The Early Stages of Implantation and Placentation in the Pig

Johnson, Gregory A.; Bazer, Fuller W.; Seo, Heewon

doi:10.1007/978-3-030-77360-1_5

Gregory A. Johnson⁹,
Fuller W. Bazer¹⁰ &
Heewon Seo⁹

Part of the book series: Advances in Anatomy, Embryology and Cell Biology ((ADVSANAT,volume 234))

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Abstract

Pregnancy in pigs includes the events of conceptus (embryo/fetus and placental membranes) elongation, implantation, and placentation. Placentation in pigs is defined microscopically as epitheliochorial and macroscopically as diffuse. In general, placentation can be defined as the juxtapositioning of the endometrial/uterine microvasculature to the chorioallantoic/placental microvasculature to facilitate the transport of nutrients from the mother to the fetus to support fetal development and growth. Establishment of epitheliochorial placentation in the pig is achieved by: (1) the secretions of uterine glands prior to conceptus attachment to the uterus; (2) the development of extensive folding of the uterine–placental interface to maximize the surface area for movement of nutrients across this surface; (3) increased angiogenesis of the vasculature that delivers both uterine and placental blood and, with it, nutrients to this interface; (4) the minimization of connective tissue that lies between these blood vessels and the uterine and placental epithelia; (5) interdigitation of microvilli between the uterine and placental epithelia; and (6) the secretions of the uterine glands, called histotroph, that accumulate in areolae for transport though the placenta to the fetus. Placentation in pigs is not achieved by invasive growth of the placenta into the uterus. In this chapter, we summarize current knowledge about the major events that occur during the early stages of implantation and placentation in the pig. We will focus on the microanatomy of porcine placentation that builds off the excellent histological work of Amoroso and others and provide a brief review of some of the key physiological, cellular, and molecular events that accompany the development of “implantation” in pigs.

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Implantation and Establishment of Pregnancy in the Pig

Placental accommodations for transport and metabolism during intra-uterine crowding in pigs

Article Open access 15 December 2014

Early Syncytialization of the Ovine Placenta Revisited

Keywords

1 Introduction: Basic Definition for Epitheliochorial Placentation

Placentation is epitheliochorial in pigs, as uterine endometrial luminal epithelium (LE) remains intact throughout pregnancy. Porcine placental trophectoderm/chorion cells directly attach to the uterine LE, and these two epithelia serve as the conduit for maternal hemotrophic support for conceptus growth and development (Bjorkmann 1973). Amoroso stated that “In its histological structure the epitheliochorial placenta is exceeding simple… .with the pig as exhibiting structurally the simplest type of placenta” (Amoroso 1952). Epitheliochorial placentation is less intimate than other types of placentation because both the uterine LE and the chorionic epithelium remain intact. The result is a significant barrier to the transfer of nutrients from the uterine vasculature to the placental vasculature. A nutrient in a subepithelial uterine capillary must pass through the cytoplasm and basement membrane of the endothelial cell of the uterine capillary. It must then pass across the remaining stromal connective tissue. The nutrient then must pass through the basement membrane and cytoplasm of the uterine LE cell, through the cytoplasm and basement membrane of the chorionic epithelial cell, across the remaining allantoic connective tissue, and through the basement membrane and cytoplasm of the endothelial cell of the allantois (see Fig. 1). Although simplistic in microscopic structure, epitheliochorial placentation and the macroscopic classification of “diffuse” characteristic of pigs are not primitive and have evolved from a more invasive placental type, hemochorial/endotheliochorial, and discoid (Wildeman et al. 2006). Indeed, although it could be inferred that the noninvasive types of placentation are the least efficient because there are more physical barriers to limit the movement of nutrients from mother to fetus, the newborn pig is relatively mature compared to the newborn of a mouse or human. Epitheliochorial placentation has arisen evolutionarily in three distinct mammalian lineages and is present in pigs, horses/donkeys, camels, some whales and primates, and in multiple other species across different genera (Amoroso 1952; Wildeman et al. 2006).

2 Uterine Histoarchitecture and Early Conceptus Development

The pig uterine wall differentiates embryologically from the Mullerian ducts into the endometrial and myometrial compartments (Mossman 1937). The myometrium is composed primarily of smooth muscle cells and vascular elements, and bundles of smooth muscle fibers are organized into inner circular and outer longitudinal layers. In contrast, the endometrium is a complex epitheliomesenchymal organ consisting of a simple columnar LE that overlays a thick lamina propria subdivided into upper stratum compactum and lower stratum spongiosum regions composed of stromal cells, immune cells, and vasculature. Invaginating downward from the LE are long branched and coiled tubular glands that traverse the lamina propria and are referred to as the glandular epithelium (GE) (Cooke et al. 1998) (see Fig. 2a). These various cell types communicate in an autocrine, paracrine and/or, endocrine manner to coordinate responses to hormones and cytokines (Geisert et al. 1982a). Examples of these complex responses include increasing uterine blood flow (Ford et al. 1982), facilitating water and electrolyte movement (Veldius et al. 1980), maternal recognition of pregnancy (Bazer and Thatcher 1977), receptivity to conceptus attachment for implantation (Keys and King 1980; Burghardt et al. 1997), and uterine secretory activity (Bazer 1975).

