Groundbreaking Study Advances Human In Vitro Gametogenesis for Infertility Treatment Newsdesk,
01 June 2024

Infertility is a pervasive issue, affecting about one in six people globally. According to the World Health Organization (WHO), millions of couples struggle with this condition, posing significant challenges to reproductive health. The American Society for Reproductive Medicine (ASRM) defines infertility as a disease marked by the inability to achieve a successful pregnancy due to a mix of medical, sexual, and reproductive factors. Often, medical intervention, such as using mature donor gametes, is necessary to achieve pregnancy.

While assisted reproductive technologies (ARTs) like in vitro fertilization (IVF) have transformed the treatment landscape for certain types of infertility, they are not universally effective. Various forms of infertility remain untreatable with current ART methods, motivating researchers to explore new avenues in reproductive medicine.

One promising new technology is human in vitro gametogenesis (IVG). This innovative approach uses pluripotent stem cells (PSCs), including induced pluripotent stem cells (iPSCs) from patients, to generate human germ cells. These germ cells have the potential to mature into gametes in culture, offering hope for treating all forms of infertility, regardless of gender. Despite its potential, human IVG research is still in its early stages. Researchers are currently focused on reconstituting the entire process of human gametogenesis in vitro.

A significant challenge in IVG research is replicating the process of epigenetic reprogramming in human primordial germ cells (hPGCs). This process involves resetting or erasing the inherited parental "memory" of cells on their DNA, a crucial step for proper germ cell differentiation. Successfully achieving this in vitro has proven difficult, hindering progress in the field.

A recent study published in Nature has made significant strides in overcoming these challenges. Led by Dr. Mitinori Saitou at Kyoto University's Institute for the Advanced Study of Human Biology (WPI-ASHBi), the research team identified robust culture conditions necessary for driving epigenetic reprogramming and germ cell differentiation into precursors of mature gametes, known as mitotic pro-spermatogonia and pro-oogonia. This achievement marks a new milestone in human IVG research.

Earlier research by Saitou's team and others successfully generated human primordial germ cell-like cells (hPGCLCs) from PSCs in vitro. These cells exhibited several fundamental features of hPGCs, including propagation capacity. However, they failed to undergo epigenetic reprogramming and differentiation. Aggregating hPGCLCs with mouse embryonic gonadal cells to mimic the microenvironment of the testis or ovary partially addressed this issue. This method, however, was inefficient and impractical for clinical applications, highlighting the need for a more effective solution.

In their new study, Saitou and his colleagues conducted a cell culture-based screen to identify signaling molecules essential for driving epigenetic reprogramming and differentiation of hPGCLCs into mitotic pro-spermatogonia and oogonia. They discovered that bone morphogenetic protein (BMP), a well-known developmental signaling molecule, played a crucial role in this process.

The discovery that BMP signaling is critical for hPGCLC reprogramming and differentiation was surprising, given its established role in germ cell specification. The hPGCLC-derived mitotic pro-spermatogonia and oogonia not only displayed similar gene expression and epigenetic profiles to actual hPGC differentiation in the body but also underwent extensive amplification. This breakthrough allows near-indefinite amplification of these cells in culture, providing the ability to store and re-expand them as needed.

The study also explored potential mechanisms by which BMP signaling facilitates epigenetic reprogramming and hPGCLC differentiation. It appears that BMP signaling attenuates the MAPK/ERK signaling pathway and the activities of DNA methyltransferase (DNMT), both de novo and maintenance. Further investigation is necessary to determine the precise mechanisms and their direct or indirect effects.

This study represents a fundamental advance in understanding human biology and the principles behind epigenetic reprogramming in humans. It also marks a significant milestone in human IVG research. Despite the remaining challenges and the long path ahead, particularly regarding the ethical, legal, and social implications of clinical applications, this research brings us closer to potentially translating IVG into reproductive medicine.

The findings of this groundbreaking study, published in Nature on May 20, 2024, provide a hopeful outlook for the future of infertility treatment. By advancing our understanding of epigenetic reprogramming and germ cell differentiation, researchers are paving the way for new, more effective treatments for infertility, bringing hope to millions of people worldwide.


News Medical. 21st May 2024. Groundbreaking study advances human in vitro gametogenesis for infertility treatment

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