Human-ape chimeras illuminate the evolution

T.Here are hundreds of different types of cells that make up the human body, each from a single source: the fertilized egg. Researchers studying how this complexity arises have created chimeric embryos between humans and animals by introducing human pluripotent stem cells into the embryos of other animals such as mice and pigs. By following the results of the human cells, they can see how capable these cells are of differentiating into different cell types and contributing to the embryo. For example, in a paper published in 2017, human cells contributed up to 1 percent of the embryonic cells in a human-mouse chimera.

In a study published today (April 15) in cellThe researchers describe their advances in creating a chimeric great ape embryo to determine whether a more closely related host would allow human cells to have a greater presence, paving the way for a better understanding of possible cell types, and possibly in the distant future be a potential way to address the shortage of human organs available for transplants. Scientists made the chimeras by injecting human expanded pluripotent stem cells (EPS) – also known as expanded potential stem cells – into early embryos of cynomolgus monkeys (Macaca fascicularis). The team grew the chimeras in culture for up to 20 days and found that up to 7 percent of the embryonic cells can trace their lineage back to human EPS cells.

EPS cells, which are created by treating pluripotent stem cells with factors that help them maintain pluripotency and contribute to embryonic and extraembryonic tissues, were developed in 2017 by Juan Carlos Izpisua Belmonte, stem cell biologist at the Salk Institute for Biological Studies and colleagues.

“An exact confirmation of the developmental power of these cells can only be achieved in vivo. . . However, chimeric assays are not easy, ”says Berna Sozen, a stem cell biologist at Yale University who was not involved in the study. In the past, researchers have had limited chimeric success, at least in part due to the evolutionary distance between humans and hosts of mice or pigs, she adds.

In the new study, Izpisua Belmonte’s team worked with Tao Tan from Kunming University of Science and Technology in China and colleagues to address the challenge of evolutionary distance. They used a strategy described in two studies by Tan’s group and another team in 2019 that allows researchers to grow monkey embryos in culture for up to 20 days.

The researchers injected 25 human EPS cells into each of 132 six-day-old monkey embryos. The next day they found human cells in all of the embryos. Where these cells were found in the embryos shifted over time. At 15 days, the 38 surviving chimeras had the highest percentage of human cells (about 7 percent) in the outermost layer of embryonic cells, and at 19 days the three surviving chimeras had the highest percentage of human cells (about 5 percent) in the innermost layer. The team didn’t see much human cell presence in the layer that would become extraembryonic tissues like the placenta.

Next, the researchers analyzed an indicator of which genes were active during chimera development and observed a different set of genes than those found in monkey embryos that were not injected with human cells. “We plan to examine more closely the molecular pathways that we have identified as involved in communication between species and determine which are critical to the success of this process,” wrote Izpisua Belmonte in an email The scientist. In other words, how do monkey and human cells interact with each other during the development of the embryo?

“These advances have accelerated our ability to study development and regeneration processes,” he continues. “This knowledge could also help advance the goals of regenerative medicine, such as developing tissues to address the critical shortage of organs for transplantation.”

“There are a number of obstacles to making this a reality,” says Jacob Hanna, a stem cell biologist at the Weizmann Institute in Israel, who was not involved in the work. The main obstacle is that, regardless of whether human cells are transplanted into mouse, porcine, or monkey embryos, “the integration efficiencies that we see in all cross-species experiments are very, very low”.

On the other hand, “It is incredible that we are now seeing so much evidence that human cells can survive and differentiate in other organisms,” he adds. The next question that needs to be answered in making human organs for transplantation is, “How can we target the integration to either a specific organ or a specific organ? . . trying to make the cells more competitive? “

Researchers around the world “try to understand [EPS] Cells, but we need to collect a lot more data before we can actually start discussing potential clinical applications, ”agrees Sozen. “It is really hard to say that it will ever be possible to grow organs for transplant by creating these animal-human chimeras. However, this research should be continued so that we understand if we will ever achieve this.”

T. Tan et al., “Chimeric Contribution of Human Enlarged Pluripotent Stem Cells to Monkey Embryos Ex vivo”, cell, doi: 10.1016 / j.cell.2021.03.020, 2021.

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