancy. The key mechanisms underlying the maternal tissue remodelling and trophoblast invasion remain poorly understood. The rat, just like human beings, exhibits a highly invasive type of placental development, the haemochorial placentation. For obvious ethical reasons, the studies of endometrial tissue remodelling throughout 1
Corresponding author: Faculdade de Farmácia da Universidade do Porto - Laboratório de Bioquímica Rua de Jorge Viterbo Ferreira No 228, 4050–313 Porto, Portugal; e-mail: [email protected]
Copyright © 2012 by the Society for Biology of Reproduction
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pregnancy in humans are greatly limited. Although the rat differs somewhat from humans with regards to the implantation process, it is an appropriate model for studying the mechanisms of decidualization as well as subsequent remodelling of the uterine tissues and fetoplacental development. As decidual remodelling is very closely linked to placentation and the maternalfetal interactions in the rat show several important similarities to human placentation, the morphological alterations occurring during the postimplantation period in the rat have been addressed in the present review. Reproductive Biology 2012 12 2: 97–118.
INTRODUCTION At implantation, the uterus is receptive to blastocysts (“window of implantation”) and is under the inuence of ovarian steroid hormones. In mice and rats, implantation occurs between days 4 and 5 of pregnancy, considering the rst day of pregnancy as the day on which a vaginal plug (mouse) or spermatozoa (rat) are present in the vagina [50, 65]. Following implantation, the endometrial broblast-like stromal cells proliferate and differentiate into decidual cells. In women, decidualization occurs spontaneously during the late secretory phase of the menstrual cycle, while in rodents decidualization occurs in response to implantation or an articial stimulus; in the latter case, it gives rise to the deciduoma. The morphology of the decidua changes with the advancement of gestation. Initially, it develops in the antimesometrial pole of the uterine lumen, forming the antimesometrial decidua. After the attainment of full development, it regresses to give room for the growing conceptus. Concomitantly with the regression of the antimesometrial decidua, the stromal cells from the mesometrium begin to differentiate into decidual cells to form the mesometrial decidua. The latter provides an affable environment for placental growth and degenerates concurrently with the invasion of trophoblast cells, supporting the establishment of the placental bed. In the present review we describe the remodelling of rat uterine tissues during gestation. We present detailed information
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Figure 1. The timeline of main events during the rat gestation. After fertilization, the sequence of events is similar among different rodent species. In response to implantation, which occurs around day 5 in rats, the antimesometrial decidua develops and subsequently regresses by day 12 (decidua capsularis). The mesometrial decidua develops concurrently with trophoblast invasion to initially form the choriovitelline placenta, which gives rise to the denitive placenta.
on the maternal-fetal interactions with the special emphasis on decidual establishment and regression. Moreover, as trophoblast invasion in the rat proceeds along two different pathways, interstitial and endovascular, we will describe this phenomenon, which shares a number of similarities with human trophoblast invasion. Figure 1 depicts the main events during rat gestation and times at which they occur. Spatio-temporal characterization of rat antimesometrial decidua Successful establishment of pregnancy is dependent upon the proper growth and development of the uterine endometrium for blastocyst implantation. The uterus must be hormonally prepared and then a stimulus, normally provided by the embryo, triggers the process of decidualization. Stromal broblasts in the endometrium proliferate and differentiate into decidual cells, which involves characteristic changes in cell morphology [1]. Although the molecular mechanisms associated with decidualization remain poorly understood, numerous factors have been implicated in the regulation of this process. Among these are ovarian hormones and other locally synthesized molecules such as interleukin 11 (IL-11; [8]), relaxin [32], prostaglandin E2 (PGE2; [42]), leukemia-inhibitory factor (LIF; [67]), and activin A [82].
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In addition, recent evidence suggests that decidual cells are important players in the recognition of implanting “competent” embryos [7, 70]. Although the embryonic factors BMP2, WNT have been suggested to act on the decidual cells and the JAK/STAT and cAMP dependent pathways have been reported to be activated in these cells, the exact mechanisms involved remains unknown [30, 46, 85]. Following the attachment of the blastocyst, apoptosis of the luminal epithelial cells and decidual cell reaction at the site of implantation occur. During the initial stages of hatched blastocyst invasion, trophoblast cells erode the uterine epithelial cells, leaving the basement membrane temporarily intact [77]. Once stimulated, the stromal broblasts from the subepithelial antimesometrium zone undergo differentiation, giving rise to the primary decidual zone [24]. Primary decidual cells are large, with basophilic cytoplasm, two or more nuclei, and abundant endoplasmic reticulum, mitochondria, lysosomes and well-developed Golgi complexes [56]. These cells express alkaline phosphatase [29] and their appearance is associated with a signicant increase in DNA, RNA and protein content indicating high decidual growth dynamics [6]. Concomitant with the appearance of the primary decidual zone, the surrounding stromal cells undergo mitosis heralding the differentiation into antimesometrial decidual cells, which results in the formation of the secondary decidual zone. By day 8 of gestation, decidualization spreads out to the basal region of the endometrium adjacent to the muscular layer (g. 2; [77]). The formation of decidua involves a tight equilibrium between decidual cell proliferation and death, which is crucial for the maintenance of pregnancy. In vivo studies demonstrated that proliferation was intense in the rst period of decidual cell reaction but it declined at the later stages [15]. In fact, the antimesometrial decidua reaches its maximum development on day 10 of pregnancy (fig. 2). By day 12, the regression of decidua is complete and it forms the decidua capsularis (g. 2; [11]). Degradation of the antimesometrial decidua occurs primarily by programmed cell death, as previously demonstrated by immunoreactive caspase-3 and TUNEL positive staining detected as early as day 8 of pregnancy [15]. However, the markers of necrosis were also detected during the regression of the antimesometrial decidua. It was suggested that apoptosis is followed
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Figure 2. An illustration of rat uterine tissue architecture from days 8 to 12 of pregnancy. The blastocyst implants on the antimesometrial side of the uterus and decidual cells develop to form the primary decidual cell zone. On day 8, the antimesometrial decidua (AMD) forms and on day 10, AMD is fully developed and decidualization is occurring in the mesometrium (MD). By day 12, trophoblast cells of the ectoplacental cone (the primordial placenta) have started to penetrate into the mesometrial decidua. By this time, the antimesometrium has completely regressed, being now referred to as decidua capsularis (DC), and the mesometrial triangle can now be observed.
