![]() ![]() ![]() We also show that patterns of gene expression found in non-viable embryos may affect cortical granule release and zona-hardening, which helps to explain the link between embryo viability and mechanical properties. Using these parameters to stratify embryos by viability, we identify important genes and pathways that play key roles in pre-implantation embryo development, most of which are reflective of oocyte nuclear and cytoplasmic maturation, DNA repair and cellular stress response. In this study, we report a set of mechanical parameters that can be measured nondestructively within hours after fertilization and can identify human zygotes destined to arrest, with >90% precision, 95% specificity and 75% sensitivity ( Fig. Embryo and oocyte stiffnesses have also been correlated to pregnancy in humans, and to maternal age in mouse, indicating that there may be a link between mechanics and viability 21, 22, 23. ![]() The response of the oocyte membrane to needle puncture during intracytoplasmic sperm injection (ICSI) was found to be predictive of embryo morphology and survival in culture 19, 20. In mouse and human embryos, cortical granule release during fertilization causes a physical change in stiffness, which is called ‘zona-hardening’ 18, a process previously described only biochemically. In recent years, studies have shown that mechanical inputs play a major role in regulating cell fate and function at the molecular level 15, and a cell’s internal state may also be reflected in its mechanical properties 16, 17. An accurate and nondestructive predictor of viability before EGA would allow us a global view of deficiencies in the oocyte transcriptome, which can lead an embryo to arrest. However, these measures of oocyte quality can only identify a subpopulation of all non-viable oocytes because chromosomal abnormalities can arise after this stage, and maternal age is not a perfect predictor of viability. Some studies have begun to explore differences at the level of transcription between high- and poor-quality oocytes by inferring quality from maternal age 12, 13 or ploidy 14. The mechanisms of developmental failure in embryos resulting from poor-quality oocytes are also largely unknown. Without a reliable predictor of embryo viability before EGA, it is still unclear to what extent developmental potential is determined by the oocyte. However, these criteria are highly subjective, and their predictive value is controversial 11. In humans, various oocyte morphological characteristics 6 have been correlated with embryo development and implantation potential, including zona thickness 7, granularity 8, perivitelline space 9 and oocyte shape 10. The major wave of transcription involved in EGA is observed at the one-cell zygote to the two-cell stage in mouse 4 and the four- to eight-cell stage in humans 5. Before EGA no transcription occurs, and so the very first steps of embryogenesis are controlled exclusively by maternal information inherited from the oocyte 1, 2, 3. It has been suggested that an embryo’s fate is determined very early in development, before embryonic genome activation (EGA), or even before fertilization 1, 2, 3. Our results suggest that embryo potential is largely determined by the quality and maturation of the oocyte before fertilization, and can be predicted through a minimally invasive mechanical measurement at the zygote stage. In addition, we show that low-quality oocytes may undergo insufficient cortical granule release and zona-hardening, causing altered mechanics after fertilization. We demonstrate that there are significant differences between the transcriptomes of viable and non-viable zygotes, especially in expression of genes important for oocyte maturation. Here we report that zygote viscoelastic properties can predict blastocyst formation in humans and mice within hours after fertilization, with >90% precision, 95% specificity and 75% sensitivity. Attempts to correlate patterns of oocyte gene expression with successful embryo development have been hampered by the lack of reliable and nondestructive predictors of viability at such an early stage. The causes of embryonic arrest during pre-implantation development are poorly understood. ![]()
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