By 26 h after fertilization within the oviduct, the one-cell porcine ovum/zygote cleaves to form a two-cell embryo that, 22–30 h later, enters the uterus at the 4- to 8-cell stage. The blastocyst forms when early embryonic cells differentiate into the embryonic disc, trophectoderm, and extraembryonic endoderm. The blastocoel forms and there is continued development to a conceptus (Bazer and Johnson 2014) (Fig. 2b). Conceptuses “hatch” from the zona pellucida and begin to elongate. At hatching, the conceptuses are 0.5–1 mm diameter spheres, then increase in size to 2–6 mm by day 10 of pregnancy. They then undergo a morphological transition to large spheres of 10–15 mm diameter, then to 15 mm by 50 mm tubular forms, and then to l mm by 100–200 mm filamentous forms on day 11 (see Fig. 2b). Pig conceptuses elongate at 30–45 mm/h during the transition from tubular to filamentous forms, primarily by proliferation, morphological remodeling, and migration of the trophectoderm and endoderm. However, the subsequent growth and elongation of the conceptus by day 15 into 800–1000 mm length filaments is supported by the hyperplasia of trophectoderm cells. An elongation zone of densely packed endoderm and trophectoderm cells extends from the inner cell mass (ICM) to the tip of the blastocyst on day 10. Then, through alterations in microfilaments and junctional complexes of trophectoderm cells and formation of filopodia by endodermal cells, there is further rapid elongation of the 100–200 mm long conceptus to a conceptus of 800–1000 mm in length by day 16 of pregnancy. Each conceptus within the litter eventually achieves maximum surface area for contact between the trophectoderm and uterine LE to facilitate uptake of nutrients from uterine LE and uterine GE, the numbers of which increase, coincidentally, with elongation of the conceptuses (Bazer and Johnson 2014) (see Fig. 2c).

3 Select Hormones and Cytokines That Prepare the Uterus for Placentation

Much is known about the localization of genes and their regulation by hormones within the uterus and conceptus during implantation and early placentation in pigs (Johnson et al. 2009; Bazer and Johnson 2014; Waclawik et al. 2017). Progesterone dominates the uterine environment during the establishment of pregnancy in pigs, but other factors are required to maintain a successful pregnancy. These include the secretion of estrogens from the conceptus (Bazer and Thatcher 1977; Geisert et al. 2005; Johnson et al. 2009), secretions from the uterine LE and GE, i.e., histotroph (Bazer 1975; Johnson et al. 2009), and cellular remodeling at the interface between the uterine LE and trophectoderm during implantation and early placentation (Burghardt et al. 2002; Johnson et al. 2014). These complex events are orchestrated through, among others, five important cell signaling pathways for endocrine and paracrine communication between the ovary, conceptus, and uterus. These five hormones and cytokines are progesterone, estrogen, prostaglandins, interleukin-1 beta (IL1B), and the interferons [interferon gamma (IFNG) and interferon delta (IFND)].

Progesterone is considered to be the hormone of pregnancy, and it profoundly influences the uterus and placenta throughout pregnancy (Bailey et al. 2010a). Progesterone binds its nuclear progesterone receptor (PGR) to exert its actions on tissues. The PGR is encoded by a single gene and has three isoforms (A, B, and C) that differ in their activities (Wetendorf and DeMayo 2014; Mulac-Jericevic and Conneely 2004). PRB is expressed in the uterine LE, GE, stromal fibroblasts, and myometrium through day 7 of the estrous cycle and pregnancy; however, prolonged exposure to progesterone downregulates PGR in the uterine LE by day 10 and in the majority of the uterine GE by day 12 of both the estrous cycle and pregnancy. PGR protein expression in uterine LE returns by day 17 of the estrous cycle, but is not expressed by the uterine LE between days 25 and 85 of gestation. Expression of PGR is maintained in the deep GE throughout the estrous cycle and early pregnancy and continues to decrease, with almost no expression in GE by day 50 of pregnancy. PGR is, however, expressed in the necks of the uterine GE that empty into the uterine lumen proximal to areolae, suggesting that these regions of GE are excretory ducts that are not involved in the synthesis of histotroph, but serve as conduits for the passage of histotroph into the lumens of areolae. In contrast to the epithelia, PGR protein expression is maintained in the uterine stroma and myometrium through day 85 of gestation (see Fig. 3a) (Geisert et al. 1994; Sukjumlong et al. 2005; Steinhauser et al. 2017). One of the major roles of progesterone is to stimulate the production and secretion of histotroph, a complex mixture of hormones, growth factors, nutrients, and other substances that are required for growth and development of the conceptus (Knight et al. 1974; Roberts and Bazer 1988; Bailey et al. 2010b). The consensus is that the role of progesterone in producing histotroph is mediated via PGR; however, PGR is not expressed in uterine LE or GE that secrete histotroph during the peri-implantation period (Geisert et al. 1994; Sukjumlong et al. 2005; Steinhauser et al. 2017). It is clear that progesterone regulation of gene expression in the endometrium during the peri-implantation period is complex. Induction of genes in uterine GE may require that progesterone downregulates PGR, thereby eliminating PGR-dependent inhibition of expression of progesterone-regulated genes. However, another explanation is that progesterone induces the expression of genes in uterine via regulation of one or more paracrine-acting factors (progestamedins) produced by the PGR-positive stromal cells (White et al. 2005).

