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Scientists use stem cells to create human/pig chimera embryos…

In greek mythology, a chimera was a fire-breathing female monster with a lion’s head, a goat’s body, and a serpent’s tail.

A chimera now, scientifically speaking, is made of cells that are derived from two (or sometimes more) organisms. These “parent” organisms may be of the same or different species. The defining feature of a chimera is that the individual cells in its body are genetically distinct. Instead of a mixture of genes from each parent organism, a given cell contains the genetic information of only one parent organism.

 Why create a chimera?

Potential applications for chimeric embryos have been pointed out:

  • platforms for the study of human development and disease

  • developing new models of neurodegenerative and psychiatric diseases

  • speed up the screening of therapeutic drugs.

The biggest application in my opinion is the potential of eradicating organ shortages for transplantation. Currently there are over 6,500 people on the UK national transplant waiting list and, during the last financial year, over 400 people died whilst on the waiting list. This is because, despite more than 500,000 people dying each year in the UK, fewer than 6,000 people die in circumstances where they can become a donor.

Researchers may one day overcome this problem by growing spare human organs in other animals.They are still far away from that, but this was an important first step.

Before that step though, scientists created a rat/mouse chimera by introducing rat cells into mouse embryos and letting them mature. Other researchers had already created a rat/mouse chimera in 2010. That chimera was a mouse with pancreatic tissue formed from rat cells.

Scientists Izpisua Belmonte and Wu built on that experiment by using genome editing to flexibly direct the rat cells to grow in specific developmental niches in the mouse. To accomplish this, they used CRISPR genome editing tools to delete critical genes in fertilized mouse egg cells, so they deleted the genes in mice that coded not only for the pancreas, but other organs, such as the heart and eyes, as well. The researchers then injected rat stem cells, which eventually grew into these missing organs.  The rat cells had a functional copy of the missing mouse gene, so as the organism matured, the rat cells filled in where mouse cells could not, forming the functional tissues of the organism’s heart, eye, or pancreas.

Rat cells also grew to form a gall bladder in the mouse, even though rats stopped developing this organ themselves over the 18 million years since rats and mice separated evolutionarily. This suggests that the reason a rat does not generate a gall bladder is not because it cannot, but because the potential has been hidden by a rat-specific developmental program. The microenvironment has evolved through millions of years to choose a program that defines a rat.

The group tried making rat-pig chimeras, but this didn’t work—the species were too different.

The team’s next step was to introduce humans’ cells into an organism. They decided to use pig embryos as hosts because the size of this animal’s organs more closely resembles humans than mice. The team encountered the scientific challenge of determining what kind of human stem cell could survive in a pig embryo.

The researchers injected several different forms of human stem cells into pig embryos to see which would survive best. The cells that survived longest and showed the most potential to continue to develop were “intermediate” human pluripotent stem cells. So-called “naïve” cells resemble cells from an earlier developmental origin with unrestricted developmental potential; “primed” cells have developed further, but still remain pluripotent. intermediate stem cells led to better integration.

The human cells survived and formed a human/pig chimera embryo. Embryos were implanted in sows and allowed to develop for between three and four weeks. That was long enough for them to try and understand how the human and pig cells mix together early on without raising ethical concerns about mature chimeric animals.

However, even using the most well-performing human stem cells, the level of contribution to the chimerized embryo was not high, and  many of the chimeric embryos were underdeveloped.

According to the authors, there are several reasons why the human-pig experiments did not work as well as the mouse-rat ones.

  • Pigs and humans about five times more distant evolutionarily than mice and rats

  • The rodents have much more similar gestation period – mice and rats differ by a few days, while pigs and humans are off by more than five months, so the researchers needed to introduce human cells with perfect timing to match the developmental stage of the pig. It’s as if the human cells were entering a motorway going faster than the normal motorway – if you have different speeds, you will have accidents.

Some consider this hurdle to be good news. One concern with the creation of human/animal chimeras is that the chimera will be too human. For instance, researchers don’t want human cells to contribute to the formation of the brain and reproductive systems. (In this study, the human cells did not become precursors of brain cells that can grow into the central nervous system. Rather, they were developing into muscle cells and precursors of other organs). There is this possibility, but scientists have ways in the lab to prevent this from happening, such techniques include terminating the experiment before the chimeric embryo is fully developed or born, and genetically and epigenetically directing the stem cells away from developing in those organs.

The next step, for the researchers, will be to develop strategies to improve the human cell contributions to the pig embryo before trying to combine it with CRISPR-Cas9 technology. They would like to reach about 0.1 to 1 percent of human cell contribution – now we only observe very few human cells, around one cell in 100,000 pig cells.The scientists’ other next challenge is to improve efficiency and guide the human cells into forming a particular organ in pigs.

To do this, the researchers are using CRISPR to perform genome editing on the pig genome, as they did with mice, to open gaps that human cells can fill in. The work is in progress.

The ultimate goal of producing organs for transplantation is still in the distant future. There was, however, another important step made this week. In a study published from the University of Tokyo, scientists reported having successfully transplanted a mouse pancreas generated in a rat back into a mouse. That organ remained functional for more than a year. The success of the study is a welcome sign that the strategy can actually work – so they were very happy to see those results.