Photo credit: www.sciencedaily.com

New Insights into Replication Dynamics of Embryonic Stem Cells

Embryonic stem (ES) cells, renowned for their pluripotent capabilities, can differentiate into all cell types of an organism. Traditionally, these cells have been believed to experience significant levels of intrinsic replication stress due to their rapid proliferation. However, recent research published in EMBO Reports by Kurashima et al. offers a fresh perspective by conducting a comprehensive molecular analysis of replication processes within these cells.

The study, led by Dr. Tomomi Tsubouchi from the National Institute for Basic Biology (NIBB) in Japan, scrutinized the dynamics of replication forks—specifically focusing on factors such as replication fork velocity, frequency of pauses, and density of origin firing during various substages of the S phase. The results revealed important and previously unexplored aspects of DNA replication not only in ES cells but also in various non-pluripotent cell types.

According to Dr. Kiminori Kurashima, the lead author of the study, “By fractionating cells into different S phase substages and conducting DNA fiber assays on these sorted populations, we found that mammalian pluripotent stem cells maintain a relatively slow replication fork speed and a high active origin density throughout the S phase, with very few pauses occurring.” This observation stands in stark contrast to non-pluripotent cells, which exhibit slower fork speeds at the beginning of the S phase but tend to accelerate as this phase progresses. Additionally, non-pluripotent cells show a notable frequency of fork pausing early in the S phase, likely to activate checkpoint mechanisms that help facilitate faster fork progression and minimize pauses.

Interestingly, the findings also indicate that once mouse ES cells undergo differentiation, their replication profiles transition to align more closely with those of non-pluripotent cells. Moreover, certain aspects of DNA replication characteristics observed in mouse ES cells are mirrored in human induced pluripotent stem (iPS) cells. This suggests that the combination of slow replication forks and high origin density might signify a critical feature of pluripotency. Notably, attempts to artificially accelerate replication forks in these cells resulted in a disconnection between the completion of genome replication and cell cycle progression.

Dr. Tsubouchi further emphasizes, “We contend that the presence of slow replication forks should not be construed as a sign of replication difficulties but rather as a fundamental aspect of DNA replication in embryonic stem cells. Our research highlights the intricate regulation of DNA replication and demonstrates how various cell types utilize unique mechanisms.” This nuanced understanding of replication dynamics could have widespread implications for stem cell research and regenerative medicine.

Source
www.sciencedaily.com