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Researchers from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) and the NUS Bia-Echo Asia Centre for Reproductive Longevity and Equality (ACRLE), based at the NUS Yong Loo Lin School of Medicine (NUS Medicine), have developed an innovative technique to significantly enhance the reproductive potential of aged oocytes, or immature egg cells, potentially paving the way for better outcomes of assisted reproductive technologies, such as in-vitro fertilisation (IVF), 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 IVF.
Female reproductive ageing 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 ageing on egg cell quality has become crucial to develop strategies for successful egg cell maturation, fertilisation, and embryo development.
Working at the forefront to understand the mechanics behind female reproductive ageing, a team of researchers led by Professor Rong LI, Director of MBI, and Dr WANG Haiyang, Senior Research Fellow at MBI, and IVF scientists and clinicians from NUS Medicine and ACRLE, has 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. It is extremely curious that the female reproductive system, especially the ovarian follicles that contain oocytes, appear to be the fastest ageing system of the human body. This fact prompted us to delve deeper to gain a much better understanding of this ageing process and to discover ways to mitigate it,” said Prof Li.
The novel approach and findings on the impact of the follicular environment on oocytes were published in Nature Aging on 9 September 2024.
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 (an immature egg cell) 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.
MBI 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 ageing, 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 (i.e. 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 toward 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 NUS team has filed a patent application for this innovation, particularly concerning the method used to rejuvenate aged oocytes by exposing them to a young follicular microenvironment.
The funding for this study was provided by ACRLE, NUS Medicine, and the National Research Foundation, Singapore.
A glimpse into the future of fertility treatments
“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,” said Dr Wang.
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.