Wednesday, December 07, 2022

Developmentally arrested IVF embryos may be forced to divide: New study finds genetic and metabolic markers of embryos that stop dividing

Why do two-thirds of in vitro fertilization (IVF) embryos go into developmental arrest? A new study published June 30 in the open-access journal PLOS Biology by Andrew Hutchins of Southern University of Science and Technology in Shenzhen, China; Guoqing Tong of Shuguang Hospital in Shanghai, China; and colleagues show that many embryos stored for IVF undergo specific genetic and metabolic changes that inhibit growth. These results help to explain the loss of developmental potential of multiple harvested embryos, and may point to strategies to increase the proportion of developmentally competent embryos.

Only 30% of IVF embryos progress to the blastocyst stage, the round ball of cells that begins to form cell layers that will eventually develop into tissues and organs. Several hypotheses have been made to explain this arrest of growth, but no single explanation has been fully supported by experiment. Animal models have offered only partial insight into the human condition because in many other species a very high proportion of externally fertilized eggs succeed in developing.

To understand the inability of so many human embryos to progress, the authors examined gene expression in arrested embryos. They found that a proportion of embryos (dubbed type 1) fail to make the transition from using stored maternal gene transcripts to activating the embryo’s own genome. This group differed from two other groups (types 2 and 3) in that this transition occurred successfully, but which displayed downregulation of several genes important for dynamic events of early development. These include notably the reduced activity of nucleosomes (the proteins that organize DNA) and ribosomes (the molecular factories that synthesize proteins) as well as gene factors important for regulating cell division.

Such changes are characteristic of cells that enter a temporary state, and senescence, a permanent loss of division ability. Embryos of both types 2 and 3 displayed low levels of glycolysis – a major energy-producing set of reactions – but differed in the level of oxidative phosphorylation, another energy-producing system. When the authors treated these embryos with resveratrol, a small molecule that activates (among other effects) a set of metabolism-regulating enzymes, more than half of the arrested embryos resumed development. , but less than 10% made it to the blastocyst stage.

“Our results suggest that many IVF embryos enter an aging-like state,” said Hutchins, “in which changes in metabolism and gene expression halt developmental progression.” It appears that it is possible for some embryos to overcome this arrested state, but much more work will be needed to determine the best strategy for doing so.”

Hutchins says, “It is surprisingly difficult to grow human embryos in vitro, which is a major problem for the treatment of human fertility. Our study suggests that several biological processes are causing the arrest, including epigenetic in embryos. and metabolic problems.”

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