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Embryo Implantation - The Molecular Mechanism

Embryo Implantation - The Molecular Mechanism

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07/20/2011

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BM
Online 
- Vol 13 No 6. 2006 833-839 Reproductive BioMedicine Online; www.rbmonline.com/Article/ 
2454 on web 5 October 2006 
 
John Aplin received his initial training in chemistry at Queen’s College Oxford, and inbiophysics at the University of British Columbia where he first became interested inglycobiology and the cell surface. As a ‘post-doc’ at the MRC laboratories in Mill Hill,London his interests turned to the biology of cell adhesion. Chance events led him intoreproductive biology, most notably implantation and placental development. He is currentlyProfessor of Reproductive Biomedicine at the University of Manchester where he is amember of the Maternal and Fetal Health Research Centre in the Medical School, with across-appointment in the Faculty of Life Sciences.
Dr John Aplin
JD AplinDivision of Human Development, Medical School, University of Manchester, UKCorrespondence: Research Floor, St Mary’s Hospital, Manchester M13 0JH, UK; e-mail: john.aplin@manchester.ac.uk
 
 Abstract
Low rates of implantation are an impediment to more efficient assisted reproduction techniques. Improved endometrialreceptivity and embryo preparation should lead to higher pregnancy rates, lower rates of early pregnancy failure and fewermultiple pregnancies. As the first site of contact between embryo and endometrium, the luminal epithelium (LE) is responsiblefor the non-receptive status of proliferative and early secretory tissue, and transformation to receptivity in the mid-secretoryphase presumably requires alterations in expression, organization or activation of adhesion systems. Luminal cells are lessabundant than their glandular counterparts, and are under-represented in global tissue datasets. Furthermore, alterations incell surface composition can be readily accomplished by mechanisms that do not rely on altered transcription or translation.Current data from in-vitro models are consistent with initial attachment to mucin in the apical glycocalyx, perhaps via acarbohydrate-mediated interaction, after which the epithelial phenotype is modified by a medium- or short-range embryonicsignal. A cascade of interactions follows, mediating embryo migration across the epithelium. Strikingly, numerous potentialmediators of adhesion at implantation are located in the lateral rather than the apical surface of LE cells. Attached embryosappear to gain rapid access to this highly adhesive lateral membrane domain.
 Keywords:
adhesion molecule, endometrium, epithelial polarity, glycocalyx, implantation, mucin
The implantation window isregulated by endometrial luminalepithelium
Observations made following embryo replacement indicate thatthe human endometrium is receptive to an implanting embryofrom about 6–10 days after the LH peak (Bergh and Navot,1992; Aplin, 2000). Hatched blastocysts attach non-selectively toendometrial stromal cells
in vitro
(Carver
et al.
2003) as well asto tissue culture dishes, indicating that it is the luminal epitheliumthat confers upon the uterus its unique property of resistance toimplantation in phases other than the mid-secretory. Though bothoriginate from progenitor cells in the basal glands during post-menstrual regeneration, luminal epithelial (LE) cells are distinctfrom their glandular (GE) counterparts (Dockery, 2002): theyare cuboidal rather than columnar; they show less pronouncedecretory and organellar changes in the secretory phase; theydevelop mid-secretory uterodomes or pinopodes, apical cellurface swellings that have been suggested as an attribute of receptive tissue (Murphy, 2000; Lopata
et al.
2002); and thereare numerous molecular markers that indicate compositionaldistinctions between the two (Seif and Aplin, 1990; Aplin
et al.
 1998; ). In the mouse, comparative microarray analysis of the GEand LE transcriptomes at the time of implantation (Niklaus andPollard, 2006) indicates that though most products are common,about 280 genes significantly differ in expression. These fall intonumerous functional categories, but one important observationis the presence of immune defence gene products in the LE, areminder that it has a primary barrier function in repelling micro-organisms in the upper reproductive tract. Discussion of theeffect of ovarian stimulation regimes and hormone replacementtherapy on receptivity has been clouded by the lack of a precise
833
OutlookEmbryo implantation: the molecular mechanismremains elusive
 
