The pre-conceptual, intrauterine, and early life environments can have a profound and long-lasting impact on the developmental trajectories and health outcomes of the offspring. Given the relatively low success rates of Assisted Reproductive Technologies (ART; ~25%), additives and adjuvants, such as glucocorticoids, are utilized to improve the success rate. Considering the dynamic developmental events that occur during this window, these exposures may alter blastocyst formation at a molecular level, and as such, affect not only the viability of the embryo and ability of the blastocyst to implant, but also the developmental trajectory of the first three cell lineages, ultimately influencing the physiology of the embryo. In this study we present a comprehensive single-cell transcriptome, methylome and small RNA atlas in the day 7 human embryo. We demonstrate that, despite no change in morphology and developmental features, preimplantation glucocorticoid exposure reprograms the molecular profile of the TE lineage and these changes are associated with an altered metabolic and inflammatory response. Our data also suggest that glucocorticoids can precociously mature the TE sub-lineages, supported by the presence of extravillous trophoblast markers in the polar sub-lineage and presence of X Chromosome dosage compensation. Further, we have elucidated that epigenetic regulation (DNA methylation and microRNAs (miRNAs)) likely underlie the transcriptional changes observed. This study suggests that exposures to exogenous compounds during preimplantation may unintentionally reprogram the human embryo, possibly leading to suboptimal development and longer-term health outcomes.
Preimplantation development is arguably one of the most critical stages of embryogenesis. Beginning with the formation of the totipotent zygote post-fertilization, a series of cell divisions and a complex coordination of physical cues, molecular mechanisms and changes in gene expression lead to the formation of the blastocyst, a structure capable of implanting into the uterine wall. The blastocyst is comprised of more specified cellular lineages, that will give rise to every tissue of the developing organism as well as the extra-embryonic lineages which support fetal growth. While the mouse has been used as a model to understand the events of preimplantation development for decades, in recent years an expanding body of work has been conducted using the human embryo. These studies have identified some crucial species differences, particularly in the transcriptional and spatio-temporal regulation of lineage markers and responses to cell signaling perturbations. In this review, recent findings pertaining to the processes of preimplantation development, with an emphasis on specification of the first cellular lineages, in the mouse and human are compared side-by-side. Highlighting differences and noting mechanisms that require further examination in the human embryo is of critical importance for both the accurate translation of results from the mouse model and our overall understanding of mammalian development. We further highlight and critique the latest advancement in Reproductive research, the development of the 3D stem cell-based models known as ‘blastoids’. This knowledge has major clinical implications for assisted reproductive technologies such as in vitro fertilization and for applications in stem cell biology.
Study question Is the guinea pig a good model for human preimplantation embryo development? Summary answer Preimplantation guinea pig embryos better recapitulate the human embryo compared to the mouse, offering a promising new model to study preimplantation, naive pluripotency and infertility. What is known already Mouse embryos have historically been used to model reproduction, but caution is warranted as several discrepancies with the human exist during preimplantation. Guinea pigs have been a long standing model of human development and are known to better recapitulate placentation and brain development compared to the mouse. We now speculate that guinea pigs may also represent a superior animal model to study preimplantation development. However, to date, guinea pig preimplantation embryos remain to be investigated in great detail. We now aim to assess the developmental dynamics of the guinea pig preimplantation embryo with cross-species comparisons to both human and mouse. Study design, size, duration In vivo guinea pig embryos were flushed 3-6 days post-fertilization (N = 10-12/ time point). Embryos (embryonic day (E)3-6 were collected and processed for downstream experiments. Participants/materials, setting, methods Immunofluorescence of Sox2 (epiblast (EPI) marker), Sox17 and Gata6 (primitive endoderm (PE) marker) and Cdx2 and Gata3 (trophectoderm (TE)) was performed. Cells were counted and the dynamics of lineage marker expression and blastocyst formation were determined. In parallel, scRNA-seq (Smartseq2) of guinea pig embryos was performed. Main results and the role of chance At the compacted morula stage (late E4.25-E4.75), similar to the human and in contrast to the mouse, we observe co-expression Sox2, Gata6 and Gata3, with no detection of Sox17 and Cdx2. Similar to the human, blastocyst formation begins between E5.0-E5.25. By mid-blastocysts (E5.25-E5.5), cells are poised for lineage specification with a high number of cells co-expressing Sox2/Sox17, and no cells co-expressing markers of all three lineages. By late blastocyst, E5.5-E5.75, specification of all three lineages is achieved and no co-expression Sox2/Sox17/Cdx2 or Sox2/Gata6/Gata3 is observed. Further, similar to the human and in contrast to the mouse, there is a disconnect between morphology and lineage specification in the early blastocyst. These data suggest that signaling pathways governing lineage specification in the human and guinea pig differ compared to the mouse. Finally, cross-species analysis of scRNA-seq revealed conserved pluripotency gene signatures between the human and guinea pig embryos, suggesting that the guinea pig may also contain naive stem cells and that plasticity of these lineages may be more similar to the human compared to the mouse. Limitations, reasons for caution Our model only explores similarities/differences between the human and guinea pig preimplantation embryo with regards to timing of development and lineage segregation. Wider implications of the findings In addition to helping us understand human preimplantation development, this new model may serve to examine the longer-term consequences of preimplantation exposures. Further, insights from this study have broad application in the fields of Reproduction, Development, ART and Stem cell biology. Trial registration number NA
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