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(The FASEB Journal. 2005;19:1056-1060.)
© 2005 FASEB

Embryonic implantation and leukocyte transendothelial migration: different processes with similar players?

F. Dominguez*,1, M. Yáñez-Mó{ddagger},1, F. Sanchez-Madrid{ddagger} and C. Simón*,{dagger},2

* Instituto Valenciano de Infertilidad Foundation (FIVI), Valencia University, Valencia, Spain;
{dagger} Department of Pediatrics, Obstetrics and Gynecology, Valencia University School of Medicine, Valencia, Spain; and
{ddagger} Servicio de Inmunologia, Hospital de la Princesa, Universidad Autonoma de Madrid, Diego de León, Madrid, Spain

2 Correspondence: Instituto Valenciano de Infertilidad Foundation (FIVI), Valencia University, C/Guadassuar 1, bajo Valencia, Spain. 46015. E-mail: csimon{at}ivi.es

ABSTRACT

A clear parallelism between the different steps in human embryo-endometrial apposition/adhesion/invasion and leukocyte-endothelium rolling/adhesion/extravasation can be established. During human implantation and leukocyte trafficking, a first wave of soluble mediators regulates the expression and functional activity of adhesion molecules such as L-selectin and integrins, which mediate both processes. Apical surfaces of human endometrial epithelium and endothelium are key elements for the initiation of molecular interactions to capture the blastocyst or leukocyte, respectively. Subsequently, the blastocyst and the leukocyte migrate through the epithelium and endothelium toward their final destination, the endometrial stroma, to initiate placentation or the inflammatory foci as part of the immune response. Similarities between the intermediate molecular mechanisms of these two physiologically unrelated processes are discussed.—Dominguez, F., Yáñez-Mó, M., Sanchez-Madrid, F., Simón, C. Embryonic implantation and leukocyte transendothelial migration: different processes with similar players?


Key Words: implantation • leukocyte trafficking • integrins • chemokines • L-selectin

LEUKOCYTE TRANSENDOTHELIAL MIGRATION is dependent on the productive interaction of leukocytes with the activated endothelial monolayer. This interaction takes place through a series of sequential steps that involve adhesive interactions between leukocyte receptors and endothelial ligands, which confer selectivity to the extravasation process. Likewise, embryonic implantation involves different developmental steps—apposition, attachment, and invasion, leading to an effective interaction between the blastocyst and the maternal endometrium that is mandatory for mammalian reproduction (1) .

During the apposition phase in implantation and leukocyte adhesion, the blastocyst/endometrium and leukocyte/endothelium dialogue relies on soluble mediators such as cytokines, chemokines, and other factors produced and acting in a bidirectional fashion (1 , 2) . So, the blastocyst might be "guided" to the final implantation site as the leukocyte is "guided" to the inflammatory focus. In the adhesion phase, the communication is based on specific ligand-receptor interaction mainly via adhesion molecules of the integrin family (3 , 4) . An active role for endothelial cells in the adhesive step comes from the development of an adhesive 3-dimensional structure (docking structure) on their apical surface (5 , 6) , resembling hormone-regulated pinopodes at the endometrial surface (7) . Finally, during invasion, the embryonic trophoblast becomes invasive, penetrates the basal membrane, and invades the stroma up to the uterine vessels using different metalloproteinases (MMP9, MMP2) (8) . Similarities between leukocyte extravasation and blastocyst implantation have been suggested before (9) . Here we extend the comparison, trying to highlight the similarities in molecular players and cellular structures and pointing out the differences. This exchange of information between immunologists and reproductive biologists can benefit the human implantation field in the development of infertility treatments or contraceptive drugs and might reveal other ideas to immunologists. Several questions arise that could open an interesting debate.

Rolling/apposition: first act
The first step in the extravasation sequence corresponds to the interaction of selectins with their carbohydrate-based ligands (10) . This interaction, named tethering, allows the leukocyte to roll on the endothelial cell wall. Selectin interactions are highly dynamic, so they are able to slow down the leukocyte through transient contacts, with the endothelial monolayer facilitating their firm adhesion (see Fig. 1 ). Leukocytes express L-selectin, which is shed from their surface to allow the transmigration process to proceed. P-Selectin glyocoprotein ligand-1 (PSGL-1) is involved in the rolling step through its interaction with endothelial E and P-selectins. Proinflammatory cytokines induce the rapid expression on endothelial cell plasma membrane of P-selectin, which is translocated from internal stores, and induce transcription of E-selectin, which is then expressed on the apical cell surface at longer times. Other adhesion molecules such as the integrin ligand VCAM-1 are able to initiate leukocyte rolling (11) .