Pig conceptuses secrete estrogens on days 11 and 12 of gestation, and the consensus since 1977 has been that pregnancy recognition in the pig is the result of secretion of estrogens by conceptuses. Evidence to support this idea includes: (1) the uterine endometrium secretes PGF during both the estrous cycle and pregnancy; (2) pig conceptuses secrete estrogens which appear to be antiluteolytic; (3) PGF is secreted toward the uterine vasculature in an endocrine manner in cyclic gilts to induce luteolysis; and (4) in pregnant gilts PGF is into the uterine lumen in an exocrine manner where it is sequestered from the corpora lutea (CL) and/or metabolized to prevent luteolysis (Bazer and Thatcher 1977). It should be noted that prostaglandin E2 (PGE2), as well as lysophosphatic acid (LPA), are also proposed to have roles in pregnancy recognition signaling. Expression of PGE2 synthase by the trophectoderm and the endometrium decreases the production of PGF in favor of PGE2, and this supports maintenance of CL (Ziecik et al. 2008; Waclawik et al. 2017). However, when estrogen synthesis by the conceptus was ablated by targeting the aromatase (CYP19A1) gene utilizing CRISPR/Cas9 genome editing technology, estrogen was observed to not be essential for preimplantation conceptus development, conceptus elongation, or early CL maintenance. Estrogen was essential for maintenance of pregnancy beyond 30 days and its ablation disrupted a number of biological pathways (Meyer et al. 2019). Conceptus estrogens also modulate uterine gene expression (Geisert et al. 1982c; Johnson et al. 2009; Waclawik et al. 2017). The importance of estrogen to porcine pregnancy is underscored by the fact that exposure of the pregnant uterus to estrogen on days 9 and 10, prior to when pig conceptuses normally secrete estrogens, results in degeneration of all pig conceptuses by day 15 (Ross et al. 2007). Figure 3b illustrates that the timing of estrogen secretion by the conceptus correlates with the induction of osteopontin [OPN, also known as secreted phosphoprotein 1 (SPP1)] expression in the uterine LE, and administration of exogenous estradiol to ovariectomized pigs induces OPN in the uterine LE (White et al. 2005). The upregulation of OPN within uterine LE in close proximity to the implanting conceptus implies paracrine regulation of genes by conceptus estrogens. It is likely that effects of estrogen on the uterus are restricted to regions near the conceptus due to the metabolic activity of trophectoderm. The endometrium of pigs can convert estradiol to estrone and then converts estrone to estrone sulfate, which is biologically inactive and present in high concentrations within the uterine lumen of pregnant pigs (Flood 1974). In contrast, the trophectoderm has sulfatase that can restore the biological activity of estrogen, allowing for estrogen to upregulate genes such as OPN in the LE immediately juxtaposed to the implanting conceptus. To date, only a limited number of estrogen-stimulated genes have been localized in the pig endometrium (reviewed in Johnson et al. 2009), but the number increases each year.

In addition to the important role in maintaining the lifespan of the CL, prostaglandins function as autocrine and paracrine regulators of conceptus development and endometrial functions during the peri-implantation period in pigs. Pig conceptuses and endometrium actively secrete PGE2 and PGF (Geisert et al. 1982a; Guthrie and Lewis 1986) and express their receptors (Waclawik et al. 2017). PGF, acting through its receptor (PTGFR), induces endometrial expression of vascular endothelial growth factor-A (VEGFA), biglycan, matrix metalloprotease 9 (MMP9), IL1A, and transforming growth factor B3 (TGFB3), suggesting that PGF is involved in angiogenesis and tissue remodeling during early pregnancy (Kaczynski et al. 2016). Elevated quantities of PGE2 in the uterine lumen during the peri-implantation period stimulate conceptus PTGER2 expression, which increases the synthesis and secretion of estrogen and enhances integrin-dependent trophoblast adhesion via an estrogen receptor-dependent mechanism and MEK/MAPK signaling (Waclawik et al. 2017). Several studies have proposed that PGE2 is involved in maternal recognition of pregnancy in the pig (Christenson et al. 1994; Ford and Christenson 1991; Gregoraszczuk and Michas 1999). Intrauterine infusion of PGE2 into cyclic gilts from days 7 to 23 delays CL regression and extends the length of the estrous cycle (Akinlosotu et al. 1986). PGE2, produced by the conceptuses and endometrium, can be directly luteoprotective due to an increase in the PGE2/PGF ratio. The conceptus produces about twice as much PGE2 as PGF to successfully protect luteal cells from regression (Gregoraszczuk and Michas 1999). Indeed, Meyer et al. (2019) demonstrated that PGE can protect the CL through day 24 in the absence of conceptus estrogen synthesis. However, when CRISPR/Cas9 gene editing was used to knock out prostaglandin-endoperoxide synthase 2 (PTGS2) during the period of conceptus elongation in pigs, the conceptuses elongated and pregnancy was maintained through day 35 of gestation (Pfeiffer et al. 2020). It is possible that conceptus production of estrogen and IL1B may compensate for the lack of PTGS2-derived prostaglandins as estrogen and IL1B2 increase endometrial PTGS2 expression and production of PGE2 (Waclawik et al. 2009a, b; Franczak et al. 2010).

As porcine conceptuses elongate and begin to secrete estrogens, they also secret large amounts of IL1B (Tuo et al. 1996; Ross et al. 2003). There is an initial and acute rise in IL1B on day 12 of pregnancy followed by a precipitous decline in the expression and secretion of IL1B by pig conceptuses by days 15–18 of gestation as the conceptuses become fully elongated filaments. The expression of receptors for IL1B increases in the uterus and conceptus in tandem with this transient expression of IL1B by pig conceptuses, between days 12 and 15 of pregnancy (Ross et al. 2003). This suggests that IL1B from the conceptus may bind IL1B receptors on conceptus and/or uterine tissues to modify interactions between the uterus and conceptus in an autocrine and/or paracrine fashion. It should be noted that there are two transcripts for IL1B expressed in the pig trophectoderm, with both genes in close proximity on chromosome 3 (Mathew et al. 2015). The classical IL1B is expressed in macrophages and endometrial tissue, but another form of IL1B, IL1B2, appears to be unique to the elongating pig conceptus and is expressed just prior to attachment of the conceptus to the uterine LE. The specific roles of conceptus IL1B in trophoblast elongation and uterine receptivity have not been determined, but when CRISPR/Cas9 gene editing was used to knock out IL1B2 during the period of conceptus elongation in pigs, the conceptuses failed to elongate. The expression of the majority of conceptus developmental genes was not altered in these conceptuses, but the conceptuses expressed less aromatase and secreted less estrogen than normal (Whyte et al. 2018).