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by secondary necrosis, which triggers the release of cellular constituents activating the inammatory processes [15]. Using the pseudopregnancy model, Tessier et al reported the expression of active caspase-3 in the decidua only after day 10, suggesting that the presence of the conceptus may accelerate the initiation of apoptosis in this tissue [81]. On day 9 of gestation, the brinoid capsule, a structure of condensed tissue, appears externally to the antimesometrial decidua (fig. 2). Between the fibrinoid capsule and the innermost smooth muscle layer of the uterus, there is a thin layer of non-decidualized stroma containing sporadic endometrial glands, which secrete various substances required for survival and development of the conceptus [35]. Although the precise role of the endometrial glands during pregnancy is not known, they appear to be required both during the peri-implantation period and placental development [5]. At the time of the brinoid capsule formation, endothelial cells in the lateral wings of the decidua proliferate rapidly, which results in the formation of large venous sinusoids. These endothelial cells are in intimate contact with decidual cells to facilitate the transfer of nutrients from the decidua to adjacent blood vessels [28]. This region, between the lateral sinusoids and antimesometrial decidua, contains the cells with high glycogenic content and is commonly known as the lateral decidua or the glycogenic wing area (g. 2; [76]). Rat mesometrial decidua: remodelling of uterine tissues during fetoplacental development Mesometrial decidual cells appear in the central region of the endometrium few days after antimesometrial decidual cell reaction as a result of the differentiation of cells from the mesometrial pole. These cells are smaller than those in the antimesometrial decidua, irregular in shape, and they contain a single nucleus. By day 12 of gestation, the mesometrial decidua is fully differentiated. With time, there is an enlargement of adjacent blood vessels and the central zone of the mesometrial decidua is invaded by the trophoblast cells of the ectoplacental cone, resulting in the formation of the denitive placenta by day 14 (g. 3). From days 14 to 16, the decidua undergoes apoptotic
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regression [15]. By day 19, it is conned to a marginal uterine region, forming the maternal component of placenta-the decidua basalis (fig. 3). In fact, the degeneration and disappearance of both antimesometrial and mesometrial decidua is a unique feature of rat placentation. During the process of decidualization, a set of specialized leukocytes, the uterine natural killer (uNK) cells, populate the decidua. These leukocytes are phenotypically and functionally different from peripheral NK cells. Although the exact mechanisms involved in the recruitment of uNK to the decidua during pregnancy are still unknown, it seems to be hormonally-controlled and involves IL-15 [84]. Moreover, as demonstrated in the deciduoma model, the colonization of the decidua by uNK cells seems to be independent of the presence of the implanting embryo [38, 54, 58]. It is, however, well documented that the conceptus plays a critical role in regulating the number and function of uterine uNK cells during decidualization [38]. With the progression of pregnancy, uNK cells become more abundant and acquire a granular phenotype. The characteristic membrane-bound granules contain perforin and granzyme B, which control the trophoblast invasion and maternal vascular remodelling [13, 45, 55]. After day 15 of pregnancy, uNK cells undergo degranulation and their number decreases as a result of an active process of programmed cell death [33]. By day 12, uNK cells are also present in the mesometrial triangle, a zone between the circular and longitudinal uterine muscle layers. Often referred to as the “metrial gland” (an obsolete term), this region enlarges with the progression of pregnancy and appears to be an extension of the mesometrial decidua [19, 20]. The mesometrial triangle also comprises the entry point for blood vessels, supplying both the placenta and fetus. Besides numerous uNK cells clustered around the vessels, the metrial gland also contains the endometrial stromal and trophoblast cells. It is apparent that decidualization involves a temporal and spatially co-ordinated sequence of events with the differentiation of various cell types occurring in different regions of the gravid uterus and at different times. The antimesometrial decidua has characteristics of an endocrine organ, secreting a variety of hormones and growth factors such as decidual prolactin-like hormones, follistatin, activin and transforming growth
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factors [36]. On the other hand, the mesometrial decidual tissue secretes high levels of 2-macroglobulin (2-MG; [79]). This glycoprotein has the ability to inhibit all types of proteases and bind numerous cytokines and growth factors. In addition, the mesometrial decidua also secretes other factors such as insulin-like growth factors (IGFs; [14, 21]) and IL-6 [23]. The progressive decidualization of the mesometrial stroma prepares the uterine lining for the presence of the invasive trophoblast. In fact, the temporal and spatial patterns of mesometrial decidua regression are closely associated with the pattern of trophoblast invasion and the resulting vascular remodelling. Placental development in the rat The placenta is a specialized pregnancy-specic structure that develops concurrently with the embryo and is composed of numerous cell types. Among these are the trophoblast cells, the earliest extra-embryonic cells to differentiate from the mammalian embryonic cells. Although the general structure of the placenta varies considerably among mammalian species, the basic morphology, main cell types and functions as well as the molecular mechanisms underlying placental development are conserved across species [47]. In contrast, the specic hormones governing the maternal recognition of pregnancy are different. The trophoblast in humans and other primates produces a chorionic gonadotropin that directly stimulates the secretion of luteal progesterone, whereas the placenta in rodents produces lactogens [31]. The trophoblast cells play a primary role in protecting the embryo from noxious deleterious substances, programming the maternal support and preventing the maternal immune rejection. They also ensure an appropriate bidirectional nutrient/waste ow required for normal growth and maturation of the embryo. Thus, through creating the milieu in which the embryo and fetus develop, placentation is fundamental for assuring successful pregnancy and it also impinges on the postnatal health status. Although several studies attempted to corroborate the molecular pathways underlying the development of the placenta, our current knowledge is mainly based on mouse studies involving transgenic animals exhibiting the defects
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Figure 3. Rat implantation unit during fetoplacental development. On day 14, the placenta is fully developed and decidual regression is apparent in both the mesometrial and antimesometrial decidua. The metrial gland, or mesometrial triangle, appears as an extension of the mesometrial decidua. By the end of pregnancy, and particularly on day 19, just a layer of few decidual cells remains to give space for placental growth.
in placental development [4, 17, 26, 69]. Several genes were identied as critical for normal placental development and function. These include the genes for cystatin C [3], cathepsins [71], plasminogen activator inhibitor type 1 (PAI-1) and 2 (PAI-2; [27]), and 2-MG [25]. The haemochorial placentation is the most invasive form of placentation, with the penetration of trophoblast cells into the uterine compartment where they establish direct contact with maternal vasculature and with extensive remodelling of the spiral arteries. The blood vessels lose their elastic lamina and smooth muscle layer, and consequently the responsiveness to circulating vasoactive compounds [61, 62]. This type of placentation occurs in humans and most rodents. Various studies of the depth of trophoblast invasion
Figure 4. Schematic representation of rat chorioallantoic placenta. A schematic of the basic structures comprising the implantation unit in mid-pregnancy: myometrium, metrial gland, decidua and placenta. Note the trophoblast lineages and their location within two distinct structures of the placenta: the basal (giant trophoblast cells, spongiotrophoblast cells and glycogenic cells) and the labyrinth zone (giant trophoblast cells and syncytiotrophoblast cells).
