introduction
The early development of the human embryo is a highly complex and precisely regulated process. Zygotes undergo a series of cell divisions and differentiation to eventually form a cell population with different fates. These cell populations include the inner cell mass (ICM), which develops into the fetus itself, and the trophectoderm (TE), which mainly forms accessory structures such as the placenta. Although previous studies have focused on mouse models, there are significant species differences in the early development of human embryos. The study "The first two blastomeres contribute unequally to the human embryo", a retrospective lineage reconstruction study based on genome sequencing and single nucleotide polymorphism analysis, reported in Cell on May 13, showed that there is a significant clonal imbalance in humans, the origin of which can be traced back to the 2-cell stage of the embryo. In this study, we explored the specific contributions of two blastomeres in the inner cell mass, ectosomes (ectoderm) and trophoblastic ectoderm of the human embryonic 2-cell stage through prospective lineage tracing and live imaging, combined with non-invasive cell labeling and computational prediction. By tracing the lineage of human embryos from the 2-cell stage to the blastocyst stage, it was found that most of the endocytomass cells were mainly derived from one of the primordium cells of the 2-cell stage. During the transition from the 8-cell stage to the 16-cell stage, the number of internalized cells is extremely small, and these internalized cells are more frequently derived from the 2-cell primordium cells that divide first. Early asymmetric cell division is an important bottleneck controlling the composition of embryonic clones. Computational models predict that this imbalance in the clonal contribution can reach more than 60% in the inner cell mass, and this imbalance is preserved and expanded in subsequent embryonic development. This study revealed a significant clonal imbalance in the early development of human embryos and identified the specific mechanism of this imbalance. Through prospective lineage tracing and computational modeling, this study provides evidence for the first time that early cellular internalization processes and asymmetric cell division have a significant impact on embryonic clonal composition. This discovery not only provides a new perspective for understanding the basic mechanism of early development of human embryos, but also provides an important reference for applied research in the field of assisted reproductive technology and embryo engineering. In the future, further research on the regulatory mechanisms in these early developmental processes will help improve the precision and effectiveness of human reproductive health and disease treatment.
In the early stages of embryonic development, the zygote first divides to form 2 blastomeres, then further divides into 4, 8, 16 cells, and finally blastocysts. Blastocysts are composed of two parts: the inner cell mass (ICM) and the trophectoderm (TE). The inner cell mass will develop into the fetus, while the trophoblastic ectoderm will form supporting structures such as the placenta. Previous studies have shown that there are significant species differences in the early development of human embryos, although studies in mouse models provide a wealth of information on developmental mechanisms. Therefore, revealing the early developmental processes of the human embryo, especially the cellular behavior of the 2-cell stage, is essential for understanding the origin of human life.
The study focuses on the following scientific questions:
Is there an imbalance in the contribution of the two primordium cells of the 2-cell stage in the inner cell mass and trophoblastic ectoderm? Is the formation of this imbalance related to early asymmetric cell division? Does the early process of cellular internalization control the clonal composition of the embryo?
To answer these questions, the research team used lineage tracing and live imaging, combined with non-invasive cell labeling and computational prediction, to observe and analyze the development of human embryos from the 2-cell stage to the blastocyst stage.
Major studies have found that the source of the inner cell mass is uneven: by tracing the lineage of human embryos from the 2-cell stage to the blastocyst stage, it has been found that most of the inner cell mass cells are mainly derived from one of the primordium cells of the 2-cell stage. This suggests that in the early stages of embryonic development, the fate of cells has begun to exhibit significant imbalances. The key role of early asymmetric cell division: During the transition from the 8-cell stage to the 16-cell stage, the number of cellular internalizations is minimal, and these internalized cells are more frequently derived from the 2-cell primordium cells that first divided. This means that the cells that divide first are more likely to form the founding cells of the inner cell mass by asymmetric division. Bottleneck effect of cellular internalization: early asymmetric cell division is an important bottleneck controlling the composition of embryonic clones. Computational models predict that this imbalance in the clonal contribution can reach more than 60% in the inner cell mass, and this imbalance is preserved and expanded in subsequent embryonic development.
Cell division and fate determine In the first cell division after fertilization, the zygote divides to form two almost identical 2-cell primordium cells. Theoretically, these two cells would each develop into half an embryo. However, retrospective genomic analysis has shown that there is a significant clonal imbalance in humans, i.e., one cell contributes more to the embryo than another. Through labeling and real-time imaging, the researchers found that this imbalance began to manifest itself in the early stages of the embryo.
Mechanism of asymmetric cell divisionDuring the transition from 8 cell stage to 16 cell stage, the cell division mode plays a key role in the formation of inner cell clusters. It was found that asymmetric cell division led to the bottleneck effect of cellular internalization, so that only a few cells were able to internalize and form endocell clusters. These internalized cells are mainly derived from the 2-cell primordium cells that divide at the earliest, suggesting that the timing of cell division has an important influence on the composition of the inner cell mass.
Computational Model PredictionTo further validate the experimental results, the research team built a computational model that simulated processes such as cell division, cell death, and cell internalization. Model predictions suggest that the smaller the number of internalized cells in the first asymmetric division of the 8-cell stage, the higher the degree of clonal imbalance. This is highly consistent with the observed imbalance in the composition of the inner cell mass.
Effect of imbalance on embryonic development This early imbalance is preserved and expanded in subsequent embryonic development. Model predictions have shown that in most embryos, a 2-cell primordium cell contributes more than 60% to the inner cell mass. This imbalance not only affects the composition of the inner cell mass, but also has a profound impact on the future development of the fetus.
Through prospective lineage tracing and computational modeling, this study revealed a significant clonal imbalance in human embryos during early development, and identified the specific mechanism of this imbalance. This discovery not only provides a new perspective for understanding the basic mechanism of early development of human embryos, but also provides an important reference for applied research in the field of assisted reproductive technology and embryo engineering.
This study provides a new perspective for us to understand the fundamental mechanisms of human embryonic development. However, more research is needed to fully unravel these mechanisms. For example, the specific regulatory mechanisms of cell division, the selection mechanisms of internalized cells, and how these processes are regulated by genes and environmental factors need to be further explored. In addition, these findings are also of great significance for assisted reproductive technology, which may further improve the success rate of IVF technology in the future by regulating the early cell division and internalization process, optimizing embryo culture and selection.
By revealing the cloning imbalance in the early development of human embryos, this study provides an important scientific basis for us to understand the origin of life and embryonic development, and also provides a new idea for the development of clinical assisted reproductive technology. This is not only an important progress in scientific research, but also brings new hope to countless families who hope to gain a new life through assisted reproductive technology.
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DOI:https://doi.org/10.1016/j.cell.2024.04.029
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