Scientists have created an infant ‘chimaeric’ monkey by injecting a monkey embryo with stem cells from a genetically distinct donor embryo¹. The resulting animal is the first live-born chimaeric primate to have a high proportion of cells originating from donor stem cells.

　　The finding, reported today in Cell, opens the door to using chimaeric monkeys, which are more biologically similar to humans than are chimaeric rats and mice, for studying human diseases and developing treatments, says stem-cell biologist Miguel Esteban at the University of Chinese Academy of Sciences in Guangzhou, a co-author of the study.

　　But the monkey chimaera had to be euthanized when it was only ten days old because of hypothermia and breathing difficulties, highlighting the need for further optimization of the approach and raising ethical concerns, say researchers.

Chasing chimaeras

　　Scientists have long sought to make animal chimaeras using embryonic stem cells, which are derived from an embryo’s inner region and can develop into a wide variety of tissues. Such stem cells can be genetically edited before being added to a recipient embryo.

　　For example, stem cells carrying genetic mutations that have been linked to a particular disease could be added to embryos without those mutations. This would allow scientists to study how cells carrying the mutations affect physiology and health.

　　In earlier chimaeric monkeys, just 0.1–4.5% of the cells in organs such as the brain, kidney and lungs were derived from donor stem cells. Because the contribution was so small, these chimaeras were unsuitable as models for human disease, says Esteban.

　　To produce a chimaera with a larger contribution, Esteban and his colleagues created recipient embryos by collecting eggs from female cynomolgus monkeys (Macaca fascicularis) and fertilizing the eggs.

　　Meanwhile, the researchers extracted embryonic stem cells from one-week-old cynomolgus embryos and genetically edited the cells to display a green fluorescent signal. To grow the stem cells in the laboratory, the team fine-tuned the nutrients and growth-promoting proteins in the liquid in which the stem cells were grown. They then injected up to 20 green embryonic stem cells into each of the recipient embryos, yielding 74 chimaeric embryos with a strong fluorescent signal.

Low pregnancy rate

　　These embryos were implanted into 40 surrogate female monkeys. Just 12 surrogates became pregnant, and only one gave birth to a live chimaeric monkey, a male that was later euthanized.

　　The team found that, on average, 67%, of the cells across the 26 tested tissues, including the brain, lungs and heart, were descendants of the donor stem cells. The highest level of chimaerism was seen in the adrenal gland: the progeny of donor stem cells made up 92% of total cells.

　　The low birth rate of chimaeric monkeys and the poor health of the one survivor suggest that the donor embryonic stem cells did not perfectly match the developmental state of the recipient embryo, says reproductive biologist Zhen Liu at the Chinese Academy of Sciences in Shanghai. The team plans to optimize this in future, he adds.

Platform for growing human organs?

　　“This work is both impressive and commendable,” says stem-cell biologist Irene Aksoy at the Stem-cell and Brain Research Institute in Lyon, France, who was not involved in the study.

　　The method might be used to grow human organs in pig or non-human primate tissues, says developmental cell biologist Shoukhrat Mitalipov, director of the Oregon Health and Science University in Portland.

　　“If we can delete the genes encoding for, say, the kidney, in a large animal such as a pig or primate, we could introduce human cells to produce that organ instead,” he says. But he adds that using human–animal chimaeras for organ collection, especially if human embryonic stem cells contribute to the nervous system, brain or reproductive cells, comes with many ethical concerns.

https://www.nature.com/articles/d41586-023-03473-w