Antiviral activity in the uterine flushings of pigs peaks on days 14 and 25 of gestation, and the media from cultured porcine conceptuses exhibits significant antiviral activity (Mirando et al. 1990). The cause for this phenomenon is that the trophectoderm of pigs secretes a Type II IFN gamma (IFNG, 75% of antiviral activity in pig conceptus secretory proteins) and a Type I IFN delta (IFND, 25% of antiviral activity in pig conceptus secretory proteins) during the peri-implantation period (La Bonnardière et al. 1991; Lefèvre et al. 1998a). There is a 567-fold increase in the abundance of IFNG mRNA in porcine conceptuses between days 13 and 20 of gestation, during the transition of conceptuses from spherical to day 14 filamentous forms (Cencič and LaBonnardiėre 2002; Joyce et al. 2007a) (see Fig. 3c). In contrast, RT-PCR analysis is required to detect IFND mRNA in the day 14 conceptuses of pigs (Joyce et al. 2007a, b). Although IFN tau (IFNT), a Type I IFN, is the pregnancy recognition signal in ruminants (Spencer et al. 2007a), IFNG and IFND do not appear to be antiluteolytic in pigs (Harney and Bazer 1989; Lefèvre et al. 1998b). However, paracrine effects for porcine conceptus IFNs are suggested by: (1) localization of IFN receptors on endometrial epithelial cells (Lefèvre et al. 1998b); (2) increased secretion of PGE2 (Harney and Bazer 1989); (3) endometrial expression of several known IFN-responsive genes (reviewed in Johnson et al. 2009); and (4) modulation of uterine stromal and GE gene expression by the IFNs in conceptus secretory protein preparations (Joyce et al. 2007a, b, 2008). Figure 3c illustrates that stromal induction of mRNA for STAT1, an IFN responsive gene, correlates with IFNG and IFND secretion by the conceptus. Indeed, intrauterine infusion of conceptus secretory proteins, which contain IFNG and IFND, into pseudopregnant pigs, increased STAT1 as compared to intrauterine infusion of control proteins (Joyce et al. 2007a). Upregulation of STAT1 within the uterine stroma and GE in close proximity to the implanting conceptus implies paracrine regulation of genes by conceptus IFNs. It is somewhat surprising that initial increases in stromal STAT1 are restricted to sites of intimate association between the conceptus and uterus in pigs because the magnitude of IFNG production by pig conceptuses appears to be similar to IFNT synthesis and secretion by ovine conceptuses (Joyce et al. 2007a). STAT1 increases universally in the stroma and GE of pregnant sheep without regard to conceptus location within the lumen, presumably due to the high levels of secretion of IFNT by conceptuses (Pontzer et al. 1988; Joyce et al. 2005a). One explanation for the more limited expression of STAT1 in the pig uterus is that IFNG and IFND act synergistically to upregulate interferon responsive genes. Interactions between Type I and Type II IFNs to enhance their activities have been demonstrated previously (Decker et al. 1989). To date, only a limited number of IFN responsive genes have been localized in the pig endometrium and specific roles for these IFN responsive genes remain elusive (reviewed in Johnson et al. 2009).

4 Attachment of the Conceptus Trophectoderm to the Uterine LE (Implantation)

In strict terms, porcine conceptuses do not penetrate the uterine LE and invade into the uterine stroma; therefore, for pigs, the term “implantation” is a misnomer. Instead, pig conceptuses undergo a central type of implantation. Nevertheless, elongation and implantation are used to describe the initial stages of placental development in pigs. Although the duration of the preimplantation period is prolonged in the pig, and type of implantation differs from many other species, the initial stages of implantation/placentation are common across species and are characterized as the “Adhesion Cascade for Implantation” (Dantzer 1985; Guillomot 1995; Burghardt et al. 2002). This adhesion cascade begins with shedding of the zona pellucida, followed by elongation of the conceptus trophectoderm. The conceptus trophectoderm then orients itself to the uterine LE in a phase called “apposition,” followed by adhesion of the apical surface of trophectoderm to the apical surface of uterine LE, and development of interdigitating microvilli between trophectoderm and uterine LE (see Fig. 4a). As this cascade concludes, adhesion seamlessly transitions to the progressive formation of epitheliochorial placentation that supports fetal-placental development throughout pregnancy (Bazer and Johnson 2014).

During the peri-implantation period of pregnancy in eutherian mammals, the conceptus trophectoderm and uterine LE develop adhesion competency in synchrony to initiate an adhesion cascade within a restricted period of pregnancy termed the “Window of Receptivity” (Fazleabas et al. 2004; Spencer et al. 2007b; Bazer et al. 2011). This window is defined by the actions of progesterone and estrogen to regulate locally produced cytokines and growth factors, cell surface glycoproteins and adhesion molecules, and extracellular matrix (ECM) proteins (Johnson et al. 2009). Progesterone initiates the adhesion cascade for implantation in pigs. Immediately prior to when the endometrium becomes receptive to implantation, just after day 10, progesterone downregulates the expression of PGR in the uterine LE (Geisert et al. 1994; Steinhauser et al. 2017). This downregulation of PGR is associated with a downregulation in the expression of the mucin 1 (MUC1), a component of the apical surface glycocalyx of the uterine LE that physically inhibits attachment of the conceptus trophectoderm to the uterine LE due to its extended carbohydrate configuration (Brayman et al. 2004). Indeed, when cyclic gilts are administered intramuscular injections of progesterone, there is a loss of MUC1 from the apical surface of the uterine LE (Bowen et al. 1996). It is accepted that in all mammals, firm attachment of the conceptus trophectoderm to the uterine LE requires a temporal loss of MUC1 at the apical surface of uterine LE cells (Brayman et al. 2004) that exposes low-affinity carbohydrate ligand-binding molecules including selectins and galectins and, perhaps heparan sulfate proteoglycan, heparin-binding EGF-like growth factors, cadherins, and CD44. These molecules are proposed to then contribute to the initial, if fragile, attachment of the conceptus trophectoderm to the uterine LE (Kimber et al. 1995; Kimber and Spanswick 2000; Spencer et al. 2004). Interactions between carbohydrates and lectins during the adhesion cascade of pigs have not been systematically investigated. However, it is likely that these carbohydrate ligands and their lectin receptors, expressed at the apical surfaces of the conceptus trophectoderm and uterine LE of pigs, undergo a series of attach-and-release events. This results in maximal apposition of the conceptus trophectoderm to the uterine LE, similar to the “rolling and tethering” that occurs when leukocytes adhere to the endothelium for extravasation out of the vasculature and into connective tissues (Kling et al. 1992). Indeed, rolling and tethering has been proposed for the initial attachment of human blastocysts to the uterine wall (Red-Horse et al. 2004). In support of this idea, other domestic farm species, including goats and sheep, express H-type-1 antigens and glycosylation-dependent glycam 1, respectively, at the interface between the conceptus trophectoderm and uterine LE during the attachment phase of implantation (Powell et al. 2000; Spencer et al. 1999). These low-affinity contacts are then stabilized by adhesion between an extensive repertoire of integrins and extracellular matrix (ECM) proteins. The binding of integrins to ECM proteins appears to be the major contributor to firm attachment of the conceptus trophectoderm to the uterine LE during implantation (Hynes 1987; Ruoslahti and Pierschbacher 1987; Aplin et al. 1994; Burghardt et al. 1997, 2002; Lessey 2002; Johnson et al. 2003, 2014). Integrins have been implicated in many cell adhesion cascades (Kling et al. 1992). They are transmembrane glycoprotein receptors composed of noncovalently linked α and β subunits. Integrin-ligand binding promotes cell-cell and cell-ECM adhesion, causes the cytoskeleton within the cells to reorganize and stabilize that adhesion, and transduces numerous intracellular signaling pathways (Giancotti and Ruoslahti 1999; Albelda and Buck 1990). There are 18 α- and 8 β-subunits that can dimerize to form 24 heterodimer combinations that then bind to numerous extracellular ligands including a variety of ECM proteins (Albelda and Buck 1990; Humphries et al. 2006; Gallant et al. 2005). Integrin receptors expressed at the apical surface of the uterine LE can bind to Gly-Arg-Gly-Asp-Ser (GRGDS) amino acid sequence containing ECM molecules and bridge to another complement of integrin receptors expressed at the apical surface of the conceptus trophectoderm (Johnson et al. 2014).