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during placentation in mice revealed significant differences when compared to the rat. In fact, in the rat both endovascular and interstitial trophoblast invasion are observed. In the mouse, trophoblast invasion into the maternal spiral arteries is limited to the decidual compartment [2, 49] and the interstitial invasion does not reach the mesometrial triangle [64]. Considering those differences, the rat is the most appropriate rodent model for the studies of extensive myometrial invasion as seen in humans [62]. Moreover, histological studies revealed important similarities between rats and humans with regards to remodelling of the spiral arteries [9, 83]. Although the placental development in the rat starts immediately after the attachment of the blastocyst to the uterine epithelium, the denitive placenta develops from the ectoplacental cone. Therefore, the two placental structures can be distinguished: the choriovitelline and chorioallantoic placenta [75]. The choriovitelline placenta is transitory, being physiologically significant between implantation and mid-gestation, and is comprised of a single differentiated trophoblast cell type, the giant trophoblast cells. The chorioallantoic placenta represents the definitive placenta and is comprised of four differentiated trophoblast cell phenotypes, namely the trophoblast giant cells, spongiotrophoblast cells, glycogenic trophoblast cells, and syncytiotrophoblast cells (g. 4; tab. 1). Two morphologically and functionally distinctive placental regions, the basal and labyrinth zones, can be seen in the chorioallantoic placenta [74]. The basal zone, also known as the junctional zone, is located between the uterine decidual tissue and the labyrinth zone. It contains giant trophoblast cells, localized at the maternal-placental interface, spongiotrophoblast and glycogenic trophoblast cells. The labyrinth zone is positioned at the fetal interface, being comprised by giant trophoblast cells, syncytiotrophoblast cells, fetal mesenchymal cells and vasculature. The majority of cell lineage studies have been carried out using mouse placenta, although there is sufficient evidence to suggest that the origin of placental cells in mice is similar to that in the rat [73]. All trophoblast cell subtypes differentiate from the trophectoderm layer of the blastocyst; however, they can be distinguished on the basis of their morphology, intraplacental location, and the pattern of gene
Spongiotrophoblast
Syncytiotrophoblast
Invasion of decidua [18]
Immunological, endocrine and structural functions [40]
Present only in the labyrinth zone - fetal interface [57]
Nutrient transport [72]
Unknown
Invasion of decidua [86]
Expands to decidua but also into spiral arteries [2, 86]
Invasiveness
Invasive and endocrine functions [37]
Functions
Present only Energy reservoir [22] in the basal zone [57]
Present only in the basal zone [57]
Derived from the ectoplacental cone [10]
Giant trophoblast
Derived from the ectoplacental cone [10] Fusion of cytotrophoblast cells [16]
The choriovitelline placenta and in both zones of the chorioallantoic placenta [57]
Derived from the ectoplacental cone; endoreduplication [10, 51]
Glycogenic trophoblast
Location
Differentiation
Cell type
Table 1. Main features of various types of differentiated rat trophoblast cells
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expression [48, 66, 68]. The term “giant trophoblast cells” derives from their enormous size, which is a consequence of genome amplication. The trophoblast cells undergoing differentiation into the giant cells exit the proliferative cell cycle and enter a genome-amplifying endocycle, also known as endoreduplication [39]. The giant trophoblast cells are analogous to human extravillous cytotrophoblast cells and exhibit characteristic invasive activity. In addition, these cells are the most important endocrine cells of the placenta that promote both local and systemic physiological adaptations in pregnancy [75]. Because of the difference in time of trophoblast cell differentiation, the giant trophoblast cells are referred to as the “primary” or “secondary” cells in the choriovitelline and chorioallantoic placenta, respectively. While the primary giant cells are formed from the trophectoderm layer of the blastocyst during implantation, the secondary giant cells arise after implantation around the margins of the ectoplacental cone [18, 37]. The spongiotrophoblast cells exhibit important endocrine functions and, as they are situated immediately beneath the giant trophoblast cells, they may also support the development of the labyrinth zone [18]. The placenta accumulates glycogen, and this is most marked in rodents, in cells called the glycogenic trophoblast cells. They are embedded in the spongiotrophoblast and are considered a potential energy reservoir [22]. The spongiotrophoblast cells and glycogenic trophoblast cells originate from the same placental structure as the giant trophoblast cells, the ectoplacental cone [10]. The syncytiotrophoblast cells are multinucleated and are formed by the fusion of the trophoblast progenitor cells, the cytotrophoblast cells. They have been implicated in bidirectional transport of nutrients and waste between maternal and fetal compartments [72]. Prior to placentation, the outer cells of the blastocyst (trophoectoderm) breach the uterine epithelium and penetrate the basement membrane and underlying connective tissue. Subsequently, a more intense invasion occurs, involving both vascular and endometrial remodelling. Endovascular invasion is the expansion of trophoblast cells into the spiral artery located in the uterine decidua. Endovascular trophoblast cells replace endothelial cells and appear as a collar of only a few cells in thickness surrounding
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the vessel [9]. The interstitial trophoblast invasion spans the penetration of trophoblast cells through the uterine stroma up to the metrial gland [59]. In the rat, the interstitial trophoblast invasion is similar to that in humans in that it extends beyond the decidua during the last third of gestation [12, 83]. Trophoblast invasion in mice is more limited and almost entirely conned to the uterine mesometrial decidua [4, 12, 60]. The trafcking of trophoblast cells from the chorioallantoic placenta into maternal tissues is well dened. Interstitial invasion follows vascular invasion. On day 16 of gestation, interstitial invasion is already significantly advanced and it continues throughout pregnancy beyond the decidua, resulting in the colonization of the mesometrial triangle by the end of pregnancy [4, 83]. It has been suggested that uNK cells are directly involved in the migration of trophoblast cells into the uterine stroma and/or myometrium [4]. In fact, the invading trophoblast cells occupy the locations previously occupied by uNK cells, indicating a regulatory role for uNK cells in trophoblast invasion. This hypothesis is further supported by the defects in mesometrial blood vessel remodelling and an alteration in the timing of trophoblast cell invasion observed in uNK decient mice [12]. Successful pregnancy requires the balance between all the factors involved. Synchronization between uNKs, invasive trophoblast cells and decidual cells is crucial to produce a suitable environment to ensure immune tolerance and sufcient vascular and decidual remodelling throughout pregnancy in order to establish an adequate nutrient transfer to the growing embryo. Abnormal placentation and its consequences for human pregnancy In mammals, the placenta is an essential interface between the maternal and the fetal circulation formed to carry O2-rich blood and nutrients to the developing fetus. It is now clear that a disturbance of the invasion of trophoblast cells (fetal origin) into the uterine tissues (maternal tissues) can result in various clinical problems. Thus, it is important to elucidate the underlying mechanisms of these processes in normal pregnancy using, for ethical reasons, an animal model. In addition to the same type of placentation, an animal model should have a deep trophoblast invasion
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comparable to that in humans. The non-human primates with a deep trophoblast invasion are the chimpanzee and gorilla that cannot be used as experimental animals, whereas the rhesus monkey and baboon exhibit a lesser interstitial invasion with only restricted endovascular invasion into the decidua [23, 63]. The rodents posses haemochorial placentae, and, in the case of the rat, a deep trophoblast invasion occurs with remodelling steps of the spiral artery that are similar to those in humans [80]. However, due mainly to the lower number of spiral arteries, the rat is not a good model to study placentation disorders in humans. The invasion of the trophoblast transforms uterine spiral arteries into open and straight vessels, resulting in a dramatic decline in the uterine arterial resistance. However, as a result of excessive restraint of trophoblast cells by the decidua, an inadequate trophoblast invasion into arteries and uterine wall can occur leading to decient blood supply and consequently lower levels of O2 delivered to the developing fetus. The main problems stemming from the inefcient blood supply are fetal prematurity, fetal growth restriction and preeclampsia [34, 41]. For example, during the preeclamptic pregnancy, trophoblast invasion into maternal tissues is abnormally shallow and uterine spiral artery remodelling is incomplete. Normally, the programmed cell death occurs in maternal tissues in order to facilitate trophoblast access to maternal vessels. However, this activity is markedly reduced during preeclampsia resulting in the formation of an arteriolar system with high resistance [52, 53]. On the other hand, it is also extremely dangerous if an excessive penetration of the uterine wall by trophoblast cells occurs as a result of an absent or decient decidua. An overly extensive trophoblast invasion results in the placenta creta, which is a cause of a massive postpartum haemorrhage and commonly leads to emergency hysterectomy [44]; without medical intervention, this condition frequently results in maternal death from haemorrhage. The exact pathogenesis of the placenta creta is unknown but it has been suggested to result from a primary deciency of decidua, abnormal maternal vascular remodelling, excessive trophoblast invasion, or a combination of these factors [43, 78]. Although the primary cause of some miscarriages cannot be clearly dened, the understanding of all mechanisms involved in the uterine-trophoblast cross-talk is crucial. Any factor disrupting
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the balance in the interactions between trophoblast and uterine tissue can have a deleterious effect on gestation.
