Problem In mammals, implantation involves interactions between an activated blastocyst and a receptive endometrium. There are controversies on the role of microRNAs in preimplantation embryo development. The actions of endometrial microRNAs on implantation are beginning to be understood. Method of Study Review of literature on microRNAs in preimplantation embryos and endometrium. Results Emerging evidence suggests a role of microRNAs in blastocyst activation and implantation. Differential expression of microRNAs is found between receptive and non‐receptive endometria. Members of the let‐7, miR‐200, miR‐30 families, and the miR‐17‐92 clusters are more commonly found to be associated with endometrial receptivity. Experimental studies show that the targets of the differentially expressed microRNAs affect endometrial receptivity, decidualization, and embryo implantation. Free and exosome/microvesicle containing microRNAs have been detected in human and ovine uterine luminal fluid (ULF). They may serve as mediators of embryo–endometrium dialog. Some observations suggest that the microRNAs in ULF may be used as biomarkers in infertility treatment. Conclusion MicroRNAs in endometrium and blastocysts are involved in the implantation process.
It is well known that embryo implantation is a critical process in which embryo should be able to reach and attach to endometrium. Until now, various types of factors are involved in the regulation of this process. S100 proteins are calcium‐binding proteins, which have vital roles in embryo implantation and have been considered as possible candidate markers for endometrial receptivity. However, studies regarding mode of actions of these proteins are scarce and more mechanistic insights are needed to clarify exact roles of each one of the S100 protein family. Understanding of function of these proteins in different compartments, stages, and phases of endometrium, could pave the way for conducting studies regarding the therapeutic significance of these proteins in some disorders such as recurrent implantation failure. In this review, we outlined roles and possible underlying mechanisms of S100 protein family in embryo implantation.
As a critical stage of pregnancy, the implantation of blastocysts into the endometrium is a progressive, excessively regulated local tissue remodeling step involving a complex sequence of genetic and cellular interplay executed within an optimal time frame. For better understanding the causes of infertility and, more importantly, for developing powerful strategies for successful implantations and combating infertility, an increasing number of recent studies have been focused on the identification and study of newly described substances in the reproductive tree. The endothelins (ET), a 21‐aminoacidic family of genes, have been reported to be responsible for the contraction of vascular and nonvascular smooth muscles, including the smooth muscles of the uterus. Therefore, this review aims to comprehensively discuss the physiological role of endothelins and signaling through their receptors, as well as their probable involvement in the implantation process.
Citation Rashid NA, Lalitkumar S, Lalitkumar PG, Gemzell‐Danielsson K. Endometrial Receptivity and Human Embryo Implantation. Am J Reprod Immunol 2011; 66 (Suppl. 1): 23–30 Problem The pre‐requisite of successful implantation involves an intricate cascade of molecular interactions which plays a crucial role in preparing receptive endometrium and implanting blastocyst. Method of study Data are hereby presented for a better understanding of endometrial receptivity in women, hoping to provide a comprehensive picture of the process and identify new areas of basic and translational research in the biology of blastocyst implantation. Results Timely regulation of the expression of a number of complex molecules like hormones, cytokines and growth factors, and their crosstalk from embryonic and maternal endometrial side play a major role in determining the fate of the embryo. The molecular basis of endometrial receptivity and the mechanisms by which the blastocyst first adheres to the luminal epithelium and then penetrates into the stroma are only just beginning to be resolved. Conclusion Advances in the development of implantation models and ‘omics’ technologies, particularly proteomics and metabolomics, are set to have a major impact on the development of this field.
Implantation failure and inadequate placental development are important contributors to infertility, recurrent miscarriage, and other pregnancy-related problems in women. Better understanding of these processes is hampered by the difficulty in obtaining human tissue from which primary cells can be prepared and by the very limited access worldwide to human blastocysts for experimentation. Therefore, the use of appropriate cell lines, particularly for functional studies of implantation and placentation, is imperative. While a number of cell lines for both endometrium and trophoblast have been developed and are widely used, it is difficult for researchers to decide which of these are most appropriate for studies of particular functions. This brief review summarizes the known phenotypes of the most widely used cell lines and indicates which might be the most appropriate for individual studies.