Seven integrin subunits have been shown to be expressed at the apical surface of both the conceptus trophectoderm and the uterine LE of pigs. These include alpha 1 (α1), α3, α4, α5, αv, beta 1 (β1), β3, and β5. The expression of α4, α5, and β1 on the uterine LE increases during the peri-implantation period, and treatment with progesterone increases the expression of these integrins at the apical surface of uterine LE cells of cyclic pigs. Further, α4, α5, αv, β1, β3, and β5 are present at porcine implantation sites on days 12 through 15 of gestation (Bowen et al. 1996). These subunits have the potential to assemble into the integrin heterodimer receptors αvβ1, αvβ3, αvβ5, α4β1, and α5β1, and these integrin receptors may function in the adhesion cascade that adheres the conceptus trophectoderm to the uterine LE (Burghardt et al. 1997). Integrin activation through binding to a ligand results in dynamic macromolecular complexes, termed integrin adhesion complexes (IACs) that are composed of the heterodimeric transmembrane integrin receptors that connect ECM proteins to the actin cytoskeleton, along with a diverse array of cell signaling intermediates (Sastry and Burridge 2000; Wozniak et al. 2004; Larsen et al. 2006). Immunofluorescence staining has revealed that αv and β3 integrin subunits co-localize with an altered distribution of an intracellular signaling intermediate within IACs called talin within large aggregates at sites of attachment between the conceptus trophectoderm and uterine LE on Days 20 and 25 of gestation (Erikson et al. 2009; Frank et al. 2017). The size and nature of these aggregates are similar to the well-characterized IACs that form at the base of cultured cells when they attach to the ECM (Sastry and Burridge 2000; Burghardt et al. 2009). To date, five ligands capable of engaging integrin receptors to induce assembly of IACs have been characterized at sites of implantation in pigs. The inter-α-trypsin inhibitor heavy chain-like (IαIH4) protein contains a von Willebrand type A domain that is a recognition site for the αvβ3 integrin receptor (Geisert et al. 1998). The Latency Associated Peptide (LAP) of transforming growth factor beta (TGFB) binds to αvβ1, αvβ3, and αvβ5 (Massuto et al. 2009a). Fibronectin is capable of binding α4β1, α5β1, and αvβ3 (Bowen et al. 1996). Vitronectin is a major ligand for αvβ3 (Bowen et al. 1996). Finally, OPN is the most promiscuous of the ligands and interacts with αvβ1, αvβ3, αvβ5, and α4β1 (Johnson et al. 2003, 2014).

The IαIH4 is part of the kallikrein-kininogen-kinin protease system. Both IαIH4 protein expression and kallikrein enzymatic activity increase within the uterine environment during the peri-implantation period of pregnancy in pigs (Geisert et al. 1998; Vonnahme et al. 1999). The IαIH4 can not only bind to the αvβ3 integrin receptor but also interact with hyaluronic acid within the ECM, both of which could be involved in conceptus implantation. However, the primary role for IαIH4 during implantation in pigs may be to act in concert with bikunin to stabilize the uterine LE surface glycocalyx during conceptus attachment for implantation (Hettinger et al. 2001). The LAP associates with TGFB to form an inactive homodimer, called the small latent complex. The small latent complex remains in the cell until it is bound by latent TGFB-binding protein to form the large latent complex (LLC) that is then secreted into the ECM (Lawrence 1996). The secreted LAP is then cleaved from the LLC by proteases to release active TGFB (Jenkins et al. 2006). In pigs, TGFB1, TGFB2, and TGFB3, and their receptors, TGFBRI and TGFBRII, are expressed by the conceptus trophectoderm and by the uterine LE between days 10 and 14 of gestation. It has been demonstrated that TGFB acts through LAP to increase fibronectin synthesis and cell adhesion to fibronectin, and LAP was shown to initiate the formation of IACs in a porcine trophectoderm cell line (Jaeger et al. 2005). In addition, conceptuses failed to implant when LAP was infused into the uteri of pregnant pigs, suggesting that the infused LAP competed with the endogenous LLC for binding to integrins expressed on the conceptus trophectoderm (Massuto et al. 2009b). In support of this idea, IACs containing LAP, β1, β3, and β5 are present at the interface between the conceptus trophectoderm and uterine LE that may support attachment of the conceptus trophectoderm to the uterine LE during porcine implantation (Massuto et al. 2009a). Both fibronectin and vitronectin are present at sites of attachment of conceptus trophectoderm to uterine LE in pigs (Bowen et al. 1996), and oncofetal fibronectin (oFN), a glycosylation variant of fibronectin, is constitutively expressed by the porcine conceptus trophectoderm as well as the uterine LE throughout gestation (Tuo and Bazer 1996). Fibronectin and vitronectin are prototype cell adhesion proteins, and fibronectin recognizes 10 integrin receptors to generate different signals depending upon the specific integrin receptor involved (Johansson et al. 1997; Humphries et al. 2006). It is noteworthy that the human conceptus trophoblast produces oFN so precisely at sites of trophoblast contact with the endometrium that it has been referred to as “trophoblast glue” (Feinberg et al. 1994), and fibronectin is a strong candidate for mediating conceptus adhesion to the uterus in rodents (Armant 2005).

