Embryo implantation in eutherian mammals is a highly complex process and requires reciprocal communication between different cell types of the embryo at the blastocyst stage and receptive uterus. The events of implantation are dynamic and highly orchestrated over a species-specific period of time with distinctive and overlapping expression of many genes. Delayed implantation in different species has helped elucidate some of the intricacies of implantation timing and different modes of the implantation process. How these events are coordinated in time and space are not clearly understood. We discuss potential regulators of the precise timing of these events with respect to central and local clock mechanisms. This review focuses on the timing and synchronization of early pregnancy events in mouse and consequences of their aberrations at later stages of pregnancy.
Failure of the human embryo to implant into the uterine wall during the early stages of pregnancy is a major cause of infertility. Implantation involves embryo apposition and adhesion to the endometrial epithelium followed by penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma. Although gene-knockdown studies have highlighted several molecules that are important for implantation in the mouse, the molecular mechanisms controlling implantation in the human are unknown. Here, we demonstrate in an in vitro model for human implantation that the Rho GTPases Rac1 and RhoA in human endometrial stromal cells modulate invasion of the human embryo through the endometrial stroma. We show that knockdown of Rac1 expression in human endometrial stromal cells inhibits human embryonic trophoblast invasion into stromal cell monolayers, whereas inhibition of RhoA activity promotes embryo invasion. Furthermore, we demonstrate that Rac1 is required for human endometrial stromal cell migration and that the motility of the stromal cells increases at implantation sites. This increased motility correlates with a localized increase in Rac1 activation and a reciprocal decrease in RacGAP1 levels. These results reveal embryo-induced and localized endometrial responses that may govern implantation of the human embryo.
Embryo implantation varies widely in placental mammals. We review this variation in mammals with a special focus on two features:the depth of implantation and embryonic diapause. We discuss the two major types of implantation depth, superficial and interstitial, and map this character on a well-resolved molecular phylogenetic tree of placental mammals. We infer that relatively deep interstitial implantation has independently evolved at least eight times within placental mammals. Moreover, the superficial type of implantation represents the ancestral state for placental mammals. In addition, we review the genes involved in various phases of implantation, and suggest a future direction in investigating the molecular evolution of implantation-related genes.
In adult animals, the significance of circadian clocks in the regulation of physiology is well established. However, the physiological roles of embryonic clock genes on early embryo development, implantation and perinatal survival are still unclear. In the present study, using genotyping, embryo culture and transfer, the early embryo development, implantation, and perinatal survival of Bmal1+/+, Bmal1+/- and Bmal1-/- embryo were studied. At cleavage stage, the genotype ratio of Bmal1+/+, Bmal1+/- and Bmal1-/- embryo was 1:1.97:0.95, respectively (p > 0.05). Morula or early blastocyst developmental ratio was 83.8 +/- 14.3, 87.1 +/- 9.2 and 88.7 +/- 1 4.5%, respectively (p > 0.05). After transferring of the three types of embryos to pseudopregnant wild-type mice, the implantation sites 4days later was 7.7 +/- 0.9, 7.2 +/- 1.2 and 7.5 +/- 0.5 (n=4, F = 0.265, p = 0.773). Mean litter size of the mice after transferring with the three types of embryos was 5.5, 6.0, and 3.0 (n = 3, F = 30.3, p = 0.001). The development of Bmal1 null embryos was not impaired in preimplantation and early implantation stages, but the litter size had a trend to decrease.
Embryo implantation is the crucial step for a successful pregnancy. Diverse factors, including adhesion molecules, growth factors, and cytokines are important for embryo implantation through improving endometrial receptivity. Benzoic acid (BA), a component of various plants, has been shown to have antifungal and antioxidant effects. However, the effect of BA on embryo implantation remains unknown. Here, we showed the contribution of BA for the enhancement of endometrial receptivity through the leukemia inhibitory factor (LIF)-dependent increase of integrin alpha V, beta 3, and beta 5 expression. Furthermore, in vivo study using a mifepristone-induced implantation failure model showed that BA definitely improves the numbers of implantation embryos. Taken together, we suggest that BA has a novel function for embryo implantation through the up-regulation of LIF-mediated integrins, and may be a candidate for therapeutic medicine to increase the pregnancy rate.
