Rejuvenating aged egg cells to improve IVF outcomes

Researchers at the National University of Singapore (NUS) have developed an innovative technique to enhance the reproductive potential of aged oocytes, or immature egg cells, potentially paving the way for better outcomes of assisted reproductive technologies for older females.

The team demonstrated the rejuvenation of oocytes from an older preclinical model by using a young follicular environment to partially restore its reproductive function, and in turn, generated a better quality egg for in vitro fertilisation (IVF). They have filed a patent application for their innovation and published their results in the journal Nature Aging.

Female reproductive aging is a natural process that is associated with changes in a woman’s reproductive system over time, including a sharp decline in egg quantity and quality. With many women choosing to have children later in life, understanding and mitigating the impacts of aging on egg cell quality has become crucial to develop strategies for successful egg cell maturation, fertilisation and embryo development.

Working to understand the mechanics behind female reproductive aging, NUS researchers led by Professor Rong Li and Dr Wang Haiyang have constructed and used hybrid ovarian follicles extracted from a preclinical model to provide direct evidence that an aged follicular environment could harm the quality and developmental potential of young oocytes. More importantly, the team demonstrated that an oocyte from an aged follicular environment can be rejuvenated by transplanting it into a young follicular environment.

“The inspiration for this research came from the growing need to address age-related fertility issues,” Li said. “It is extremely curious that the female reproductive system, especially the ovarian follicles that contain oocytes, appear to be the fastest aging system of the human body. This fact prompted us to delve deeper to gain a much better understanding of this aging process and to discover ways to mitigate it.”

Revitalising an aged egg cell

An ovarian follicle is a basic functional unit in the mammalian ovary, composed of somatic cells (granulosa cells) that surround and support an oocyte as it grows and matures before ovulation. The granulosa cells communicate with the oocyte to provide essential nutrients and components through channels known as transzonal projections. In turn, the oocyte provides key components that signal the growth and development of granulosa cells.

The researchers tapped on this understanding of the relationship between somatic cells of the ovarian follicle and the oocyte to create hybrid ovarian follicles through an ex vivo 3D culturing platform, building upon previous methods. The team then extracted the oocyte from its original follicular environment and transplanted it to a new follicular environment, whose own oocyte had been removed, to construct the hybrid ovarian follicle.

For a start, the researchers confirmed that aged granulosa cells, compared to young granulosa cells, exhibited an increase in the hallmarks of aging, such as an increase in indicators of DNA damage and other factors linked to programmed cell death. They showed that this aged follicular environment can reduce the quality and developmental potential of a young oocyte.

The research team then created hybrid ovarian follicles containing an aged oocyte (ie, an immature egg cell from an aged follicular environment) in a young follicular environment. The researchers demonstrated that the quality and developmental competence of the aged oocyte can be substantially, though not fully, restored through ‘nurturing’ in a young follicular environment. The team found that the restoration of the quality of the aged oocyte was attributed to the reshaping of its metabolism and gene expression.

The researchers discovered that the young granulosa cells, which were much better at establishing transzonal projections towards the aged oocyte, helped to facilitate this restoration. In addition, there was an improvement in the function and health of oocyte mitochondria, crucial organelles for energy production and cellular metabolism.

The team further provided evidence that the young follicular environment could support much more accurate partitioning of the oocyte genome, which must occur properly during oocyte maturation to prevent aneuploidy — the presence of an abnormal number of chromosomes in a cell or organism. All these improvements enhance the success of embryonic development after IVF, leading to a live birth rate around three times higher than that achieved with aged oocytes not exposed to the young follicular environment.

The researchers hope to bring the potential application of their cutting-edge discovery to fruition by conducting more thorough studies to understand how the young follicular environment can improve the quality of an aged oocyte, validate the key findings of this study with human cells and oocytes, and develop an optimised follicle cell line that can be used to improve egg quality for better IVF outcomes.

“The findings from this study provide a proof of concept and the basis for the development of non-invasive cell-based strategies to improve the quality of eggs from older women or women whose reproductive ability is affected by other health conditions, which could lead to improved outcomes of assisted reproductive technologies such as IVF,” Wang said.

Image courtesy National University of Singapore.