Of the ECM adhesion proteins expressed at the interface between the conceptus trophectoderm and the uterine LE during the peri-implantation period of pregnancy in pigs, OPN is the most extensively studied (Johnson et al. 2003, 2014) (see Fig. 4b). OPN is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of ECM proteins that has multiple physiological functions (Denhardt and Guo 1993; Butler et al. 1996; Sodek et al. 2000), but with regard to implantation, focus has been on OPNs ability to bind integrins to mediate cell adhesion and cell migration (Senger et al. 1994). OPN is an abundant component of the intrauterine environment of pregnant humans, mice, rabbits, sheep, cattle, goats, and pigs (Johnson et al. 1999a, b; Garlow et al. 2002; Apparao et al. 2003; Kimmins et al. 2004; Mirkin et al. 2005; Joyce et al. 2005b; White et al. 2006). In pigs, conceptus estrogens induce OPN expression just prior to the initiation of implantation, beginning on day 13, in discrete regions of the uterine LE next to the conceptus trophectoderm. By day 20, OPN expression extends along the entire uterine LE when stable adhesion of the conceptus trophectoderm to uterine LE occurs, and OPN expression remains high at the uterine–placental interface throughout gestation (Garlow et al. 2002; White et al. 2005). In vitro affinity chromatography and immunoprecipitation experiments have shown that OPN binds the αvβ6 integrin heterodimer on porcine trophectoderm cells, and the αvβ3 integrin heterodimer on porcine uterine LE cells (Erikson et al. 2009). OPN binding, particularly to the αv integrin, promotes dose-dependent attachment of porcine trophectoderm and uterine LE cells and stimulates haptotactic trophectoderm cell migration, meaning that the cells migrated along a physical gradient of nonsoluble OPN (Erikson et al. 2009; Frank et al. 2017). Immunofluorescence staining for integrins at implantation sites of pigs revealed IACs containing these same integrins distributed in a pattern similar to that suggested by in vitro binding to OPN (Erikson et al. 2009; Frank et al. 2017). Immunofluorescent staining for the αv integrin subunit revealed large IACs at the junction between the apical surfaces of conceptus trophectoderm and uterine LE cells, suggesting these IACs facilitate conceptus trophectoderm attachment to the uterine LE for implantation. The β3 subunit, however, appeared in aggregates at the apical surface of uterine LE cells only, agreeing with affinity chromatography data indicating in vitro binding of αvβ3 to OPN on uterine LE cells (Erikson et al. 2009). Finally, OPN-coated microspheres were used to demonstrate co-localization of OPN, the αv integrin subunit, and talin to IACs at the apical domain of porcine trophectoderm cells (Erikson et al. 2009). Collectively, results indicate that OPN binds integrins to stimulate integrin-mediated IAC assembly within conceptus trophectoderm and uterine LE cells, attachment of conceptus trophectoderm to uterine LE cells, and migration of conceptus trophectoderm cells to promote conceptus implantation in pigs.

The physical changes that occur to the interface between the conceptus trophectoderm and uterine LE during the initial stages of epitheliochorial placentation in pigs have been eloquently described by Dantzer (1985). On all days examined, the glycocalyx at the surface of the uterine LE is thicker than the glycocalyx at the surface of the conceptus trophectoderm. On days 13 and 14, the uterine LE develops protrusions that become enclosed by caps of conceptus trophectoderm cells, and this unique configuration physically immobilizes the conceptus at the uterine LE surface. By day 14, there is close apposition between the apical membranes of conceptus trophectoderm and uterine LE cells, and microvilli form and interdigitate between these plasma membranes through days 15 and 16. The interface between the conceptus trophectoderm and uterine LE cells becomes increasingly complex as it functionally transitions from histotrophic to hemotrophic nutrient transport between days 15 and 20 of pregnancy. It is characterized by apical domes on the uterine LE cells that are closely apposed to the conceptus trophectoderm cells and provide long cytoplasmic extensions into a luminal space between the apical domes. Finally, adhesion transitions into placentation through ever-increasing development of interdigitating microvilli between the conceptus trophectoderm and uterine LE cells that extends into the peripheral zone by day 26 of gestation.