Implantation failure is a major limiting factor in assisted reproduction improvement. Dysfunction of embryo-maternal immuno-tolerance pathways may be responsible for repeated implantation failures. This fact is supported by immunotropic theory stipulating that maternal immune cells, essentially uterine CD56(+) natural killer cells, are determinants of implantation success. In order to test this hypothesis, we applied endometrium immuno-modulation prior to fresh embryo transfer for patients with repeated implantation failures. Peripheral blood mononuclear cells were isolated from repeated implantation failure patients undergoing assisted reproductive technology cycles. On the day of ovulation induction, cells were isolated and then cultured for 3 days and transferred into the endometrium cavity prior to fresh embryo transfer. This immunotherapy was performed on 27 patients with repeated implantation failures and compared with another 27 patients who served as controls. Implantation and clinical pregnancy were increased significantly in the peripheral blood mononuclear cell test versus control (21.54, 44.44 vs. 8.62, 14.81%). This finding suggests a clear role for endometrium immuno-modulation and the inflammation process in implantation success. Our study showed the feasibility of intrauterine administration of autologous peripheral blood mononuclear cells as an effective therapy to improve clinical outcomes for patients with repeated implantation failures and who are undergoing in vitro fertilization cycles.
The aim of this study was to explore whether the morphology of polar bodies (PBs) estimated at 16-18 h after insemination can be used as an additional marker for predicting human embryo quality or pregnancy outcome. The data from 355 patients who received standard in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment after controlled ovarian hyperstimulation were recruited. Normal fertilized 3048 zygotes from 382 cycles were divided into two groups, PBs intact or fragmented, according to the morphology of PBs assessed at 16-18 h after insemination. Embryo quality and pregnancy outcome were compared between the two groups. It was shown that the day 3 (D3) good embryo rate, good quality blastocyst rate and available embryo rate of the PBs intact group were all significantly higher than that of the corresponding fragmented groups. However, no significant differences in pregnancy rate (PR) or implantation rate (IR) were observed between the intact and fragmented groups. Although PBs morphology estimated at 16-18 h after insemination had little effect on PR or IR in fresh embryo transfer cycles, a better embryo quality can be achieved in the PB-intact group, which is valuable for embryo selection.
Frozen embryo transfer cycles are now common practice, however, various aspects regarding the potential of frozen embryos remain unclear. The main goal of the present study was to assess embryo quality before and after slow freezing procedure, and more specifically blastomere loss and embryo quality as indicator of viability. A single center retrospective analysis of single frozen-thawed embryo replacements (s-FER) was performed. The embryo quality before and after slow freezing and thawing, implantation, and pregnancy rates were recorded. One hundred and twenty seven s-FER were included in the final analysis. The probability of achieving an ongoing pregnancy was significantly associated with embryo quality and the percentage of blastomere loss after thawing. Considering thawed embryos, a non-significant difference in term of implantation rate was observed, regardless to their post-thawing quality and the percentage of blastomeres loss. In conclusion, current data suggest that thawed embryos are capable of implantation regardless of their morphological quality and the degree of cryoinjury sustained. (C) 2016 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Sp. z o.o. All rights reserved.
A critical point in mammalian development is when the early embryo implants into its mother's uterus. This event has historically been difficult to study due to the fact that it occurs within the maternal tissue and therefore is hidden from view. In this review, we discuss how the mouse embryo is prepared for implantation and the molecular mechanisms involved in directing and coordinating this crucial event. Prior to implantation, the cells of the embryo are specified as precursors of future embryonic and extra-embryonic lineages. These preimplantation cell fate decisions rely on a combination of factors including cell polarity, position and cell-cell signalling and are influenced by the heterogeneity between early embryo cells. At the point of implantation, signalling events between the embryo and mother, and between the embryonic and extraembryonic compartments of the embryo itself, orchestrate a total reorganization of the embryo, coupled with a burst of cell proliferation. Newdevelopments in embryo culture and imaging techniques have recently revealed the growth and morphogenesis of the embryo at the time of implantation, leading to a new model for the blastocyst to egg cylinder transition. In this model, pluripotent cells that will give rise to the fetus self-organize into a polarized three-dimensional rosette-like structure that initiates egg cylinder formation.
Implantation of the embryo is critical for the initiation of intrauterine development of early embryos. It depends on the proper soil formed by the decidualized pregnant uterus. In the present article I have reviewed the evolution of the modern concepts of decidualization and embryonic implantation, emphasizing how closely interrelated these two processes are. Special emphasis and recognition is given to the Boston pathologist Arthur T. Hertig, who studied for 15 years with another Bostonian, John Rock, a gynecologist, human implantation and early embryogenesis, thus providing the basis for future studies of human reproductive biology, infertility and contraception.