GENERAL DISCUSSION Pregnancy involves complex alterations in the structure and function of the uterus both before and after implantation. Decidualization constitutes the primary process responsible for uterine remodelling during pregnancy, though the specic functions of the decidual cells are still an intriguing and unresolved issue. The rat, due to its supercial implantation, is not an appropriate animal model to study this process, but it is a good model for studying the mechanisms of decidualization and remodelling of the uterine spiral arteries in humans. The main difference between rodent and human decidualization is that the process starts spontaneously in humans, whereas in rodents decidualization occurs only in response to the blastocyst or an articial stimulus; the latter ultimately results in the deciduoma. As pregnancy progresses, decidual tissue regresses and, concomitantly, the formation of the placenta and invasion of trophoblast cells into maternal tissues occur. In comparison to primates, rodents have a shorter gestation period with a fully functional placenta present for only one week and a low number of spiral arteries. In spite of these differences, rodent species resemble humans in that they exhibit haemochorial placentation and, in the case of rats, a pronounced decidual cell reaction and trophoblast invasion, which require a strict interaction between the maternal blood vessels and placenta [1, 9, 60]. The mouse is a frequently used species for either decidua or fetoplacental development studies, mainly because of numerous advancements in the gene-targeting technology. However, in contrast to humans and rats, the mouse uNK cells seem to be more important for arterial remodelling than trophoblast cells. In addition, the interstitial invasion in mice is not as deep as in the rat. Trophoblast invasion in the rat proceeds along two different pathways, interstitial and endovascular [9, 83], similar to human beings. Moreover, the depth of endovascular trophoblast invasion and vascular
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remodelling of spiral arteries in the rat are similar to those in humans [9, 60]. Therefore, the rat constitutes a good experimental model for the studies of trophoblast invasion, which is intimately associated with the remodelling of maternal tissues during the normally progressing pregnancy. However, as mentioned above, it is not an appropriate model to study human pregnancy disorders. Lastly, the environment created by decidua is crucial for the maintenance of pregnancy and it pre-determines the extension of trophoblast invasion observed in both rats and humans. Hence, the abnormalities in either the establishment or remodelling of decidual tissue may have a negative impact on normal gestation and are commonly associated with some pregnancy-related pathological conditions such as preeclampsia or spontaneous abortions.
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40. Iwatsuki K, Shinozaki M, Sun WY, Yagi S, Tanaka S, Shiota K 2000 A novel secretory protein produced by rat spongiotrophoblast. Biology of Reproduction 62 1352-1359. 41. Kaufmann P, Black S, Huppertz B 2003 Endovascular trophoblast invasion: Implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biology of Reproduction 69 1-7. 42. Kennedy TG, Ross HE 1993 Effect of prostaglandin E2 on rate of decidualization in rats. Prostaglandins 46 243-250. 43. Khong TY, Robertson WB 1987 Placenta creta and placenta praevia creta. Placenta 8 399-409. 44. Kim KR, Jun SY, Kim JY, Ro JY 2004 Implantation site intermediate trophoblasts in placenta cretas. Modern Pathology 17 1483-1490. 45. King A 2000 Uterine leukocytes and decidualization. Human Reproduction Update 6 28-36. 46. Lee KY, Jeong JW, Wang JR, Ma LJ, Martin JF, Tsai SY, Lydon JP, DeMayo FJ 2007 Bmp2 is critical for the murine uterine decidual response. Molecular and Cellular Biology 27 5468-5478. 47. Leiser R, Kaufmann P 1994 Placental structure: in a comparative aspect. Experimental and Clinical Endocrinology 102 122-134. 48. Lin G, Martins-Taylor K, Xu RH 2010 Human embryonic stem cell derivation, maintenance, and differentiation to trophoblast. Methods in Molecular Biology 636 1-24. 49. Malassine A, Frendo JL, Evain-Brion D 2003 A comparison of placental development and endocrine functions between the human and mouse model. Human Reproduction Update 9 531-539. 50. Mayer G, Nilsson O, Reinius S 1967 Cell membrane changes of uterine epithelium and trophoblasts during blastocyst attachment in rat. Z Anat Entwicklungsgesch 126 43-48. 51. Nakayama H, Scott IC, Cross JC 1998 The transition to endoreduplication in trophoblast giant cells is regulated by the mSNA zinc nger transcription factor. Developmental Biology 199 150-163. 52. Neale DM, Mor G 2005 The role of Fas mediated apoptosis in preeclampsia. Journal of Perinatal Medicine 33 471-477. 53. Noris M, Perico N, Remuzzi G 2005 Mechanisms of disease: Pre-eclampsia. Nature Clinical Practice Nephrology 1 98-114; quiz 120. 54. Ordi J, Casals G, Ferrer B, Creus M, Guix C, Palacin A, Campo E, Balasch J 2006 Uterine (CD56+) natural killer cells recruitment: association with decidual reaction rather than embryo implantation. American Journal of Reproductive Immunology 55 369-377. 55. Parham P 2004 NK cells and trophoblasts: partners in pregnancy. The Journal of Experimental Medicine 200 951-955.
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56. Parr MB, Tung HN, Parr EL 1986 The ultrastructure of the rat primary decidual zone. American Journal of Anatomy 176 423-436. 57. Peel S, Bulmer D 1977 Proliferation and differentiation of trophoblast in the establishment of the rat chorio-allantoic placenta. Journal of Anatomy 124 675-687. 58. Peel S, Stewart I, Bulmer D 1979 Metrial gland cells in deciduomata of pseudopregnancy. Journal of Anatomy 129 21-30. 59. Pijnenborg R, Robertson WB, Brosens I, Dixon G 1981 Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta 2 71-91. 60. Pijnenborg R, Bland JM, Robertson WB, Brosens I 1983 Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta 4 397-413. 61. Pijnenborg R, Vercruysse L, Hanssens M 2006 The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 27 939-958. 62. Pijnenborg R, Vercruysse L, Brosens I 2011 Deep placentation. International Journal of Gynecology and Obstetrics 25 273-285. 63. Pijnenborg R, Vercruysse L, Carter AM 2011 Deep trophoblast invasion and spiral artery remodelling in the placental bed of the chimpanzee. Placenta 32 400-408. 64. Redline RW, Lu CY 1989 Localization of fetal major histocompatibility complex antigens and maternal leukocytes in murine placenta. Implications for maternalfetal immunological relationship. Laboratory Investigation 61 27-36. 65. Reinius S 1967 Ultrastructure of blastocyst attachment in the mouse. Zeitschrift für Zellforsch und Mikroskopische Anatomie 77 257-266. 66. Rielland M, Hue I, Renard JP, Alice J 2008 Trophoblast stem cell derivation, crossspecies comparison and use of nuclear transfer: new tools to study trophoblast growth and differentiation. Developmental Biology 322 1-10. 67. Robb L, Dimitriadis E, Li RL, Salamonsen LA 2002 Leukemia inhibitory factor and interleukin-11: cytokines with key roles in implantation. Journal of Reproductive Immunology 57 129-141. 68. Rossant J 2001 Stem cells from the Mammalian blastocyst. Stem Cells 19 477-482. 69. Rossant J, Cross JC 2001 Placental development: lessons from mouse mutants. Nature Reviews Genetics 2 538-548. 70. Salker M, Teklenburg G, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Macklon NS, Brosens JJ 2010 Natural selection of human embryos: impaired decidualization of endometrium disables embryomaternal interactions and causes recurrent pregnancy loss. PLoS One 5 e10287. 71. Screen M, Dean W, Cross JC, Hemberger M 2008 Cathepsin proteases have distinct roles in trophoblast function and vascular remodelling. Development 135 3311-3320. 72. Sibley CP 1994 Review article: mechanisms of ion transfer by the rat placenta: a model for the human placenta? Placenta 15 675-691.