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  		Figure 1. Comparison of the sequential adhesion steps involved in leukocyte transmigration and embryonic implantation and their molecular players. Leukocyte rolling, via the interaction of selectins with their carbohydrate ligands, slows down the leukocyte and facilitates the binding of chemokines to their GPCR receptors. Chemokines induce the high-affinity conformation of leukocyte integrins that bind to ICAM-1 (blue) and VCAM-1 (green), including into tetraspanin microdomains and anchored to the cortical actin cytoskeleton on the apical surface of endothelial cells. Upon leukocyte adhesion, endothelial cells develop a 3-dimensional docking structure that prevents the detachment of the adhered leukocyte, allowing it to proceed to diapedesis. During diapedesis, leukocyte integrins interact with endothelial JAM adhesion molecules (pink), which reseal the junction by homophylic interactions once the leukocyte has traversed the monolayer. In embryonic implantation, chemokines (MCP-1, purple; RANTES, blue) and chemokine receptors (CCR5 and CCR2 blue and purple, respectively) are implicated in embryonic apposition. Blastocyst presents CCR5 and CCR2 on its surface whereas chemokine ligands adhere to glycosaminoglycans in the endometrial epithelium. L-selectin/L-selectin ligands initial contacts are important in this first phase. Adhesion and anti-adhesion molecules such as integrins subunits on pinopode structures and MUC-1 on the endometrial surface facilitates/prevents the embryo adhesion. The role of tetraspanin microdomains is still unknown in blastocyst attachment. In the final invasion phase, the blastocyst breaches the epithelial barrier increasing the number of apoptotic cells beneath it, then the trophoblast advances through the stroma, expressing different metalloproteinases like MMP-2 and -9 (in purple and green, respectively).

The L-selectin system is critically involved in the embryonic apposition phase (9) . Carbohydrate ligands that bind L-selectin are localized on the luminal epithelium at the time of implantation, whereas the trophoectoderm expresses L-selectin strongly after hatching. Cytotrophoblast progenitors, cytotrophoblasts in cell columns, and invasive cytotrophoblast react strongly with L-selectin antibodies. Trophoblast lineages use L-selectin to bind to uterine epithelial oligosaccharide ligands; when L-selectin is blocked with specific antibodies, adhesion to the epithelium is impaired (9) . Also exposed in the glycocalix of human endometrial epithelial cells (EEC) are mucins such as MUC1, which increases its expression from the proliferative to secretory phase in endometrial tissue (12) and is induced by the human blastocyst (13) . Possible substrate candidates for MUC1 binding include L-selectins (12) or intercellular adhesion molecules, but its function as an adhesion or anti-adhesion molecule is still controversial.

From this comparative view, several unanswered issues emerge: Why are L-selectin-deficient mice fertile? Do other selectins or integrin ligands compensate for this deficiency or is the role of L-selectin in implantation restricted to humans? Is selectin shedding critical for embryonic implantation? Is the blastocyst subjected to similar fluid stress in the uterus?

Adhesion and polarization: critical step
Leukocyte rolling favors the encounter of the chemokines presented at the endothelial apical surface on glycosaminoglycans (14 , 15) . Chemokines induce the activation in situ of leukocyte integrins (14) and, in cooperation with integrin-dependent signals, polarization of the cell (16 , 17) . Polarized leukocytes firmly adhere to the endothelial monolayer through the integrin receptor/counter-receptor pairs LFA1/ICAM-1,2 and VLA-4/VCAM-1 (5 , 16) . Endothelial ICAM-1 and VCAM-1 are induced by proinflammatory cytokines. In the polarized morphology, leukocytes display their chemokine receptors at the leading edge, whereas a plethora of adhesion molecules are relocated at the rear pole (uropod), which is not in direct contact with the endothelium (see Fig. 1 ) (17) . The cytoskeleton is rearranged by localizing the actin polymerization machinery at the front and the microtubule organizing center at the neck of the uropod. This redistribution elongates the leukocyte, making it more flexible for a more efficient migratory task.

During embryonic apposition, chemokines are the first wave of molecules produced locally by the endometrium. An array of different chemokines is expressed and produced in the human endometrium at the time of implantation (18 , 19) . Chemokines such as IL-8, RANTES, or MCP-1 secreted locally either by the endometrium during the implantation window or by the human blastocyst in the apposition phase (20) might act as signals for receptor polarization and activation of endometrial adhesion molecules. On the other hand, immunoreactive CCR2B (MCP-1 receptor) and CCR5 (RANTES receptor) are localized at the human blastocyst (21) . Furthermore, the human blastocyst induces the expression and polarization of CXCR1 (IL-8 receptor), CXCR4 (SDF-1{alpha} receptor), and CCR5 in endometrial epithelial cells (21) .

