A few days ago, a team of Chinese and foreign scientists published a paper announcing the construction of the world’s first human-monkey chimera embryo, which is an embryo with both human-derived cells and monkey-derived cells.
"Chimera" in English is Chimera (Chimera), which originally refers to a monster of lion head, sheep body, and snake tail in Greek mythology. In reality, why are scientists so obsessed with making such puzzle-like "monsters"?
"Some friends often exclaimed that our work was too sci-fi and terrifying." Tan Tao, a professor at Kunming University of Science and Technology and one of the first and corresponding authors of the paper, said dubiously. "But this is really not a scientist's evil taste. It's research work of very practical significance."
"Far neighbors are not as good as close relatives", why?
Approximately 2 million people worldwide are in desperate need of organ transplantation every year to save lives, but the main source of organs is still donations, and the gap is huge. "Many patients, especially young patients, died while waiting, which is very regrettable." Tan Tao said. There are three main ideas for solving this problem: xenogeneic organ transplantation, organoids and 3D printing, and xenogeneic mosaicism. The ideal prospect of heterogeneous chimerism is to allow animals to grow human organs that are truly transplantable.
Which animal is suitable for raising organs for humans? Scientists first think of pigs. "The organ size, growth rate, and breeding cost of pigs are all appropriate, and they don't involve serious ethical issues like primates," Tan Tao explained.
However, past studies have shown that, including commonly used experimental animals such as pigs, rats and mice, the chimerism of human cells in embryos that are relatively distant from humans is very limited, and it is almost impossible to form real human organs.
In January 2017, Wu Jun, a researcher at the Salk Institute of Biology (currently an assistant professor at the Southwestern Medical Research Center in the United States) and others announced that they had successfully cultivated the first human-pig chimera embryo, which developed in pigs for 3 to 4 weeks. However, the mosaic efficiency of these embryos is very low, "I guess there may be less than 1 human cell per 100,000 pig cells." Wu Jun said.
They tried to explore the mechanism. At the beginning of 2021, Wu Jun and several research teams within the United Nations reported a strange phenomenon: early mouse embryos can use the cell competition mechanism to "kill" foreign human stem cells, resulting in a low rate of chimeric human-mouse embryos. This phenomenon is significantly related to species kinship, because there is no obvious stem cell competition among species with close kinship, such as rats and mice, and human monkeys.
Under the leadership of Academician Ji Weizhi of the Chinese Academy of Sciences, Tan Tao, Niu Yuyu, Dai Shaoxing and others of Kunming University of Science and Technology, and Juan Carlos Izpisuya Belmont, Wu Jun and others of the Salk Institute of Biology have reached an agreement. The cooperation hopes to find ways to improve the efficiency of human cell mosaicism in distantly related species by studying the chimeric process of human cells in early primate embryos.
What are the communication codes of human and monkey cells?
The researchers injected human expanded pluripotent stem cells (human EPS cells) into the early blastocysts of more than 150 cynomolgus monkeys. Using the monkey embryo in vitro culture system recently developed by the research group, the survival time of these embryos reached 20 days, which is the limit time that monkey embryos can be cultured in vitro.
At this time, the chimeric embryo has entered the gastrulation period, that is, the blastocyst begins to differentiate between ectoderm, mesoderm and endoderm. Researchers have observed mosaicism in the three germ layers of the outer, middle and inner germ layers. However, these embryos have not undergone in vivo transplantation experiments, thus avoiding some possible ethical controversies.
According to statistics, the chimeric efficiency of human cells in cynomolgus monkey embryos is about 4%, far exceeding the previous human-pig chimeric embryos.
"We are aware that the mosaic process between different species is indeed very different. For example, it is difficult for human EPS cells to differentiate into trophoblast cells in cynomolgus monkey embryos, and it is easier to differentiate into epidermal cells. There are obvious differences in the previous human-mouse chimera experiments." Tan Tao said.
What surprised them even more was that with the injection of human cells, the cells of the monkey embryo itself became like human cells in terms of expression characteristics, and at the same time, the human cells also undergo a similar transformation, becoming like monkey cells. Compared with the normal development process of human embryos, the development process of human-monkey chimera embryos is slower.
"This is very interesting." Wu Jun said, "This shows that although human cells and monkey cells have differences in the early development process, there may be cross-species cell synergy between the cells, which helps human cells differentiate and differentiate in monkey embryos. Survival.” They then screened out many cell signaling pathways that may be involved in these processes, and hope that in future studies, these signaling pathways can be adjusted to improve the chimerism of human cells in embryos of pigs or other distant species.
"This work provides theoretical evidence for organ regeneration through heterogeneous mosaicism. Compared with previous work, it also points out that differences between species are the main obstacle to heterogeneous mosaicism." Institute of Zoology, Chinese Academy of Sciences, who did not participate in this research Researcher Li Wei said, "If we can use this platform to better understand the main regulatory mechanisms that lead to the success and failure of heterogeneous chimerism, it may provide new theoretical guidance and technical strategies for heterogeneous chimerism to achieve organ regeneration."
Human-monkey chimerism behind the powerful combination of scientists
first individual - born monkey chimeric embryos, technological progress is inseparable from related fields in recent years, as well as the layout and the accumulation of domestic research institutions.
The human EPS cells used in this work came from a new pluripotent stem cell line published by Peking University professor Deng Hongkui's group in 2017. Compared with conventional human pluripotent stem cells (hPS cells), these cells have higher chimerism and developmental potential. The newly developed monkey embryo in vitro culture system at Kunming University of Science and Technology also plays an important role.
Previously, research on chimerism between humans and primates was limited by technology, funding, experimental conditions, and ethical norms, and relatively few developments were carried out. Fortunately, the Institute of Primate Translational Medicine established by Kunming University of Science and Technology in 2014 has accumulated rich experience in the research of primate reproduction and development; Juan Carlos and Wu Jun are well-known scholars in the field of chimera research—— "The complementary advantages of the two parties make it possible for monkey chimera embryos." Tan Tao said.