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73. Simmons DG, Cross JC 2005 Determinants of trophoblast lineage and cell subtype specication in the mouse placenta. Developmental Biology 284 12-24. 74. Soares MJ 1987 Developmental-Changes in the Intraplacental Distribution of Placental-Lactogen and Alkaline-Phosphatase in the Rat. Journal of Reproduction and Fertility 79 93-98. 75. Soares MJ, Chapman BM, Rasmussen CA, Dai G, Kamei T, Orwig KE 1996 Differentiation of trophoblast endocrine cells. Placenta 17 277-289. 76. Stewart I, Peel S 1978 The differentiation of the decidua and the distribution of metrial gland cells in the pregnant mouse uterus. Cell and Tissue Research 187 167-179. 77. Tachi S, Tachi C, Lindner HR 1970 Ultrastructural Features of Blastocyst Attachment and Trophoblastic Invasion in Rat. Journal of Reproduction and Fertility 21 37-56. 78. Tantbirojn P, Crum CP, Parast MM 2008 Pathophysiology of placenta creta: the role of decidua and extravillous trophoblast. Placenta 29 639-645. 79. Teixeira NA, O’Grady JE 1992 Two forms of decidualization-associated protein and their physicochemical relationship with acute-phase alphamacrofetoprotein in rats. Journal of Reproduction and Fertility 94 501-509. 80. Teklenburg G, Salker M, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Brosens JJ, Macklon NS 2010 Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation. PLoS One 5 e10258. 81. Tessier C, Prigent-Tessier A, Ferguson-Gottschall S, Gu Y, Gibori G 2001 PRL antiapoptotic effect in the rat decidua involves the PI3K/protein kinase B-mediated inhibition of caspase-3 activity. Endocrinology 142 4086-4094. 82. Tessier C, Prigent-Tessier A, Bao L, Telleria CM, Ferguson-Gottschall S, Gibori GB, Gu Y, Bowen-Shauver JM, Horseman ND, Gibori G 2003 Decidual activin: its role in the apoptotic process and its regulation by prolactin. Biology of Reproduction 68 1687-1694. 83. Vercruysse L, Caluwaerts S, Luyten C, Pijnenborg R 2006 Interstitial trophoblast invasion in the decidua and mesometrial triangle during the last third of pregnancy in the rat. Placenta 27 22-33. 84. Ye W, Zheng LM, Young JD, Liu CC 1996 The involvement of interleukin (IL)-15 in regulating the differentiation of granulated metrial gland cells in mouse pregnant uterus. The Journal of Experimental Medicine 184 2405-2410. 85. Yee GM, Kennedy TG 1993 Prostaglandin E2, cAMP and cAMP-dependent protein kinase isozymes during decidualization of rat endometrial stromal cells in vitro. Prostaglandins 46 117-138. 86. Zybina TG, Stein GI, Zybina EV 2011 Endopolyploid and proliferating trophoblast cells express different patterns of intracellular cytokeratin and glycogen localization in the rat placenta. Cell Biology International 35 649-655.
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REVIEW
The rat as an animal model for fetoplacental development: a reappraisal of the post-implantation period Bruno M. Fonseca, Georgina Correia-da-Silva, Natércia A. Teixeira1 Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto and Institute for Molecular and Cell Biology (IBMC), Porto, Portugal
Received: 5 August 2011; accepted: 25 March 2012
SUMMARY Following implantation in rodents, the uterine stromal broblasts differentiate into densely packed decidual cells. This process, called decidualization, is wellorchestrated and progresses both antimesometrially and mesometrially, creating two regions with distinctive cellular morphologies. In addition, subsequent placental development is dependent on the invasion of the trophoblast, the process intimately linked to the endometrial tissue remodelling and depending largely on the environment created by the decidua; this phenomenon is crucial for the establishment and maintenance of pregnancy. The key mechanisms underlying the maternal tissue remodelling and trophoblast invasion remain poorly understood. The rat, just like human beings, exhibits a highly invasive type of placental development, the haemochorial placentation. For obvious ethical reasons, the studies of endometrial tissue remodelling throughout 1
Corresponding author: Faculdade de Farmácia da Universidade do Porto - Laboratório de Bioquímica Rua de Jorge Viterbo Ferreira No 228, 4050–313 Porto, Portugal; e-mail: [email protected]
Copyright © 2012 by the Society for Biology of Reproduction
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pregnancy in humans are greatly limited. Although the rat differs somewhat from humans with regards to the implantation process, it is an appropriate model for studying the mechanisms of decidualization as well as subsequent remodelling of the uterine tissues and fetoplacental development. As decidual remodelling is very closely linked to placentation and the maternalfetal interactions in the rat show several important similarities to human placentation, the morphological alterations occurring during the postimplantation period in the rat have been addressed in the present review. Reproductive Biology 2012 12 2: 97–118.
INTRODUCTION At implantation, the uterus is receptive to blastocysts (“window of implantation”) and is under the inuence of ovarian steroid hormones. In mice and rats, implantation occurs between days 4 and 5 of pregnancy, considering the rst day of pregnancy as the day on which a vaginal plug (mouse) or spermatozoa (rat) are present in the vagina [50, 65]. Following implantation, the endometrial broblast-like stromal cells proliferate and differentiate into decidual cells. In women, decidualization occurs spontaneously during the late secretory phase of the menstrual cycle, while in rodents decidualization occurs in response to implantation or an articial stimulus; in the latter case, it gives rise to the deciduoma. The morphology of the decidua changes with the advancement of gestation. Initially, it develops in the antimesometrial pole of the uterine lumen, forming the antimesometrial decidua. After the attainment of full development, it regresses to give room for the growing conceptus. Concomitantly with the regression of the antimesometrial decidua, the stromal cells from the mesometrium begin to differentiate into decidual cells to form the mesometrial decidua. The latter provides an affable environment for placental growth and degenerates concurrently with the invasion of trophoblast cells, supporting the establishment of the placental bed. In the present review we describe the remodelling of rat uterine tissues during gestation. We present detailed information
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Figure 1. The timeline of main events during the rat gestation. After fertilization, the sequence of events is similar among different rodent species. In response to implantation, which occurs around day 5 in rats, the antimesometrial decidua develops and subsequently regresses by day 12 (decidua capsularis). The mesometrial decidua develops concurrently with trophoblast invasion to initially form the choriovitelline placenta, which gives rise to the denitive placenta.
on the maternal-fetal interactions with the special emphasis on decidual establishment and regression. Moreover, as trophoblast invasion in the rat proceeds along two different pathways, interstitial and endovascular, we will describe this phenomenon, which shares a number of similarities with human trophoblast invasion. Figure 1 depicts the main events during rat gestation and times at which they occur. Spatio-temporal characterization of rat antimesometrial decidua Successful establishment of pregnancy is dependent upon the proper growth and development of the uterine endometrium for blastocyst implantation. The uterus must be hormonally prepared and then a stimulus, normally provided by the embryo, triggers the process of decidualization. Stromal broblasts in the endometrium proliferate and differentiate into decidual cells, which involves characteristic changes in cell morphology [1]. Although the molecular mechanisms associated with decidualization remain poorly understood, numerous factors have been implicated in the regulation of this process. Among these are ovarian hormones and other locally synthesized molecules such as interleukin 11 (IL-11; [8]), relaxin [32], prostaglandin E2 (PGE2; [42]), leukemia-inhibitory factor (LIF; [67]), and activin A [82].