The best-characterized cell adhesion molecule on the luminal surface of the endometrium is the {alpha}vß3 integrin (22) . Its ligand, osteopontin (OPN), colocalizes with {alpha}vß3 and might play a role in endometrial or embryo signaling, facilitating embryo attachment to the apical surface prior to invasion. OPN is a consensus gene found in all studies of wide genome analysis of human receptive endometrium (23 24 25) . Integrin knockout studies reveal that ß1 null mice (–/–) embryos develop normally to the blastocyst stage but fail to implant (26) . However, no implantation-related phenotypes have been observed in other knockouts lacking different subunits {alpha}4, {alpha}5, {alpha}6, or {alpha}v. The human embryo regulates ß3, {alpha}4, and {alpha}1 integrins in human EEC at the protein level in the apposition phase (27) . Furthermore, the embryonic IL-1 system seems to be involved in the EEC ß3 up-regulation. Therefore, after breaking the glycocalix barrier, the embryo could induce a favorable epithelial integrin pattern for its implantation, reinforcing the concept of precise paracrine cross-talk between blastocyst and endometrial epithelium.

In humans, adhesion of the embryo to the endometrium occurs in a specific polarized manner. The trophoblast became adhesive at the pole where the inner cell mass (ICM) is; in mice the adhesive trophoblast is opposite the ICM. Nevertheless, the detailed molecular mechanism by which the human blastocyst polarizes remains unsolved. Some clues about the guidance of blastocyst by chemokines have been obtained recently in animal models. The chemokine interferon-inducible protein 10 kDa (IP-10) has been involved in the regulation of blastocyst migration, apposition, and initial adhesion in ruminants (28) . More indirect evidence that confirms the implication of chemokines in the attraction of the blastocyst comes from clinical trials demonstrating that scar tissue from previous cesarean section or endometrial surgery (that is, a persistent inflammatory focus) becomes an attractive implantation site (29) .

Many intriguing questions arise from the comparison of the adhesion and polarization step: Do human blastocysts express polarized chemokine receptors in response to endometrial chemokines as leukocytes do? Are blastocysts guided to their final implantation site in as leukocytes are attracted to inflammatory foci by gradients of different chemokines? What kind of assays could be designed to demonstrate this hypothesis? Are blastocyst and leukocyte integrins similarly regulated?

Final destination: diapedesis/trophoblast invasion
In the diapedesis step, leukocytes have to squeeze into the endothelial cell-to-cell junctions. During this process, the permeability of the endothelial monolayer usually is not compromised. Leukocyte integrins interact with tight junction molecules such as junctional adhesion molecules (JAMs), establishing heterotypic connections that are replaced by JAM-JAM homotypic interactions once the leukocyte has traversed the monolayer, thus restoring the initial situation (30 , 31) .

In the apposition phase, the size of the blastocyst prevents the migration between EEC; therefore, another strategy is needed. When the blastocyst adheres to the EEC monolayer in humans and mice, a paracrine apoptotic reaction is induced (32 , 33) . This embryo-induced apoptotic mechanism is triggered by direct contact between the blastocyst and EEC and is mediated at least in part by the Fas-Fas ligand system (32) . To achieve successful invasion, trophoblasts must induce a repertoire of genes involved in the degradation of the extracellular matrix. MMP-9 is closely associated with the invasive phenotype of trophoblasts (8) .

Once the blastocyst traverses the basal membrane, the migration of first trimester trophoblasts is stimulated by insulin-like growth factor-II (IGF-II) and IGFBP-1; it can be inhibited by transforming growth factor ß (TGF-ß), as has been demonstrated using an in vitro trophoblast migration assay (34) . Several lines of evidence demonstrate the relevance of adhesion molecules in trophoblast invasion. First, expression of several integrins by cytotrophoblasts in pre-eclampsia is abnormal (35) . Second, E- and P-selectins have been localized to vascular endothelial cells in human deciduas, being important for adhesion between endovascular trophoblast and decidual endothelial cells (36 , 37) . Decidual endothelial cells express VCAM-1, ICAM-1, and ICAM-2 (36) . Expression of a specific repertoire of adhesion molecules ({alpha}vß4, {alpha}1ß1, VE-cadherin, VCAM-1, and PECAM-1) in the trophoblast is also needed for correct placentation (38) .

