Biologists have created mouse-human chimeras whose bodies were composed of up to 4 per cent human cells when the early embryos were destroyed after 17 days. The highest proportion previously achieved is around 0.1 per cent.
The reason for creating the chimeras is to find ways to grow organs for people who need transplants, says Jian Feng at the University at Buffalo in New York.
Feng’s team injected around 10 human stem cells into 3.5-day-old mouse blastocysts, bundles of many cells. The human cells contributed to all kinds of tissues in the developing mouse embryo, including forming eye, liver and red blood cells.
In one mouse embryo, around 4 per cent of all the cells were human. The proportion probably varied from tissue to tissue, but the team didn’t look at the proportion in specific tissues such as the brain.
“My immediate reaction is ‘wow’,” says Pablo Ross at the University of California, Davis. “This is great if we want to generate human organs in animals.”
Previous studies have shown that the reason why attempts to create mouse-human chimeras haven’t been very successful is that human stem cells are in a more developmentally advanced “primed” state, whereas the mouse stem cells are in a “naive” state.
If mouse stem cells in a primed state are added to a mouse blastocyst, many of the embryos end up dying, just as when human stem cells are added.
Feng’s team has found a way to make human stem cells revert to the naive state by inhibiting a molecule called mTOR kinase for 3 hours. Another reason for their success, says Feng, is that the ethics committee allowed the team to let the embryos grow for 17 days, a week longer than most previous studies. Such chimeras aren’t allowed to develop longer because of concern that they are more human than normal mice.
“That’s a valid question,” says Feng. But it is the host embryo that determines what animal a chimera develops into, he says. If you add rat cells to a mouse embryo, for instance, you get a mouse and vice versa, not some kind of mix between the two species.
“It’s not a matter of the percentage [of human cells in the brain],” says Feng. “It’s how they are connected.”
The next step is to try the approach in a large animal such as a pig or sheep, whose organs are a similar size to ours. The idea here would be to genetically modify animals so they cannot develop specific organs. In chimeric animals, these organs should then develop from human cells and be mostly human.
The 1 to 4 per cent proportion of human cells achieved by Feng should be enough to make this feasible, says Ross. However, Feng says his team lacks the resources to work with large animals.
Even if human organs can be grown in chimeric animals, Feng suspects they will be too much of a mix to be suitable for transplant. However, he thinks that growing human organs in animals could be an essential step towards finding ways to grow organs outside bodies, in some kind of incubator. Societies need to discuss the ethical issues and potential benefits, and decide on what can and cannot be done in this area, he says.
Journal reference: Science Advances, DOI: 10.1126/sciadv.aaz0298
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