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In addition, recent evidence suggests that decidual cells are important players in the recognition of implanting “competent” embryos [7, 70]. Although the embryonic factors BMP2, WNT have been suggested to act on the decidual cells and the JAK/STAT and cAMP dependent pathways have been reported to be activated in these cells, the exact mechanisms involved remains unknown [30, 46, 85]. Following the attachment of the blastocyst, apoptosis of the luminal epithelial cells and decidual cell reaction at the site of implantation occur. During the initial stages of hatched blastocyst invasion, trophoblast cells erode the uterine epithelial cells, leaving the basement membrane temporarily intact [77]. Once stimulated, the stromal broblasts from the subepithelial antimesometrium zone undergo differentiation, giving rise to the primary decidual zone [24]. Primary decidual cells are large, with basophilic cytoplasm, two or more nuclei, and abundant endoplasmic reticulum, mitochondria, lysosomes and well-developed Golgi complexes [56]. These cells express alkaline phosphatase [29] and their appearance is associated with a signicant increase in DNA, RNA and protein content indicating high decidual growth dynamics [6]. Concomitant with the appearance of the primary decidual zone, the surrounding stromal cells undergo mitosis heralding the differentiation into antimesometrial decidual cells, which results in the formation of the secondary decidual zone. By day 8 of gestation, decidualization spreads out to the basal region of the endometrium adjacent to the muscular layer (g. 2; [77]). The formation of decidua involves a tight equilibrium between decidual cell proliferation and death, which is crucial for the maintenance of pregnancy. In vivo studies demonstrated that proliferation was intense in the rst period of decidual cell reaction but it declined at the later stages [15]. In fact, the antimesometrial decidua reaches its maximum development on day 10 of pregnancy (fig. 2). By day 12, the regression of decidua is complete and it forms the decidua capsularis (g. 2; [11]). Degradation of the antimesometrial decidua occurs primarily by programmed cell death, as previously demonstrated by immunoreactive caspase-3 and TUNEL positive staining detected as early as day 8 of pregnancy [15]. However, the markers of necrosis were also detected during the regression of the antimesometrial decidua. It was suggested that apoptosis is followed
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Figure 2. An illustration of rat uterine tissue architecture from days 8 to 12 of pregnancy. The blastocyst implants on the antimesometrial side of the uterus and decidual cells develop to form the primary decidual cell zone. On day 8, the antimesometrial decidua (AMD) forms and on day 10, AMD is fully developed and decidualization is occurring in the mesometrium (MD). By day 12, trophoblast cells of the ectoplacental cone (the primordial placenta) have started to penetrate into the mesometrial decidua. By this time, the antimesometrium has completely regressed, being now referred to as decidua capsularis (DC), and the mesometrial triangle can now be observed.
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by secondary necrosis, which triggers the release of cellular constituents activating the inammatory processes [15]. Using the pseudopregnancy model, Tessier et al reported the expression of active caspase-3 in the decidua only after day 10, suggesting that the presence of the conceptus may accelerate the initiation of apoptosis in this tissue [81]. On day 9 of gestation, the brinoid capsule, a structure of condensed tissue, appears externally to the antimesometrial decidua (fig. 2). Between the fibrinoid capsule and the innermost smooth muscle layer of the uterus, there is a thin layer of non-decidualized stroma containing sporadic endometrial glands, which secrete various substances required for survival and development of the conceptus [35]. Although the precise role of the endometrial glands during pregnancy is not known, they appear to be required both during the peri-implantation period and placental development [5]. At the time of the brinoid capsule formation, endothelial cells in the lateral wings of the decidua proliferate rapidly, which results in the formation of large venous sinusoids. These endothelial cells are in intimate contact with decidual cells to facilitate the transfer of nutrients from the decidua to adjacent blood vessels [28]. This region, between the lateral sinusoids and antimesometrial decidua, contains the cells with high glycogenic content and is commonly known as the lateral decidua or the glycogenic wing area (g. 2; [76]). Rat mesometrial decidua: remodelling of uterine tissues during fetoplacental development Mesometrial decidual cells appear in the central region of the endometrium few days after antimesometrial decidual cell reaction as a result of the differentiation of cells from the mesometrial pole. These cells are smaller than those in the antimesometrial decidua, irregular in shape, and they contain a single nucleus. By day 12 of gestation, the mesometrial decidua is fully differentiated. With time, there is an enlargement of adjacent blood vessels and the central zone of the mesometrial decidua is invaded by the trophoblast cells of the ectoplacental cone, resulting in the formation of the denitive placenta by day 14 (g. 3). From days 14 to 16, the decidua undergoes apoptotic
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regression [15]. By day 19, it is conned to a marginal uterine region, forming the maternal component of placenta-the decidua basalis (fig. 3). In fact, the degeneration and disappearance of both antimesometrial and mesometrial decidua is a unique feature of rat placentation. During the process of decidualization, a set of specialized leukocytes, the uterine natural killer (uNK) cells, populate the decidua. These leukocytes are phenotypically and functionally different from peripheral NK cells. Although the exact mechanisms involved in the recruitment of uNK to the decidua during pregnancy are still unknown, it seems to be hormonally-controlled and involves IL-15 [84]. Moreover, as demonstrated in the deciduoma model, the colonization of the decidua by uNK cells seems to be independent of the presence of the implanting embryo [38, 54, 58]. It is, however, well documented that the conceptus plays a critical role in regulating the number and function of uterine uNK cells during decidualization [38]. With the progression of pregnancy, uNK cells become more abundant and acquire a granular phenotype. The characteristic membrane-bound granules contain perforin and granzyme B, which control the trophoblast invasion and maternal vascular remodelling [13, 45, 55]. After day 15 of pregnancy, uNK cells undergo degranulation and their number decreases as a result of an active process of programmed cell death [33]. By day 12, uNK cells are also present in the mesometrial triangle, a zone between the circular and longitudinal uterine muscle layers. Often referred to as the “metrial gland” (an obsolete term), this region enlarges with the progression of pregnancy and appears to be an extension of the mesometrial decidua [19, 20]. The mesometrial triangle also comprises the entry point for blood vessels, supplying both the placenta and fetus. Besides numerous uNK cells clustered around the vessels, the metrial gland also contains the endometrial stromal and trophoblast cells. It is apparent that decidualization involves a temporal and spatially co-ordinated sequence of events with the differentiation of various cell types occurring in different regions of the gravid uterus and at different times. The antimesometrial decidua has characteristics of an endocrine organ, secreting a variety of hormones and growth factors such as decidual prolactin-like hormones, follistatin, activin and transforming growth
