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Scientists take the first step to master an all-powerful cell type from the beginning of life

Scientists take the first step to master an all-powerful cell type early in life

Chemically induced ciTotiSC from mESC (OCT4-green fluorescence-labeled pluripotent stem cells and MERVL-red fluorescence-labeled totipotent stem cells). Credit: Tsinghua University

From cloning to regeneration, how to find alternative avenues to create or rejuvenate life has been one of the big questions for biologists. It is this question that underlies the work of generations of scientists who have won Nobel Prizes. It is also this question that drives the recent research led by Sheng Ding at Tsinghua University, School of Pharmaceutical Sciences, now published in Nature

In the current study, Ding and colleagues identified a drug cocktail that induces an omnipotent stem cell type at will, a cell type that can morph into an entire organism on its own. The researchers are also able to maintain the differentiation potential of the resulting cells in the lab, creating a stable system for later researchers to demystify the origin of life. This alternate path — obtaining a clean slate of life’s earliest raw materials from more mature cells, rather than new sperm and eggs — could have a wide variety of implications. “Such an alternative to how nature creates the beginning of life is a holy grail of biology,” Ding says.

The origin of life begins with one cell. Your blood, brain, and liver cells can all be traced back to this single-celled embryo or zygote.

In nature, a zygote is produced when sperm and egg fuse. And the event starts an irreversible process where the zygote divides, forms new cells and the new cells continue to divide and become more and more specialized.

As specialization is gained, something is lost along the way. Once the unicellular embryo divides and reaches the two-cell embryo stage, the later cells will quickly lose the differentiation potential to give rise to all cell types to generate a whole organism and its supporting tissues such as the yolk sac and placenta, becoming less potent stem cells .

Scientists call these omnipotent cells in the single-cell and two-cell embryo stages totipotent stem cells. And there are pluripotent and multipotent stem cells further down the continuum. “Normally, none of the other stem cells after totipotent cells has the ability to live on their own,” Ding says.

To better study and control the totipotent stem cells, Ding and his team set up a system that allows for the induction and maintenance of these cells, confirming their identity with strict criteria.

With 20 years of work and understanding of cell fate and stem cell regulation by chemical compounds, the team selected and screened thousands of combinations of small molecules. Through several rounds of analysis, they identified three small molecules that could convert pluripotent mouse stem cells into cells with totipotent characteristics. The researchers called the molecules TAW cocktail. Each letter in TAW represents a molecule known to regulate a specific decision about a cell’s fate. But their combined effect wasn’t known until the current discovery, Ding explains.

Next, the researchers examined cells that received the TAW cocktail treatment in detail, both their totipotency and non-pluripotency. These cells met strict molecular testing criteria, at all levels of transcriptome, epigenome, and metabolome. For example, the team found that hundreds of crucial genes were turned on in the TAW cells. These genes are most commonly found in totipotent cells and have been suggested by other researchers in the field as the benchmark for determining totipotency. At the same time, genes associated with pluripotent cells were silenced in the TAW cells.

To further prove that the resulting cells have a true totipotent state, the team tested their differentiation potential in vitro and also injected them into an early mouse embryo to see the differentiation potential in vivo. They found that the cells not only behaved like true totipotent cells in a petri dish, but also differentiated in vivo into both embryonic and extraembryonic lineages. This is a typical feature of normal totipotent cells, which have the potential to develop into fetus as well as surrounding yolk sac and placenta, while pluripotent cells can only develop into fetus.

In addition, when the researchers used special culture conditions for the TAW cocktail-induced totipotent cells, the subsequent cells also showed similar totipotency characteristics. This observation suggests that the totipotency of TAW-induced cells can be maintained in a laboratory environment and thus establish a stable system.

Such a system is important, because it will enable much scientific research into the beginning of life. For example, scientists can use this system to manipulate the totipotent cells to better understand the highly orchestrated process at the beginning of life. “Certain cells will have to appear at the right time and in the right location for life to take place,” Ding says, and you can’t study this without the right tools.

In that sense, “this document is the first step and offers huge opportunities,” he says.

In addition, a deeper understanding and thus control of totipotent cells will have a wide range of implications, such as earning a second chance at creating individual life and even accelerating the evolution of a species.

Many of the possibilities will spark controversy, Ding admits. It’s worth noting that while those possibilities are in the distant future, he says, it’s hard to predict what society’s ethical concerns will be. After all, the scientific community has not seen any lighter restrictions on research on human embryos in the past ten years. But last year, people started seriously considering how long a human embryo can be kept in a petri dish from the original 14-day rule.

While the team is well aware of ethical considerations, Ding believes that as scientists their most important job is to focus on making discoveries in the present and laying the groundwork for generations to come. Then the latter has the knowledge and tools to make decisions.


Researchers can reprogram cells to their original state for regenerative medicine


More information:
Yanyan Hu et al, Induction of mouse totipotent stem cells by a defined chemical cocktail, Nature (2022). DOI: 10.1038/s41586-022-04967-9

Provided by Tsinghua University


Quote: Scientists take first step to master an omnipotent cell type from the beginning of life (2022, June 23) retrieved June 23, 2022 from https://phys.org/news/2022-06-scientists -master-all- powerful-cell-life.html

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