5 Folding of the Uterine–Placental Interface to Facilitate Hemotrophic Support of the Fetus

As pregnancy progresses, the uterine–placental interface, composes of the uterine (maternal) placenta and the fetal placenta, undergoes considerable morphological changes to progressively develop more complex folds that increase the surface area of contact between uterine LE and placental chorionic epithelium (CE) for exchange of nutrients, gases and waste products (Vallet and Freking 2007; Vallet et al. 2009). The interface between the maternal (uterine) placenta and fetal placenta of pigs begins to fold by day 25 of pregnancy, and these early folds increase in length through day 35, and again increase in length between days 50 and 60 of gestation (Seo et al. 2020) (see Figs. 5a and 6a, c). Placental and uterine capillaries lie immediately beneath these epithelia, minimizing the distance between maternal and fetal blood vessels (Dantzer and Leiser 1994). Therefore, the increase in folding at the maternal placental (uterine)–fetal placental (chorioallantoic) interface directly increases the surface area of contact between maternal and placental microvasculatures to optimize the potential for transport of nutrients from maternal to placental blood vessels for eventual utilization by the embryo/fetus. The small intestine utilizes a similar strategy to maximize exposure of the microvasculature for micronutrient transport (Hilton 1902; Simons 2013). Friess et al. (1980) described the microarchitecture of these folds at Days 30 and 58 of gestation. By day 30 of pregnancy, the chorioallantoic and endometrial surfaces interlock into folds composed of endometrial ridges and chorioallantoic troughs. The trophectoderm cells at the bottom of the chorioallantoic troughs are columnar and 40 μm in height, and the trophectoderm cells at the sides and tops of the troughs are 20 μm in height. The height of the uterine LE cells does not vary along the interface of the folds. The apical surfaces of the trophectoderm cells possess long microvilli which interdigitate with microvilli on the apical surfaces of the uterine LE cells. The subepithelial capillaries of both the chorioallantois and endometrium remain separated from the epithelial basal laminae by a limited, but easily visualized, layer of connective tissue (Friess et al. 1980). By day 58 of pregnancy, the height of the trophectoderm cells is 35 μm at the bottom of the chorioallantoic troughs, and these cells are high columnar and narrow in width. Along the sides and tops of the chorioallantoic troughs, the trophectoderm cells are 15 μm in height. The uterine LE cells opposite the base of the chorioallantoic troughs are 25 μm, whereas the uterine LE cells along the sides and at the top of the chorioallantoic troughs are 15 μm. The subepithelial capillaries indent into the trophectoderm cells on the sides and tops of the chorioallantoic troughs, and where the capillaries protrude into the trophectoderm cells, the trophectoderm cell height is reduced to 2 μm. In summary, the lateral sides and tops of the chorioallantoic ridges are designed for gaseous exchange, and the chorioallantoic barrier can often be less than 2 μm, whereas the base of the chorioallantoic troughs is designed for the transport of blood-borne nutrients, i.e., hemotroph (Friess et al. 1980).

An emerging concept is that tissues respond to mechanical forces that coordinate morphogenesis, and it is hypothesized that mechanotransduction and mechanosensation at the interface between the uterus and placenta drives the morphological development of folding characteristic of the epitheliochorial placentation of pigs (Seo et al. 2020). Changes in the length of the placental folds, expression of mechanotransduction-implicated molecules in uterine and placental tissues, and changes in the size of subepithelial blood vessels were examined for days 20 through 60 of gestation in pigs (see Fig. 5). It was observed that: (1) the length of folds increased (2) OPN, talin, and focal adhesion kinase co-localized into aggregates at the uterine–placental interface; (3) filamin, actin-related protein 2, and F-actin were enriched at the tops of uterine folds extending into placental tissue (the bottom of the chorioallantoic troughs described in the preceding paragraph); (4) uterine stromal fibroblasts acquired alpha smooth muscle actin; and (5) uterine blood vessels increased in size. These observations indicate that the lengthening of the folds is associated with polymerization of actin that coincides with IAC assembly, endometrial fibroblasts differentiate into myofibroblasts, and dilation of subepithelial blood vessels correlates with the development of the folds. It is proposed that dilation of subepithelial uterine blood vessels delivers increased blood flow that pushes upward on the interface between the uterine LE and the placental chorioallantois, protrusive forces from growing uterine blood vessels trigger IAC assembly and actin polymerization between the uterine LE and chorionic epithelium at the bottoms of the chorioallantoic troughs, and uterine fibroblasts differentiate into contractile myofibroblasts that pull the connective tissue downward and inward to sculpt folds at the uterine–placental interface (see Fig. 5b, c).

6 Areolae Provide for Histotrophic Support of the Fetus

In addition to having chorionic epithelium closely apposed to the uterine LE, there are specialized epithelial cells of the chorionic areolae at the openings of the mouths of uterine glands (see Fig. 6). These are tall columnar cells that have numerous vacuoles containing the secretions of uterine glands (histotroph or uterine milk). Indeed, the open space between the chorion and LE is filled with uterine milk (Dempsey et al. 1955). The blood vessels that supply the folds of the wall of the areolae form a ring towards the periphery and the areolar capillaries converge into one or two stem veins indicating facilitated external inflow of blood into the areola and outflow in a manner different from that of the inter-areolar regions of the placenta (Dantzer and Leiser 1993). This anatomy allows areolae to transport glandular secretions such as macromolecules, particularly proteins, by fluid-phase pinocytosis across the placenta and into the fetal-placental circulation.

