Female doctor consulting young couple patients in fertility clinic about IVF or IUI for infertility.
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Researchers at the Institute for the Advanced Study of Human Biology (ASHBi) at Kyoto University have made a breakthrough in understanding the mechanisms driving epigenetic reprogramming and differentiation during human germ cell development.

The study, published in Nature, could lead to new treatments for infertility, affecting approximately one in six people worldwide.

Infertility, as defined by the American Society for Reproductive Medicine, is the inability to achieve a successful pregnancy due to various factors and often requires medical intervention. While assisted reproductive technologies like in vitro fertilization (IVF) have successfully helped many, they do not address all forms of infertility. A promising technology known as human in vitro gametogenesis (IVG) has recently emerged, using pluripotent stem cells from patients to generate human germ cells capable of becoming mature gametes in culture, offering potential solutions across all genders.

A key challenge in human IVG research has been replicating the complete process of human gametogenesis—the development of sex cells in living organisms. Specifically, researchers have struggled to achieve epigenetic reprogramming in human primordial germ cells (hPGCs), an essential step where the inherited parental “memory” of cells is reset, allowing germ cell differentiation.

Previous attempts to generate hPGC-like cells (hPGCLCs) from stem cells in vitro were only partially successful, as these cells could propagate but not undergo full epigenetic reprogramming and differentiation.

Led by Mitinori Saitou, the ASHBi team have now identified robust culture conditions necessary for driving epigenetic reprogramming and differentiation of hPGCLCs into mitotic pro-sperm and egg cells, precursors to mature sex cells, representing a new milestone in human IVG and infertility research.

The team discovered that bone morphogenetic protein (BMP), a well-known developmental signaling molecule, plays a crucial role in this process. An unexpected finding, as BMP signaling was previously established for germ cell specification but not for driving epigenetic reprogramming.

The study showed that these hPGCLC-derived mitotic pro-sperm and egg cells not only exhibited gene expression and epigenetic profiles similar to actual hPGC differentiation in the body but also underwent extensive amplification, multiplying over 10 billion-fold.

“Our approach enables near-indefinite amplification of mitotic pro-spermatogonia and oogonia in culture, and we can now store and re-expand these cells as needed,” said Saitou, principal investigator at the department of life science frontiers at ASHBi and senior author of the study.

Additionally, the researchers explored the mechanisms by which BMP signaling facilitates epigenetic reprogramming and hPGCLC differentiation. They found that BMP signaling might decrease the MAPK/ERK pathway and influence DNA methyltransferase activities, though further investigation is needed to confirm whether these effects are direct or indirect.

“Although many challenges remain and the path will certainly be long, especially considering the ethical, legal, and social implications associated with the clinical application of human IVG, we have now made one significant leap forward towards the potential translation of IVG into reproductive medicine,” Saitou concluded in a press statement.

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