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factors [36]. On the other hand, the mesometrial decidual tissue secretes high levels of 2-macroglobulin (2-MG; [79]). This glycoprotein has the ability to inhibit all types of proteases and bind numerous cytokines and growth factors. In addition, the mesometrial decidua also secretes other factors such as insulin-like growth factors (IGFs; [14, 21]) and IL-6 [23]. The progressive decidualization of the mesometrial stroma prepares the uterine lining for the presence of the invasive trophoblast. In fact, the temporal and spatial patterns of mesometrial decidua regression are closely associated with the pattern of trophoblast invasion and the resulting vascular remodelling. Placental development in the rat The placenta is a specialized pregnancy-specic structure that develops concurrently with the embryo and is composed of numerous cell types. Among these are the trophoblast cells, the earliest extra-embryonic cells to differentiate from the mammalian embryonic cells. Although the general structure of the placenta varies considerably among mammalian species, the basic morphology, main cell types and functions as well as the molecular mechanisms underlying placental development are conserved across species [47]. In contrast, the specic hormones governing the maternal recognition of pregnancy are different. The trophoblast in humans and other primates produces a chorionic gonadotropin that directly stimulates the secretion of luteal progesterone, whereas the placenta in rodents produces lactogens [31]. The trophoblast cells play a primary role in protecting the embryo from noxious deleterious substances, programming the maternal support and preventing the maternal immune rejection. They also ensure an appropriate bidirectional nutrient/waste ow required for normal growth and maturation of the embryo. Thus, through creating the milieu in which the embryo and fetus develop, placentation is fundamental for assuring successful pregnancy and it also impinges on the postnatal health status. Although several studies attempted to corroborate the molecular pathways underlying the development of the placenta, our current knowledge is mainly based on mouse studies involving transgenic animals exhibiting the defects
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Figure 3. Rat implantation unit during fetoplacental development. On day 14, the placenta is fully developed and decidual regression is apparent in both the mesometrial and antimesometrial decidua. The metrial gland, or mesometrial triangle, appears as an extension of the mesometrial decidua. By the end of pregnancy, and particularly on day 19, just a layer of few decidual cells remains to give space for placental growth.
in placental development [4, 17, 26, 69]. Several genes were identied as critical for normal placental development and function. These include the genes for cystatin C [3], cathepsins [71], plasminogen activator inhibitor type 1 (PAI-1) and 2 (PAI-2; [27]), and 2-MG [25]. The haemochorial placentation is the most invasive form of placentation, with the penetration of trophoblast cells into the uterine compartment where they establish direct contact with maternal vasculature and with extensive remodelling of the spiral arteries. The blood vessels lose their elastic lamina and smooth muscle layer, and consequently the responsiveness to circulating vasoactive compounds [61, 62]. This type of placentation occurs in humans and most rodents. Various studies of the depth of trophoblast invasion
Figure 4. Schematic representation of rat chorioallantoic placenta. A schematic of the basic structures comprising the implantation unit in mid-pregnancy: myometrium, metrial gland, decidua and placenta. Note the trophoblast lineages and their location within two distinct structures of the placenta: the basal (giant trophoblast cells, spongiotrophoblast cells and glycogenic cells) and the labyrinth zone (giant trophoblast cells and syncytiotrophoblast cells).
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during placentation in mice revealed significant differences when compared to the rat. In fact, in the rat both endovascular and interstitial trophoblast invasion are observed. In the mouse, trophoblast invasion into the maternal spiral arteries is limited to the decidual compartment [2, 49] and the interstitial invasion does not reach the mesometrial triangle [64]. Considering those differences, the rat is the most appropriate rodent model for the studies of extensive myometrial invasion as seen in humans [62]. Moreover, histological studies revealed important similarities between rats and humans with regards to remodelling of the spiral arteries [9, 83]. Although the placental development in the rat starts immediately after the attachment of the blastocyst to the uterine epithelium, the denitive placenta develops from the ectoplacental cone. Therefore, the two placental structures can be distinguished: the choriovitelline and chorioallantoic placenta [75]. The choriovitelline placenta is transitory, being physiologically significant between implantation and mid-gestation, and is comprised of a single differentiated trophoblast cell type, the giant trophoblast cells. The chorioallantoic placenta represents the definitive placenta and is comprised of four differentiated trophoblast cell phenotypes, namely the trophoblast giant cells, spongiotrophoblast cells, glycogenic trophoblast cells, and syncytiotrophoblast cells (g. 4; tab. 1). Two morphologically and functionally distinctive placental regions, the basal and labyrinth zones, can be seen in the chorioallantoic placenta [74]. The basal zone, also known as the junctional zone, is located between the uterine decidual tissue and the labyrinth zone. It contains giant trophoblast cells, localized at the maternal-placental interface, spongiotrophoblast and glycogenic trophoblast cells. The labyrinth zone is positioned at the fetal interface, being comprised by giant trophoblast cells, syncytiotrophoblast cells, fetal mesenchymal cells and vasculature. The majority of cell lineage studies have been carried out using mouse placenta, although there is sufficient evidence to suggest that the origin of placental cells in mice is similar to that in the rat [73]. All trophoblast cell subtypes differentiate from the trophectoderm layer of the blastocyst; however, they can be distinguished on the basis of their morphology, intraplacental location, and the pattern of gene
Spongiotrophoblast
Syncytiotrophoblast
Invasion of decidua [18]
Immunological, endocrine and structural functions [40]
Present only in the labyrinth zone - fetal interface [57]
Nutrient transport [72]
Unknown
Invasion of decidua [86]
Expands to decidua but also into spiral arteries [2, 86]
Invasiveness
Invasive and endocrine functions [37]
Functions
Present only Energy reservoir [22] in the basal zone [57]
Present only in the basal zone [57]
Derived from the ectoplacental cone [10]
Giant trophoblast
Derived from the ectoplacental cone [10] Fusion of cytotrophoblast cells [16]
The choriovitelline placenta and in both zones of the chorioallantoic placenta [57]
Derived from the ectoplacental cone; endoreduplication [10, 51]
Glycogenic trophoblast
Location
Differentiation
Cell type
Table 1. Main features of various types of differentiated rat trophoblast cells
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expression [48, 66, 68]. The term “giant trophoblast cells” derives from their enormous size, which is a consequence of genome amplication. The trophoblast cells undergoing differentiation into the giant cells exit the proliferative cell cycle and enter a genome-amplifying endocycle, also known as endoreduplication [39]. The giant trophoblast cells are analogous to human extravillous cytotrophoblast cells and exhibit characteristic invasive activity. In addition, these cells are the most important endocrine cells of the placenta that promote both local and systemic physiological adaptations in pregnancy [75]. Because of the difference in time of trophoblast cell differentiation, the giant trophoblast cells are referred to as the “primary” or “secondary” cells in the choriovitelline and chorioallantoic placenta, respectively. While the primary giant cells are formed from the trophectoderm layer of the blastocyst during implantation, the secondary giant cells arise after implantation around the margins of the ectoplacental cone [18, 37]. The spongiotrophoblast cells exhibit important endocrine functions and, as they are situated immediately beneath the giant trophoblast cells, they may also support the development of the labyrinth zone [18]. The placenta accumulates glycogen, and this is most marked in rodents, in cells called the glycogenic trophoblast cells. They are embedded in the spongiotrophoblast and are considered a potential energy reservoir [22]. The spongiotrophoblast cells and glycogenic trophoblast cells originate from the same placental structure as the giant trophoblast cells, the ectoplacental cone [10]. The syncytiotrophoblast cells are multinucleated and are formed by the fusion of the trophoblast progenitor cells, the cytotrophoblast cells. They have been implicated in bidirectional transport of nutrients and waste between maternal and fetal compartments [72]. Prior to placentation, the outer cells of the blastocyst (trophoectoderm) breach the uterine epithelium and penetrate the basement membrane and underlying connective tissue. Subsequently, a more intense invasion occurs, involving both vascular and endometrial remodelling. Endovascular invasion is the expansion of trophoblast cells into the spiral artery located in the uterine decidua. Endovascular trophoblast cells replace endothelial cells and appear as a collar of only a few cells in thickness surrounding