Active role of the endometrium and endothelium apical surfaces in the adhesion of blastocysts or leukocytes
Selectins and their ligands are located at the microvilli in leukocytes and at the apical surface of endothelial monolayer (10 , 39) . This localization is based on their interaction with linker proteins that anchor them to the actin cytoskeleton of microvilli and has proved to be essential for their function in rolling (5) . ICAM-1 and VCAM-1 are presented at apical endothelial microvilli through their association to ezrin-radixin-moesin (ERMs) (6) . Interaction of PSGL-1 with the tyrosine kinase Syk through the ITAM motifs present in ERM proteins (40) give ERMs a dual function, acting both as structural moieties, anchoring adhesion receptors to the actin microvillar cytoskeleton, and in intracellular signaling cascades by their association with tyrosine kinases. Adhesion receptors involved in leukocyte-endothelium interaction deliver the appropriate intracellular signals that trigger the cytoskeletal rearrangements in both cells to allow the subsequent step to occur. This intracellular signaling will prime the leukocyte to induce the genes necessary to carry out effector functions at the inflamed tissue. On the endothelial cell side, adhesion receptors initiate intracellular signaling cascades that lead to the cytoskeletal rearrangements necessary for the formation of the 3-dimensional docking structure. This structure concentrates ICAM-1 and VCAM-1, and virtually surrounds the adhered leukocyte preventing its detachment under flow conditions (6) . Tetraspanins are a group of hydrophobic proteins with four transmembrane domains and two extracellular loops. The association of tetraspanins with some integrins is well characterized (41) . Remarkably, tetraspanin microdomains are crucial in regulating the appropriate adhesive function of ICAM-1 and VCAM-1 at the apical surface of the endothelial cell monolayer (42) . Cytoskeletal components are involved in regulating junctional permeability during diapedesis (5) . Selectins and Ig molecules VCAM-1 and ICAM-1 act as signaling receptors. The signaling cascades triggered involve calcium fluxes, oxygen reactive species, and Rho GTPases. Ligation of ICAM-1 triggers gene expression mechanisms in endothelial cells, thus amplifying the inflammatory response (5) .

Endometrial pinopodes resemble morphologically the docking structure of the endothelium. These hormone-dependent structures appear at the time of implantation in the apical membrane of the epithelial endometrium. In vitro experimental studies of human blastocyst attachment to an artificial endometrium indicate a preference for human blastocysts attachment to pinopode-presenting areas on the endometrial surface (7) . Furthermore, it has been demonstrated that pinopodes are integrin-enriched areas (43) , but their functional role during human implantation remains to be elucidated. Endometrial membrane/actin cytoskeleton linkers such as ezrin and moesin stabilize the actin/microvilli-associated cytoskeleton and hence directly (via steric hindrance) or indirectly (by providing an unpermissive membrane proteins pattern) impair embryo attachment. Endometrial ezrin peaks during the implantation window whereas moesin increases progressively at the end of the cycle, localizing mainly at the epithelial compartment (44 , 45) .

In fertilization, adhesion molecules such as PSGL-1 in pig (46) or the tetraspanin CD9 in mice are key molecules (47 , 48) . Mice deficient for CD9 display a severe reduction of fertility because oocytes were ovulated but not successfully fertilized. Intracytoplasmic sperm injection experiments demonstrated that when sperm were injected into CD9–/– oocytes, the fertilized eggs developed to term, indicating the cause of this infertility was due only to the fertilization failure. However, the functional role of CD9 in human implantation remains unclear. CD9 is expressed in human endometrial cells and trophoblasts in association with integrins {alpha}6, {alpha}3, and ß1 (49) mainly localized on the cell surface of glandular epithelium; its expression levels remain similar through the menstrual cycle (49) , but its role in blastocyts adhesion has not been explored yet.

As now demonstrated for endothelial cells, endometrial receptivity will probably not be circumscribed to the expression of selectins or integrins, but a series of cytoskeletal rearrangements in these cells might also be important. Moreover, are adhesion signals important for the future development of the blastocyst? What are the critical molecular components of the apical surface of EEC that dictate the implantation site? How is the EEC cytoskeleton regulated during implantation? Do tetraspanin microdomains form part of pinopodes structures as they do in endothelial docking structure for transmigrating leukocytes?

Hence, a comparison of these two unrelated processes points to several aspects of similarity and divergence that open new fields of research for immunologists and reproductive biologists.

ACKNOWLEDGMENTS

This work was supported by grants Agencia Valenciana de Ciencia y Tecnologia GRUPOS 03/043 to C.S. and FISS 02/1169, BMC-2002 00563 from the Ministerio de Ciencia y Tecnología, Ayuda a la Investigación Básica Juan March 2002, to F.S.

FOOTNOTES

1 These authors contributed equally to this manuscript.

Received for publication February 3, 2005. Accepted for publication March 9, 2005.

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