Researchers have created a groundbreaking method to rejuvenate aged oocytes, which are immature egg cells, to enhance their quality. This advancement promises better results in in-vitro fertilization (IVF) procedures. The method involves forming hybrid ovarian follicles by moving aged oocytes into a youthful follicular setting, partially restoring their reproductive capabilities.
A team of 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), affiliated with the NUS Yong Loo Lin School of Medicine (NUS Medicine), has introduced an innovative approach to significantly improve the reproductive potential of aged oocytes. This is crucial for enhancing the effectiveness of assisted reproductive technologies like in-vitro fertilization (IVF), particularly for older women. The team successfully rejuvenated oocytes from an older preclinical model by placing them in a youthful follicular environment, leading to the generation of higher-quality eggs suitable for IVF.
As women age, their reproductive system undergoes natural changes, resulting in a marked decrease in both the amount and quality of eggs. Given that many women now opt to start families later in life, understanding how to address the impact of aging on egg quality is essential for creating effective strategies for egg maturation, fertilization, and embryo development.
At the forefront of investigating female reproductive aging are researchers led by Professor Rong LI, Director of MBI, and Dr. WANG Haiyang, a Senior Research Fellow at MBI. Collaborating with IVF specialists and clinicians from NUS Medicine and ACRLE, they constructed hybrid ovarian follicles from a preclinical model. Their work confirmed that an aged follicular environment can detrimentally affect the quality and developmental prospects of younger oocytes. Importantly, they found that oocytes from an aged environment can be revitalized when transplanted into a younger follicular environment.
“Our research was motivated by the increasing need to tackle age-related fertility challenges. Notably, the female reproductive system, particularly the ovarian follicles housing oocytes, appears to age more rapidly than other systems within the human body. This realization pushed us to explore this aging phenomenon deeper and seek ways to counteract its effects,” stated Prof. Li.
The findings detailing the influence of the follicular environment on oocytes were published in Nature Aging on September 9, 2024.
Revitalising an aged egg cell
Ovarian follicles are fundamental units in mammalian ovaries, consisting of supporting somatic cells called granulosa cells that envelop and nurture an oocyte during its growth before ovulation. These granulosa cells interact with the oocyte through structures known as transzonal projections, supplying essential nutrients while the oocyte sends signals for granulosa cell development.
Utilizing their knowledge of the interactions within ovarian follicles, MBI researchers developed hybrid ovarian follicles using an ex-vivo 3D culturing platform, building on past methodologies. They extracted oocytes from their original environments and placed them in new follicular settings, where the original oocyte had been removed, creating the hybrid follicles.
The team first established that aged granulosa cells show more signs of aging compared to younger granulosa cells, including increased DNA damage and indicators associated with programmed cell death. They also revealed that this older follicular environment reduces the quality and developmental ability of young oocytes.
Next, the researchers formed hybrid ovarian follicles with aged oocytes placed in a young follicular environment. They demonstrated that the quality and developmental viability of the aged oocytes could be significantly, albeit not entirely, improved through this nurturing in a young setting. The enhancements in the aged oocyte were credited to changes in its metabolism and gene expression.
It was found that the young granulosa cells were more adept at forming transzonal projections towards the aged oocyte, which facilitated its restoration. Additionally, there were improvements in the function and health of oocyte mitochondria, which are vital for energy production and cellular metabolism.
The team also presented evidence that the young follicular environment aids in better partitioning of the oocyte genome, a crucial process during maturation needed to avoid aneuploidy, or an abnormal number of chromosomes in cells. These improvements substantially increase the likelihood of successful embryonic development post-IVF, achieving live birth rates up to three times higher compared to aged oocytes that were not exposed to a youthful follicular environment.
The NUS team has applied for a patent concerning this innovation, specifically the techniques used to rejuvenate aged oocytes via exposure to a youthful follicular microenvironment.
The study was funded by ACRLE, NUS Medicine, and the National Research Foundation, Singapore.
A glimpse into the future of fertility treatments
“The outcomes of this research offer a proof-of-concept for developing non-invasive, cell-based approaches to enhance the egg quality of older women or those whose fertility is compromised by other health issues, potentially leading to better results with assisted reproductive technologies like IVF,” noted Dr. Wang.
The researchers aim to bring their innovative discovery into practical use by conducting more in-depth studies to fully comprehend how a young follicular environment can enhance aged oocyte quality, validate their key findings with human cells and oocytes, and create an optimized follicle cell line that improves egg quality for enhanced IVF success.
