Reconstituting Epigenetic Reprogramming in Human Germ Cells: Insights from In Vitro Experiments

Alapfogalmak

Establishing a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell-derived human primordial germ cell-like cells into mitotic pro-spermatogonia or oogonia, with extensive amplification.

Kivonat

The content describes an in-depth study on the process of epigenetic reprogramming in the human germ line. Key highlights:

Epigenetic reprogramming is crucial for resetting parental epigenetic memories and differentiating primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia, ensuring sexually dimorphic germ cell development for totipotency.

The researchers established a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell (PSC)-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (over 10 billion-fold).

BMP signaling was identified as a key driver of these processes. BMP-driven hPGCLC differentiation involves attenuation of the MAPK/ERK pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, likely promoting replication-coupled, passive DNA demethylation.

hPGCLCs deficient in the active DNA demethylase TET1 differentiated into extraembryonic cells, including amnion, with de-repression of key genes bearing bivalent promoters. These cells failed to fully activate genes vital for spermatogenesis and oogenesis, with their promoters remaining methylated.

The study elucidates the framework of epigenetic reprogramming in humans, representing a fundamental advance in human biology, and the generation of abundant mitotic pro-spermatogonia and oogonia-like cells is a milestone for human in vitro gametogenesis (IVG) research and its potential translation into reproductive medicine.

Statisztikák

The content mentions an over 10 billion-fold amplification of the pluripotent stem cell-derived human PGC-like cells.

Idézetek

"Strikingly, bone morphogenetic protein (BMP) signalling is a key driver of these processes: BMP-driven hPGCLC differentiation involves an attenuation of the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, likely promoting replication-coupled, passive DNA demethylation."
"On the other hand, hPGCLCs deficient in tens-eleven translocation (TET) 1, an active DNA demethylase abundant in human germ cells 2,3, differentiate into extraembryonic cells, including amnion, with de-repression of key genes bearing bivalent promoters; these cells fail to fully activate genes vital for spermatogenesis and oogenesis, with their promoters remaining methylated."

Főbb Kivonatok

In vitro reconstitution of epigenetic reprogramming in the human germ line - Nature

by Yusuke Muras... : www.nature.com 05-20-2024

https://www.nature.com/articles/s41586-024-07526-6

Mélyebb kérdések

What are the potential applications of the in vitro reconstitution of epigenetic reprogramming in human germ cells beyond reproductive medicine?

The in vitro reconstitution of epigenetic reprogramming in human germ cells has implications beyond reproductive medicine. One potential application is in the field of regenerative medicine. The ability to induce epigenetic reprogramming and differentiate pluripotent stem cell-derived human PGC-like cells into specific germ cell lineages opens up possibilities for generating gametes for individuals who may be infertile due to various reasons. This could revolutionize fertility treatments and offer new options for individuals struggling with infertility. Additionally, the knowledge gained from this research could have implications for understanding and potentially treating certain genetic disorders that arise from epigenetic abnormalities. By studying the mechanisms involved in epigenetic reprogramming, we may uncover new therapeutic targets for conditions beyond reproductive health.

How might the findings on the role of BMP signaling and TET1 in epigenetic reprogramming inform our understanding of germ cell development and differentiation in other species?

The findings on the role of BMP signaling and TET1 in epigenetic reprogramming in human germ cells can provide valuable insights into germ cell development and differentiation in other species. BMP signaling has been shown to play a crucial role in various developmental processes across different organisms, indicating its evolutionary conservation. By understanding how BMP signaling influences the differentiation of human PGC-like cells into specific germ cell lineages, we can extrapolate this knowledge to other species and potentially uncover similar mechanisms at play. Similarly, the involvement of TET1, an active DNA demethylase, in human germ cell development suggests a conserved mechanism of DNA demethylation in germ cells of different species. Studying the role of TET1 in epigenetic reprogramming can shed light on its function in germ cell development across various organisms, contributing to a broader understanding of evolutionary conserved pathways in germ cell differentiation.

What are the ethical considerations and regulatory frameworks surrounding the use of in vitro gametogenesis techniques for human reproduction, and how might they evolve as the field progresses?

The use of in vitro gametogenesis techniques for human reproduction raises significant ethical considerations and regulatory challenges. One major ethical concern is the potential misuse of this technology for purposes other than fertility treatment, such as designer babies or creating gametes from individuals without their consent. There are also concerns about the safety and long-term effects of using artificially generated gametes in reproduction. Regulatory frameworks need to address issues related to consent, safety, and the potential implications of using manipulated gametes in reproduction. As the field of in vitro gametogenesis progresses, regulatory bodies will need to adapt to ensure that these technologies are used responsibly and ethically. This may involve establishing guidelines for the use of artificially generated gametes, monitoring the safety and efficacy of these techniques, and addressing any societal implications that may arise from their widespread use.