Limiting the rate of DNA replication could be a breakthrough for stem cell therapy

DNA replication in mouse embryonic stem cells. Red: newly synthesized DNA. Credit: Helmholtz Zentrum München / Tsunetoshi Nakatani

Adult cells in our body can only give rise to the same type of cell. For example, a skin cell cannot give rise to a muscle cell but only skin cells. This limits the potential use of adult cells for therapy. Early in development, however, the cells of the embryo have the ability to generate all types of cells in our body, including stem cells. This ability, called totipotency, has served as inspiration for researchers to find new ways to recapitulate totipotency through cellular reprogramming in the laboratory.

Totipotent cells have their own speed

Totipotent cells have many properties, but we don’t know them all yet. Researchers from Helmholtz Munich have just made a new discovery: “We have discovered that in totipotent cells, the mother cells of stem cells, DNA replication occurs at a different rate compared to other more differentiated cells. It’s much slower than in any other cell type we’ve studied,” says Tsunetoshi Nakatani, first author of the new study.

DNA replication, in fact, is one of the most important biological processes. During our lifetime, each time a cell divides, it generates an exact copy of its DNA, so the resulting daughter cells carry identical genetic material. This fundamental principle allows a faithful transmission of our genetic material.

The researchers found that the speed of DNA replication is also low in totipotent type cells, which scientists can culture in a petri dish. Tsunetoshi Nakatani adds: “This led us to the question: if we manage to modify the speed at which DNA replicates, can we improve the reprogramming of cells into totipotent cells?”

Less speed, improved cell reprogramming

In a remarkable experimental effort, researchers have indeed observed that slowing the rate of DNA replication – for example by limiting the substrate that cells use for DNA synthesis – increases the efficiency of reprogramming, c i.e. the rate at which cells can convert to another cell type. .

“It’s amazing,” says Maria-Elena Torres-Padilla, head of the study. “Over the years, we have studied totipotent cells to learn how nature made them so incredibly capable of generating every type of cell in our body. This is a fundamental strategy of our research towards regenerative medicine approaches. This new concept is very simple, but extremely important and we believe it is a huge step forward for stem cell therapy.

Reference: “DNA Replication Fork Rate Underlies Cell Fate Changes and Promotes Reprogramming” by Tsunetoshi Nakatani, Jiangwei Lin, Fei Ji, Andreas Ettinger, Julien Pontabry, Mikiko Tokoro, Luis Altamirano-Pacheco , Jonathan Fiorentino, Elmir Mahammadov, Yu Hatano, Capucine Van Rechem, Damayanti Chakraborty, Elias R. Ruiz-Morales, Paola Y. Arguello Pascualli, Antonio Scialdone, Kazuo Yamagata, Johnathan R. Whetstine, Ruslan I. Sadreyev and Maria-Elena Torres -Padilla, March 7, 2022, Natural genetics.
DOI: 10.1038/s41588-022-01023-0

Professor Maria-Elena Torres-Padilla is responsible for the Stem Cell Center at Helmholtz Munich and heads the Institute for Epigenetics and Stem Cells. She is also a professor of stem cell biology at the Ludwig-Maximilans-Universität München (LMU). Tsunetoshi Nakatani is the first author of this study and is a post-doctoral fellow in Torres-Padilla’s group at Helmholtz Munich.

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