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the vessel [9]. The interstitial trophoblast invasion spans the penetration of trophoblast cells through the uterine stroma up to the metrial gland [59]. In the rat, the interstitial trophoblast invasion is similar to that in humans in that it extends beyond the decidua during the last third of gestation [12, 83]. Trophoblast invasion in mice is more limited and almost entirely conned to the uterine mesometrial decidua [4, 12, 60]. The trafcking of trophoblast cells from the chorioallantoic placenta into maternal tissues is well dened. Interstitial invasion follows vascular invasion. On day 16 of gestation, interstitial invasion is already significantly advanced and it continues throughout pregnancy beyond the decidua, resulting in the colonization of the mesometrial triangle by the end of pregnancy [4, 83]. It has been suggested that uNK cells are directly involved in the migration of trophoblast cells into the uterine stroma and/or myometrium [4]. In fact, the invading trophoblast cells occupy the locations previously occupied by uNK cells, indicating a regulatory role for uNK cells in trophoblast invasion. This hypothesis is further supported by the defects in mesometrial blood vessel remodelling and an alteration in the timing of trophoblast cell invasion observed in uNK decient mice [12]. Successful pregnancy requires the balance between all the factors involved. Synchronization between uNKs, invasive trophoblast cells and decidual cells is crucial to produce a suitable environment to ensure immune tolerance and sufcient vascular and decidual remodelling throughout pregnancy in order to establish an adequate nutrient transfer to the growing embryo. Abnormal placentation and its consequences for human pregnancy In mammals, the placenta is an essential interface between the maternal and the fetal circulation formed to carry O2-rich blood and nutrients to the developing fetus. It is now clear that a disturbance of the invasion of trophoblast cells (fetal origin) into the uterine tissues (maternal tissues) can result in various clinical problems. Thus, it is important to elucidate the underlying mechanisms of these processes in normal pregnancy using, for ethical reasons, an animal model. In addition to the same type of placentation, an animal model should have a deep trophoblast invasion
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comparable to that in humans. The non-human primates with a deep trophoblast invasion are the chimpanzee and gorilla that cannot be used as experimental animals, whereas the rhesus monkey and baboon exhibit a lesser interstitial invasion with only restricted endovascular invasion into the decidua [23, 63]. The rodents posses haemochorial placentae, and, in the case of the rat, a deep trophoblast invasion occurs with remodelling steps of the spiral artery that are similar to those in humans [80]. However, due mainly to the lower number of spiral arteries, the rat is not a good model to study placentation disorders in humans. The invasion of the trophoblast transforms uterine spiral arteries into open and straight vessels, resulting in a dramatic decline in the uterine arterial resistance. However, as a result of excessive restraint of trophoblast cells by the decidua, an inadequate trophoblast invasion into arteries and uterine wall can occur leading to decient blood supply and consequently lower levels of O2 delivered to the developing fetus. The main problems stemming from the inefcient blood supply are fetal prematurity, fetal growth restriction and preeclampsia [34, 41]. For example, during the preeclamptic pregnancy, trophoblast invasion into maternal tissues is abnormally shallow and uterine spiral artery remodelling is incomplete. Normally, the programmed cell death occurs in maternal tissues in order to facilitate trophoblast access to maternal vessels. However, this activity is markedly reduced during preeclampsia resulting in the formation of an arteriolar system with high resistance [52, 53]. On the other hand, it is also extremely dangerous if an excessive penetration of the uterine wall by trophoblast cells occurs as a result of an absent or decient decidua. An overly extensive trophoblast invasion results in the placenta creta, which is a cause of a massive postpartum haemorrhage and commonly leads to emergency hysterectomy [44]; without medical intervention, this condition frequently results in maternal death from haemorrhage. The exact pathogenesis of the placenta creta is unknown but it has been suggested to result from a primary deciency of decidua, abnormal maternal vascular remodelling, excessive trophoblast invasion, or a combination of these factors [43, 78]. Although the primary cause of some miscarriages cannot be clearly dened, the understanding of all mechanisms involved in the uterine-trophoblast cross-talk is crucial. Any factor disrupting
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the balance in the interactions between trophoblast and uterine tissue can have a deleterious effect on gestation.
GENERAL DISCUSSION Pregnancy involves complex alterations in the structure and function of the uterus both before and after implantation. Decidualization constitutes the primary process responsible for uterine remodelling during pregnancy, though the specic functions of the decidual cells are still an intriguing and unresolved issue. The rat, due to its supercial implantation, is not an appropriate animal model to study this process, but it is a good model for studying the mechanisms of decidualization and remodelling of the uterine spiral arteries in humans. The main difference between rodent and human decidualization is that the process starts spontaneously in humans, whereas in rodents decidualization occurs only in response to the blastocyst or an articial stimulus; the latter ultimately results in the deciduoma. As pregnancy progresses, decidual tissue regresses and, concomitantly, the formation of the placenta and invasion of trophoblast cells into maternal tissues occur. In comparison to primates, rodents have a shorter gestation period with a fully functional placenta present for only one week and a low number of spiral arteries. In spite of these differences, rodent species resemble humans in that they exhibit haemochorial placentation and, in the case of rats, a pronounced decidual cell reaction and trophoblast invasion, which require a strict interaction between the maternal blood vessels and placenta [1, 9, 60]. The mouse is a frequently used species for either decidua or fetoplacental development studies, mainly because of numerous advancements in the gene-targeting technology. However, in contrast to humans and rats, the mouse uNK cells seem to be more important for arterial remodelling than trophoblast cells. In addition, the interstitial invasion in mice is not as deep as in the rat. Trophoblast invasion in the rat proceeds along two different pathways, interstitial and endovascular [9, 83], similar to human beings. Moreover, the depth of endovascular trophoblast invasion and vascular
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remodelling of spiral arteries in the rat are similar to those in humans [9, 60]. Therefore, the rat constitutes a good experimental model for the studies of trophoblast invasion, which is intimately associated with the remodelling of maternal tissues during the normally progressing pregnancy. However, as mentioned above, it is not an appropriate model to study human pregnancy disorders. Lastly, the environment created by decidua is crucial for the maintenance of pregnancy and it pre-determines the extension of trophoblast invasion observed in both rats and humans. Hence, the abnormalities in either the establishment or remodelling of decidual tissue may have a negative impact on normal gestation and are commonly associated with some pregnancy-related pathological conditions such as preeclampsia or spontaneous abortions.
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