By slipping human stem cells into the embryos of other animals, we might someday grow new organs for people with faltering hearts or kidneys. In a step toward that goal, researchers have created the first embryos with a mixture of human and monkey cells. These chimeras could help scientists hone techniques for growing human tissue in species better suited for transplants, such as pigs.
"The paper is a landmark in the stem cell and interspecies chimera fields,” says stem cell biologist Alejandro De Los Angeles of Yale University. The findings hint at mechanisms by which cells of one species can adjust to survive in the embryo of another, adds Daniel Garry, a stem cell biologist at the University of Minnesota (UM), Twin Cities.
In 2017, researchers reported growing pancreases from mouse stem cells inserted into rat embryos. Transplanting the organs into mice with diabetes eliminated the disease. But cells from more distantly related species, such as pigs and humans, haven’t gotten along as well. That same year, developmental biologist Juan Carlos Izpisúa Belmonte of the Salk Institute for Biological Studies and colleagues reported injecting human stem cells into pig embryos. After the embryos had developed in surrogate mother pigs for 3 to 4 weeks, only about one in 100,000 of their cells were human.
The pig study used human skin cells that had been reprogrammed into stem cells. But so-called extended pluripotent stem (EPS) cells, made by exposing stem cells to a certain molecular cocktail, can spawn a greater variety of tissues. In the new study, Izpisúa Belmonte, reproductive biologist Weizhi Ji of Kunming University of Science and Technology, and colleagues tested those more capable cells in a closer human relative—cynomolgus monkeys. They inserted 25 human EPS cells into each of 132 monkey embryos and reared the chimeras in culture dishes for up to 20 days.
The team reports today in Cell that the human cells showed staying power: After 13 days, they were still present in about one-third of the chimeras. The human cells seemed to integrate with the monkey cells and had begun to specialize into cell types that would develop into different organs.
By analyzing gene activity, the researchers identified molecular pathways that were switched on or turned up in the chimeras, possibly promoting integration between human and monkey cells. Izpisúa Belmonte says manipulating some of those pathways may help human cells survive in embryos of species “more appropriate for regenerative medicine.”
Still, the human and monkey cells didn’t quite mesh, notes UM stem cell biologist Andrew Crane. The human cells often stuck together, making him wonder whether there’s “another barrier that we aren’t seeing” that could prevent human cells from thriving if the embryos were to develop further.
In the United States, federal funding cannot be used to create certain types of chimeras, including early nonhuman primate embryos containing human stem cells. The new study was performed in China and funded by Chinese government sources, a Spanish university, and a U.S. foundation. Bioethicist Karen Maschke of the Hastings Center in New York says she is satisfied that the work, which passed layers of institutional review and drew on advice from two independent bioethicists, was performed responsibly.
Human-monkey chimeras do raise a worry, addressed in a report released last week by the National Academies of Sciences, Engineering, and Medicine (p. 218): that human nerve cells might enter animals’ brains and alter their mental capabilities. But that concern is moot for the chimeras in this study because they don’t have a nervous system. They “can’t experience pain and aren’t conscious,” says bioethicist Katrien Devolder of the University of Oxford. “If the human-monkey chimeras were allowed to develop further,” she says, “that would be a very different story.”