After the apposition of the conceptus trophectoderm to the uterine LE at days 13–15 of gestation, by days 15–17, the chorioallantois immediately around each of the openings of the uterine glands begins to reach over the mouth of the gland(s) to develop a cavity that separates the uterine LE from the chorioallantois. These structures are termed the areolae. They are initially observed as small white circular discs with a prominent peripheral thickening of 1 mm in diameter (Friess et al. 1981), but quickly develop to cover the openings of the uterine gland(s). The cavity that forms receives the secretions of the uterine glands, and the columnar chorionic epithelial cells that line the placental border of this cavity form a seal between the uterine LE and the walls of the placental areola to prevent dissipation of histotroph into inter-areolar regions of the placenta. The allantoic vasculature that receives the histotroph is clearly discernable from the vasculature that supplies inter-areolar regions of the placenta (Leiser and Dantzer 1994). The endometrial vasculature that supplies the areola develops more slowly than the endometrial vasculature of inter-areolar regions presumably due a less intimate association with the trophectoderm. This prevents direct physical interaction between the trophectoderm and endometrium and decreases the influence of paracrine products that are secreted by the trophectoderm. As the placenta grows, areolar diameter increases and a stretching of the areolar capillary network leads to a progressively widening size. During the early stages of placentation, the placental surface of the areolae is flat, but as placentation progresses the flat surface becomes more complex with formation of ridges and papilla-like structures lined by a columnar chorionic epithelium (Amoroso 1952). The balloon shape of the areola implies that there is an interior pressure against the chorioallantoic surface of the areola delivered by the continuous accumulation of histotroph from the uterine glands. Indeed, the cavity of an areola is a small reservoir for the histotroph that is potentially secreted by the much larger uterine glands (Leiser and Dantzer 1994). There are some 2500 areolae distributed over the entire chorioallantois, and their number is correlated with fetal weight (r = 0.65). There are approximately 6 areolae per square centimeter of chorioallantois at mid-pregnancy, but approximately 2.5 areolae per square centimeter of chorioallantois by the end of gestation (Knight et al. 1977). The microanatomy of areolae facilitate the transport of glandular secretions such as macromolecules and proteins, including those for the transport of iron and vitamins, by fluid-phase pinocytosis across the placenta and into the fetal-placental circulation. Macromolecules and proteins are then transported to the heart via the fetal venous system for distribution to all fetal-placental tissues (Renegar et al. 1982; Ducsay et al. 1984; Roberts et al. 1986; Bazer et al. 1991). All nutrients transferred across the placenta may be cleared via the kidney and into the bladder from which they can enter the allantoic sac via the urachus for metabolism, degradation, or reuptake into the placental circulation for redistribution to affect development and function of fetal-placental tissues (Bazer 1989).

7 Conclusion

Figure 7 summarizes some of the major events during implantation and placentation in the pig. A primary function of the placenta is the transplacental exchange of gases, micronutrients (amino acids, glucose), and macromolecules (proteins), as well as the production of hormones, cytokines, and other regulatory molecules that affect growth and development of the conceptus throughout gestation. In all mammals, placentation initiates with implantation that includes specialized cell adhesion and cell migration leading to attachment of conceptus trophectoderm to the uterine LE. Once attached, maternal and fetal blood must be brought into close apposition to allow for transplacental exchange of molecules while maintaining separation of the maternal and fetal circulatory systems. Endometrial and placental tissues are remodeled to achieve areas of reduced interhaemal distance regardless of whether the placenta is epitheliochorial, synepitheliochorial, endotheliochorial, or hemochorial. Extensive remodeling to form chorionic (placental) ridges and corresponding endometrial invaginations results in folding that further increases the area of uterine-placental association. Indentation of the uterine LE and conceptus trophectoderm by underlying capillaries further reduces the distance between maternal and fetal blood, providing a short diffusion distance across the placenta.

Placentation is epitheliochorial in pigs as uterine LE remains intact throughout pregnancy. Porcine conceptus trophectoderm directly attaches to the uterine LE, and these epithelia serve as the conduit for maternal hematotrophic and histotrophic support for conceptus growth and development. There is progressive interdigitation of microvilli on conceptus trophectoderm and uterine LE. The interface between the maternal (uterine) placenta and fetal placenta of pigs begins to fold by day 25 of pregnancy, and these early folds increase in length through day 35, and again increase in length between days 50 and 60 of gestation to eventually cover the entire placenta, except at the openings of uterine glands. Here the conceptus trophectoderm never fuses with uterine LE, rather it forms a pocket referred to as an areola. Secretions from superficial GE and deep uterine glandular GE, as well as molecules representing selective transudation from maternal serum into uterine GE and LE, are absorbed and transported across the chorioallantoic placenta by fluid-phase pinocytosis for release into the fetal circulation.

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Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
Gregory A. Johnson & Heewon Seo
Department of Animal Science, Texas A&M University, College Station, TX, USA
Fuller W. Bazer

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Heewon Seo
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Correspondence to Gregory A. Johnson .

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Division of Animal Sciences, University of Missouri, Columbia, MO, USA
Rodney D. Geisert
Division of Animal Sciences, University of Missouri, Columbia, MO, USA
Thomas Spencer

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Johnson, G.A., Bazer, F.W., Seo, H. (2021). The Early Stages of Implantation and Placentation in the Pig. In: Geisert, R.D., Spencer, T. (eds) Placentation in Mammals. Advances in Anatomy, Embryology and Cell Biology, vol 234. Springer, Cham. https://doi.org/10.1007/978-3-030-77360-1_5

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The Early Stages of Implantation and Placentation in the Pig

Abstract

Similar content being viewed by others

Implantation and Establishment of Pregnancy in the Pig

Placental accommodations for transport and metabolism during intra-uterine crowding in pigs

Early Syncytialization of the Ovine Placenta Revisited

Keywords

1 Introduction: Basic Definition for Epitheliochorial Placentation

2 Uterine Histoarchitecture and Early Conceptus Development

3 Select Hormones and Cytokines That Prepare the Uterus for Placentation

4 Attachment of the Conceptus Trophectoderm to the Uterine LE (Implantation)

5 Folding of the Uterine–Placental Interface to Facilitate Hemotrophic Support of the Fetus

6 Areolae Provide for Histotrophic Support of the Fetus

7 Conclusion

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The Early Stages of Implantation and Placentation in the Pig

Abstract

Similar content being viewed by others

Implantation and Establishment of Pregnancy in the Pig

Placental accommodations for transport and metabolism during intra-uterine crowding in pigs

Early Syncytialization of the Ovine Placenta Revisited

Keywords

1 Introduction: Basic Definition for Epitheliochorial Placentation

2 Uterine Histoarchitecture and Early Conceptus Development

3 Select Hormones and Cytokines That Prepare the Uterus for Placentation

4 Attachment of the Conceptus Trophectoderm to the Uterine LE (Implantation)

5 Folding of the Uterine–Placental Interface to Facilitate Hemotrophic Support of the Fetus

6 Areolae Provide for Histotrophic Support of the Fetus

7 Conclusion

References

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Authors and Affiliations

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