Scientists have found a new type of stem cell, one that can develop into any kind of tissue in the body, that may make research on early embryonic cell states easier — and could lead to new research opportunities for developmental disorders.
The new human embryonic stem cells were injected into mouse embryos in the lab, leading to different early-stage tissues after 36 hours, according to the paper published in Nature. That’s in contrast to two types of conventionally used human stem cells, which didn’t develop when injected into the non-viable mouse embryos.
Today’s new kind of stem cell may allow scientists to better study developmental disorders at their earliest stages and "has huge implications for regenerative medicine," says study author Juan Carlos Izpisua Belmonte. With improvements in the technology, it may be possible to generate human cells, tissues, and organs in another species, like a pig — which can then be used for transplant, he says. "Of course, the ethical implications behind creating a human-animal chimera for the purpose of obtaining human tissues and organs to save lives of millions need to be carefully evaluated."
This isn’t the first time that human cells have been integrated into a mouse embryo. In 2006, scientists injected human embryonic stem cells into a non-viable mouse embryo and let the cells develop for a few days; the human cells contributed a little. Another similar experiment was published by Nature in 2013, also showing some human cell contributions. But today’s paper is the only one that determined that the human cells created the three germ layers of cells — suggesting that these cells can produce all types of cells in the body.
For the last several years, scientists have recognized that different kinds of pluripotent stem cells — the ones that produce all the body’s cell types — exist. In living creatures, these pluripotent states don’t last long; they’re only around in the earliest stages of development.
"The kick for me was the human data.""At first, I looked at this like okay, fine, we have a new pluripotent state," says Kathrin Plath, an associate professor at UCLA’s Broad Center of Regenerative Medicine and Stem Cell Research. She wasn’t involved in the research. "But when I got to the primate data, that was what made me excited about the paper. The kick for me was the human data."
Previously scientists have derived pluripotent stem cells from structures containing clustered cells that eventually become the embryo, called blastocysts, or early post-implantation embryos. These lineages need to be cultured in the lab dissimilarly, show different molecular characteristics and behave distinctly when they’re injected back into host blastocysts.
Mouse chimeras have been crucial for exploring how genes work in the body One puzzling thing about these cells has been that mouse and human embryonic stem cells behave very differently, even though they’re derived from a stage in development that seems to be "reasonably equivalent," says Uta Grieshammer, the science officer at the California Institute for Regenerative Medicine. That may be because those states aren’t really that similar, she says. Mouse embryonic stem cells are considered "naive," meaning that when they’re injected into a blastocyst that can’t make embryonic tissue, a whole mouse results. Mice made using this technique are called chimeras; they contain cell types from genetically distinct cells. (Chimeras occur naturally as well; if you have a friend with different-colored eyes, you know a chimera — that person was twins who merged in the womb.)
Mouse embryonic stem cells (the clump in the middle) surrounded by feeder cells (Joseph Elsbernd)
Mouse chimeras have been crucial for exploring how specific genes work in the body. Scientists insert bits of DNA in mouse embryonic stem cells to create "knockout mice," mice who lack a specific gene or set of genes. That enabled better modeling of human disease in mice, leading to medical breakthroughs. In 2007, a team of researchers won the Nobel Prize for pioneering the knockout mouse.
Human embryonic stem cells aren't as flexible as mouse cells But human embryonic stem cells aren’t as flexible as mouse cells, and the technique likely wouldn’t work in people. Genetic testing of human embryonic stem cells suggests they resemble stem cells derived from later-stage mouse embryos, called epiblast stem cells, Grieshammer says. "It’s not perfect, and there are some exceptions, but that’s the general feeling in the field," she says.
Studies in other primates suggest that the problem isn’t limited to human stem cells. In 2012, a group of researchers from Oregon Health and Science University found it was impossible to create chimeric monkeys by injecting embryonic stem cells into a host embryo. We’re much more closely related to monkeys than mice, so that study may mean that stem cells can’t contribute to monkey chimeras because the cells are already too advanced.
In 2010, researchers created a mouse with a rat pancreas So far, studies of human-mouse chimeras have only looked into a few days’ worth of development. But the new pluripotent state may aid more radical approaches in creating chimeras, Grieshammer says. In 2010, researchers created a mouse with a rat pancreas. They used knockout technology to prevent the mouse from creating its own pancreas, and injected the embryo with rat stem cells instead, which generated the organ. The structure of the pancreas created with this method was part rat and part mouse, the researchers found. It’s possible to imagine chimeric animals, like pigs, that could harbor human organs for use in transplant. But that’s far in the future, Grieshammer and Izpisua Belmonte say.
In the nearer term, being able to more readily culture human embryonic cell types in the lab may make research on diseases of early development easier, UCLA’s Plath says. For instance, there’s a type of autism called Rett syndrome, which occurs only in women. It’s due to a mutation on the X chromosome; male embryos, which have only one X chromosome, are lost early in development. "It’s hard to study this because it’s hard to capture those male embryos," Plath says. Female embryos make it farther — to birth, in fact — since the second, normal X chromosome confers protection from the mutation’s effects.
Being able to culture human embryonic stem cells more easily and embed them in other embryos "just opens up more possibilities we can pursue," Plath says. "And on top of the more practical things, this could get us a better understanding of the early development that gets us all these cell types."