Outlook -
Molecular mechanism of embryo implantation -
 JD Aplin
nderstanding of the key attributes (molecular or structural) thatonfer receptive status on endometrium. In fact, there is evidencehat a range of phenotypes will support implantation; it may wellbe that healthy embryos can to some extent overcome endometrialefects.
Identifying the molecular mediatorsof implantation
ommon assumptions that underpin experimental approacheso the identification of components involved in embryottachment and subsequent phases of implantation deserve closercrutiny: (i) it appears imperative that protein expression shouldccur in the implantation phase LE and in the trophectoderm of theatched blastocyst; (ii) since initial attachment occurs at the apicalide of maternal cells, display at this surface appears important;(iii) candidate components on the maternal and embryonic surfaceshould be capable of receptorligand interaction; (iv) in order toxplain varying receptivity, it is often assumed that expressionill be regulated with highest levels in the mid-secretory phase;nd (v) if mice null for the respective gene product show impairedmplantation, the hypothesis that there is involvement in humanss strengthened, though by no means proven.icroarray studies based on assumption (iv) have soughto identify a molecular signature characteristic of receptivendometrium (see, e.g. Ponnampalam
et al.
2004; Talbi
et al.
,006). Though informative in other respects, these studies haveot thus far been particularly helpful in identifying candidate geneproducts or pathways that might play a role in embryo attachment.ne problem is that LE contributes a minority of the cells presentn a typical endometrial biopsy; another is that endometrial tissueomposition has inherent variability, as seen very obviously inglandular and stromal histology (Buckley and Fox, 1989). Thiseads to uncertainty in histological dating (Coutifaris
et al.
2004;yers
et al.
2004). Furthermore, the proportion of epithelial andtromal cell-derived mRNA in similarly timed biopsies can varyidely (Jasper
et al.
2006).
Epithelial polarity and implantation
Work carried out in earlier decades led to recognition that epithelialpolarity plays a key role in uterine function (Denker, 1993;lasser and Mulholland, 1993). Thus, for example, key aspects of he steroid response in endometrial epithelial cells are controlledndirectly by paracrine signals reaching the basal epithelial surfacerom receptor-positive, steroid-responsive stromal cells (Cooke
el.
2002). The apical epithelial surface, as well as providing anmmune barrier (innate and acquired via immunoglobulin A), islearly the first site of interaction with the embryo. To preventpithelial cavities from sealing up, apical surfaces must normallybe non-self-adhesive. Thus, the hypothesis arose that implantationight occur in the context of altered maternal epithelial polarity.he epithelial glycocalyx, which contains MUC1 (Aplin
el.
1998; Meseguer
et al.
2001) and other higher molecularass mucin glycoproteins MUC4 (Idris and Carraway, 2000),UC6 (Gipson
et al.
1997) and MUC16 (CA125; Mylonas
el.
2003), is a key attribute of the apical epithelial surface. Itsbsence from basolateral cell surfaces in normal luminal (andglandular) endometrial epithelium defines these cells as showinga primary polarity and an apical barrier. In carcinoma cells, thistightly defined polarity of MUC1 expression is lost and novelglycoforms appear. There is evidence that the glycocalyx isaltered at the surface of uterodomes in the mid-secretory LE, withloss of MUC1 epitopes (Horne
et al.
2005).
First phase attachment
MUC1 can play a dual role in relation to cellular interactions.By virtue of high expression at the cell surface, density of glycosylation and extended conformation, it is capable of sterically hindering interaction with other cell surfaces mediatedby families of conformationally smaller adhesion molecules suchas integrins and cadherins (Hilkens
et al.
1992). On the other hand,some isoforms of MUC-1 are able to bind intracellular adhesionmolecule (ICAM)-1 (via the exposed core protein) (Regimbald
et al.
1996), and MUC-1 glycoforms carrying selectin ligandscan be observed in the endometrium (Hey and Aplin, 1996). Thishas led to the suggestion that L-selectin on the trophectodermalsurface of the blastocyst might mediate initial interaction withligand on the LE (Genbacev
et al.
2003), but other studies havefailed to detect L-selectin on the blastocyst (Campbell
et al.
 1995b; Bloor
et al.
, 2002) and more work is required to clarifythis important point. MUC-1 is polymorphic, with expression atthe cell surface of two alleles differing in the number of tandemrepeats in the mucin domain. The suggestion has been made thatvariation at this locus may be associated with infertility, but thisrequires further investigation (Goulart
et al.
2004).
Clearance of apical surface mucin byattaching embryos
In mouse and rat, MUC1 is strongly expressed at the apical LEsurface, but it is removed under maternal hormonal control inadvance of embryo attachment (reviewed in Aplin and Kimber,2004). This occurs even in leukaemia inhibitory factor (LIF)-nullfemale mice, which have a block to implantation (Chen
et al.
 2000). Here, embryos appear to attach normally to the epithelialsurface, but implantation arrests thereafter (Fouladi-Nashta
et al.
 2005). MUC1 is also lost from luminal epithelium in macaquesunder maternal control (Julian
et al.
2005). In humans, MUC-1is continuously present at the luminal surface of the endometrialcavity throughout the cycle, with an increase in the secretoryphase (Hey
et al.
1994). However, the human embryo attachesto primary cultured MUC1+ endometrial epithelial monolayers,and MUC1 immunostaining is lost from cells beneath andimmediately adjacent to the attachment site (Meseguer
et al.
 2001). Surprisingly, mouse embryos also appear to be capableof removing MUC1 from the surface of epithelial cells beneathand adjacent to their site of attachment, suggesting that a rescuepathway may be available in this species for circumstances inwhich MUC1 is not fully cleared under maternal control. Themechanism of clearance is still unknown, though it has beenshown that both ADAM 17 (TACE) and matrix metalloproteinase(MMP)-14 (MT-MMP1) are capable of releasing MUC1 from thecell surface (Thathiah
et al.
2003; Thathiah and Carson, 2004).It is clear that soluble signals pass locally between the embryoand receptors on maternal cells: chemokines (Dominguez
et al.
 2003), leptin (Cervero
et al.
2005) and chorionic gonadotrophin(Zhou
et al.
1999; Cameo
et al.
2004) may all play a role inmediating this early dialogue.
 
834
 
Based on these findings, one can postulate that initial attachmentto glycocalyx is followed by lateral clearance of mucin, leadingto interaction of trophoblast with higher affinity epithelialadhesion systems (
Figure 1
). Thus, the glycocalyx could act bothas an adhesion substrate and a barrier. Uterodomes represent apecialized area of LE plasma membrane that could be used forattachment, but this has not been observed (Bentin-Ley, 2000).
835
utlook -
Molecular mechanism of embryo implantation -
 JD Aplin
Figure 1.
(
a
Initial attachment is to the glycocalyx and may be mediated by a lectin
carbohydrate interaction. The lateral luminalepithelium (LE) membranes are rich in adhesion molecules. () Second phase attachment follows the clearance of apical glycocalyxin response to an embryonic signal. The lateral LE borders open and trophectodermal processes insert between the LE cells. MUC1 = mucin 1; OPN = osteopontin.
ab

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