As naive as they get

Realizing the vision of growing organs for use in life-saving transplant procedures is still a long way off. Prof. However, Jacob Hanna’s work with stem cells paves the way for this to become a reality.

(lr) Sergey Viukov, Dr. Noa Novershtern, Dr. Muneef Ayyash, Prof. Jacob Hanna and Tom Shani. Not so naive

Hanna and his team from the Weizmann Institute of Sciences Department of Molecular Genetics have found a way to grow human stem cells in a much earlier state than was previously possible. Not only that, the stem cells they have created are far more competent, which means they are able to integrate more effectively with their host environment. This significantly improves the chances of achieving what is called a cross-species chimera – allowing cells from one being to play a significant role in the evolution of another.

The recently published results show that very early human cells can be created and then successfully integrated into mice due to their undifferentiated or “naive” state, where they can develop into any type of cell in the body, including other stem cells. In addition, researchers are developing a protocol to significantly increase the efficiency (or competence) with which these cells can be integrated. Improving our ability to create and study these cell types may in the future be used to transfer cells – if not organs – from one animal to another, including humans.

Development of chimeric mouse fetus. In particular, human cells (green) colonize different areas of the brain and heart

Hanna’s laboratory broke ground in 2013, when they were the first to inject human stem cells into mice, demonstrating that they can be successfully integrated into the latter’s developing embryos. Eight years after this study was first published, Hanna and his team felt they could go a step further by trying to produce an even earlier, “fully” naive type of stem cell for use in similar procedures. While considering the idea, Hanna knew that this could be almost, if not completely, impossible to achieve. “Our experience in producing similar cells in mice has taught us to expect challenging obstacles along the way,” says Hanna.

These cells usually suffer from genetic as well as epigenetic instability, and in the end they do not differentiate too well, which is the key to proper embryonic development and a prerequisite for their integration into another animal’s embryo. In fact, only about 1-3 percent of cells that have been transferred between species actually manage to integrate and contribute to evolution.

Jonathan Bayerl. One of the main contributors to the study

To increase these numbers, the researchers in the new study inhibited two additional signaling pathways for producing naive human stem cells with a stable genome, relatively few gene regulation errors, and most importantly, they differentiate perfectly. The researchers also mutated an important gene that contributes to the stability of the genome, resulting in not only competent but also competitive stem cells that can integrate well without causing damage to the host. “We found a way to make human stem cells more competent and competitive, which increased the chances of a successful transfer by about five times compared to what we were able to do in the past,” Hanna concludes.

“” If in the future we were to want to grow a pancreas in pigs for human transplantation, we would have to take into account these huge evolutionary differences between species – starting with mice and humans. “

While the previous study showed that human naive stem cells can differentiate into primordial gametes – the stem cells for eggs or sperm – the completely naive stem cells produced in this study can also differentiate into extraembryonic tissues, placenta and yolk sacs that maintain the developing embryo. Such cells could e.g. used as a source for the development of synthetic embryos without the need for donor eggs. “Reaching this state with mouse stem cells is particularly difficult to achieve,” Hanna explains, noting that “human cells appear to be different.”

This is perhaps the most surprising finding that researchers have made – highlighting the differences between the behavior of human and mouse stem cells and between the different states of naive cells. These differences reveal the work that still needs to be done to make the dream of developing “made-to-order” bodies a reality.

The spinal cord of a developing chimeric mouse fetus. Human cells (green) have been shown to contribute to the development of the nervous system and leave a neuronal signature (pink – spinal cord neurons, blue – cell nuclei)

According to Hanna, understanding these differences will be crucial in overcoming a myriad of problems that still face the field of stem cell research and use: “If in the future we were to want to grow a pancreas in pigs for human transplantation, we would f .ex. have to take into account these huge evolutionary differences between species, starting with mice and humans. ” For now, it looks like Hanna and his team have taken a constructive leap in that direction.

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