Metabolic and epigenetic dysfunctions underlie the arrest of in vitro fertilized human embryos in a senescent-like state

Abstract

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3- to 8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a senescent-like state, marked by cell cycle arrest, the down-regulation of ribosomes and histones and down-regulation of MYC and p53 activity. The arrested embryos can be divided into 3 types. Type I embryos fail to complete the maternal-zygotic transition, and Type II/III embryos have low levels of glycolysis and either high (Type II) or low (Type III) levels of oxidative phosphorylation. Treatment with the SIRT agonist resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype, which is accompanied by changes in metabolic activity. Overall, our data suggests metabolic and epigenetic dysfunctions underlie the arrest of human embryos.

Modulating the epigenetic state promotes the reprogramming of transformed cells to pluripotency in a line-specific manner

“…Aneuploidy is a common feature of cancer, although the role of aneuploidy in transformation remains unclear (Chunduri & Storchova, 2019). A normal karyotype is required for post-implantation embryonic development (Shahbazi et al , 2020), but may not be incompatible with pluripotency (Gaztelumendi & Nogues, 2014; Taapken et al , 2011; Yang et al , 2022). To rule out the impact of karyotype abnormalities on reprogramming capability we confirmed a normal karyotype for four of the lines that the subsequent study will mainly focus on ( Figure S2j ).…”

Assisted Reproductive Technology without Embryo Discarding or Freezing in Women ≥40 Years: A 5-Year Retrospective Study at a Single Center in Italy

“…There is evidence that the longer the in vitro cultures last (i.e., blastocyst transfer in comparison to the cleavage stage), the more epigenetic changes occur [ 65 , 66 ]. We know that only a percentage of fertilized oocytes arrive at the blastocyst stage in vitro and recent observations suggest that metabolic and epigenetic dysfunctions underlie the arrest of human ART embryos before their compaction [ 67 ].…”

Dissecting the molecular features of bovine-arrested eight-cell embryos using single-cell multi-omics sequencing

“…Chromosomal abnormalities inherited from gametes or that occur during preimplantation development are major causes of implantation failure, miscarriage, and other abnormalities [62, 63]. Previous studies have suggested that aneuploidies contribute to embryonic arrest, and the levels of aneuploidy can be greater than 70% in human embryos [17]. In this study, we observed that blastomeres from arrested eight-cell embryos were more prone to CNVs than blastomeres from blastocyst-developed eight-cell embryos, which indicates that aneuploidies are likely associated with developmental delay of preimplantation embryos in cattle.…”

“…Developmental block of embryos produced in vitro remains the major concern in assisted reproductive technologies used in domestic animals [14]. Cattle are one of the most economically valuable livestock species, but the in vitro rate of blastocyst formation of bovine embryos is inefficient at only 20-40% [15][16][17][18]. Therefore, improvement to the blastocystformation rate of bovine embryos produced in vitro is the principal and urgent goal for efficient in vitro embryo production.…”