Uterine glands are essential for pregnancy establishment. By employing forkhead box A2 (FOXA2)-deficient mouse models coupled with leukemia inhibitory factor (LIF) repletion, we reveal definitive roles of uterine glands in embryo implantation and stromal cell decidualization. Here we report that LIF from the uterine glands initiates embryo-uterine communication, leading to embryo attachment and stromal cell decidualization. Detailed histological and molecular analyses discovered that implantation crypt formation does not involve uterine glands, but removal of the luminal epithelium is delayed and subsequent decidualization fails in LIF-replaced glandless but not gland-containing FOXA2-deficient mice. Adverse ripple effects of those dysregulated events in the glandless uterus result in embryo resorption and pregnancy failure. These studies provide evidence that uterine glands synchronize embryo-endometrial interactions, coordinate on-time embryo implantation, and impact stromal cell decidualization, thereby ensuring embryo viability, placental growth, and pregnancy success.
Cell adhesion in endometrial epithelium is regulated to maintain the continuity and protectiveness of the luminal covering cell layer while permitting interstitial implantation of the embryo during a restricted period of about 4 days. Many apparently normal embryos fail to implant, and epithelial‐embryo adhesion remains a poorly understood phenomenon. After menstruation, epithelial regeneration occurs by epiboly from the basal residues of glands, an activity that requires migration on extracellular matrix as well as cell–cell cohesion. Here we review current knowledge of adhesion molecules in the epithelium.
: The success of embryonic implantation relies on an ideal cross‐talk between the embryo and the receptive endometrium. This article focuses on the role of leukemia inhibitory factor (LIF) and its receptors in human embryo implantation. LIF is a secreted glycoprotein first described as a factor that induced the differentiation of mouse myeloid leukemic M1 cells into macrophages and later proposed as a marker of the embryo implantation process. An important role for LIF in implantation was shown on LIF knockout mice, when embryo implantation did not occur. In endometrium of healthy women, LIF and LIF mRNA are expressed throughout the menstrual cycle with a striking increase in the midsecretory phase, coinciding with a supposed window of implantation. Correlation in the expression of LIF and some other markers of implantation has been reported. LIF acts on cells by binding to the LIF receptor (LIFR) and gp130. Human blastocysts express mRNAs for LIFR and gp130, participating actively in establishing contact with the endometrium. In the endometrium, LIFR and gp130 are expressed in the endometrial epithelium throughout the cycle with strong increase in the midsecretory phase. Endometrium of infertile women produces significantly less LIF during the period of receptivity. The role of LIF gene mutations in unexplained infertility and implantation failures in IVF patients is not clear yet. Infertile patients showed reduced secretion of LIFR and gp130 compared with fertile controls during the implantation window. Recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.
Objective To study the potential role of miR-30a-3p in embryo implantation and explore underlying mechanisms. Methods We first established normal pregnancy, pseudopregnancy, delayed implantation, and artificial decidualization mouse models. Next, we detected miR-30a-3p expression profiles of these models with real-time reverse transcription PCR(qRT-PCR), then predicted potential target genes through a dual-luciferase assay. Immunofluorescence-fluorescence in situ hybridization co-located miR-30a-3p and target genes. We then examined the effect of miR-30a-3p on embryo implantation in vivo and in vitro. Wound healing and transwell assays were employed to explore possible miR-30a-3p effects on epithelial-mesenchymal transition (EMT), before molecules related to the latter process were examined with qRT-PCR. Results MiR-30a-3p expression decreased significantly on embryo implantation day, compared with the peri-implantation period (P<0.05). Identified target gene Snai2 expression increased significantly during implantation (P<0.05). In vivo and in vitro analysis showed that up-regulation of miR-30a-3p by agomir and mimics resulted in decreased implantation sites and embryo implantation rate. Transfection of miR-30a-3p mimics to HEC-1-b cells decreased expression of Snai2 and mesenchymal markers (Vimentin and N-cadherin). Furthermore, wound healing area decreased, as did migration and invasion capacity. Conclusion MiR-30a-3p is down-regulated in the embryo implantation period and might have some effect on embryo implantation by acting as a suppressor of EMT through targeting Snai2. MiR-30a-3p is down-regulated on the embryo implantation day and suppresses the EMT through targeting Snai2, and up-regulation of miR-30a-3p weakens the capacity of migration and invasion.