Unwelcome infiltrators. Dark-brown T cells—a sign of immune rejection—invade tissue formed by iPS cells.

Yang Xu/UC San Diego

Mice Reject Reprogrammed Cells

Scientists have high hopes that stem cells called induced pluripotent stem (iPS) cells can be turned into replacement tissues for patients with injury or disease. Because these cells are derived from a patient’s own cells, scientists had assumed that they wouldn’t be rejected—a common problem with organ transplants. But a new study suggests that the cells can trigger a potentially dangerous immune reaction after all.

To make iPS cells, scientists use a technique called cellular reprogramming. By activating a handful of genes, they turn the developmental clock backward in adult cells, converting them into an embryolike state. The reprogrammed cells become pluripotent, which means they have the ability to differentiate into all of the body’s cell types. Scientists are already using these iPS cells to study diseases and test drugs.

Induced pluripotent stem cells have a couple of advantages over embryonic stem (ES) cells. They don’t require the use of embryos, so they avoid some of the ethical and legal issues that have complicated research with embryonic stem cells. They also allow researchers to make genetically matched cell lines from patients. Many scientists have assumed that would provide a source of transplantable cells that wouldn’t require the immune system to be suppressed to avoid rejection, as is necessary with organ transplants.

That assumption might not be correct, however. Immunologist Yang Xu of the University of California, San Diego, and his colleagues tested what happened to several kinds of pluripotent cells when they were transplanted into genetically matched mice. Inbred mouse strains are the genetic equivalent of identical twins, and they can serve as organ donors for each other without any immune suppression. The researchers used two popular inbred strains, called B6 and 129, for their experiments.

When the researchers implanted ES cells from a B6 mouse embryo into a B6 mouse, it formed a typical growth, called a teratoma, which is a mixture of differentiating cell types. (Teratoma formation is a standard test of ES and iPS cells’ pluripotency.) ES cells from a 129 mouse, on the other hand, were unable to form teratomas in B6 mice because the animals’ immune systems attacked the cells, which they recognized as foreign.

The researchers then implanted iPS cells made from B6 mouse cells into B6 mice. To their surprise, many of the cells failed to form teratomas at all—similar to what the researchers saw when they transplanted ES cells from one mouse strain to another. The teratomas that did grow were soon attacked by the recipient’s immune system and were rejected, the team reports online today in Nature. The immune response “is the same as that triggered by organ transplant between individuals,” Xu says.

The immune reaction was less severe when the researchers used iPS cells made with a newer technique. The new method ensures that the added genes that trigger reprogramming turn off after they’ve done their job. But the reaction didn’t go away completely. The researchers showed that the iPS cell teratomas expressed high levels of certain genes that could trigger immune cells to attack. That is probably due to incomplete reprogramming that leaves some genes misexpressed, Xu says.

The results add to a series of findings that iPS cells differ in subtle but potentially important ways from ES cells. George Daley, a stem cell scientist at Children’s Hospital Boston, says the new study is “fascinating,” but he doesn’t think immune rejection will be an insurmountable problem for iPS cells. Once iPS cells have differentiated into the desired tissue type, they may not express the problematic genes, he notes. And dozens of labs are working on ways to improve the reprogramming process so that the stray gene expression is eliminated. In principle, he says, “we should be able to make iPS cells that are the same as ES cells.”

In the meantime, both Xu and Daley say the results underscore the need to continue work with ES cells so that researchers can fully understand—and try to overcome—the differences. “It’s a reminder that we can’t dismiss ES cells,” Daley says.