Induced Pluripotent Stem Cells Do Not Induce Immune Response

In 2007, scientists from Japan and the United States discovered that cells from a person’s own body could be reprogrammed to an embryo-like cell known as induced pluripotent stem cells or iPSCs. These cells seemed to provide an endless source of pluripotent stem cells that are matched to the patient to treat diseases or for model systems for research.

The formation of iPSCs seems to provide a solution to the ethical concerns that surround the derivation of embryonic stem cells. However, worries about the use of iPSCs emerged with the publication of a 2011 study published in Nature that threw doubt on one of the key advantages of iPSCs. In this study, iPS cells could provoke an immune response when injected into the mice from which they had been derived (Zhao, T., Zhang, Z.-N., Rong, Z. & Xu, Y. Nature 474, 212–215 (2011).

However, a more recent study also published in Nature has shown that iPSCs do not induce immune responses in the laboratory animals from which they were derived. Masumi Abe, who works as a geneticist at the National Institute of Radiological Sciences in Chiba, Japan, and co-workers took iPS cells derived from mice and injected them back into the animals. As a control, they injected other mice with embryonic stem (ES) cells. Contrary to the 2011 study, which observed that injected iPS cells induced an immune response but injected ES cells did not, Abe’s team were not able to find any differences between the immune responses elicited by iPSCs or ES cells. Abe and his colleagues also transplanted skin and bone-marrow cells derived from iPS or ES cells into mice and achieved similar success rates between the groups. The immune responses to both sets of tissues were, in the words of Abe, “indistinguishable.”

Konrad Hochedlinger, a stem-cell scientist at Massachusetts General Hospital in Boston, says that the result will probably “calm people down” about iPS cells. “It is definitely reassuring,” he says.

These findings from Abe’s laboratory come on the heels of another positive study on iPS cells that was published late last year. This study showed that the reprogramming process caused fewer mutations than previously thought. Flora Vaccarino, a Yale University neuroscientist (New Haven, Connecticut) and her colleagues used high-resolution DNA analysis to compare the genomes of iPS cells and the adult cells from which they were derived. They discovered that most of the DNA mutations in the iPS cells did not arise as a result of reprogramming but had been present in the parent cells (Abyzov, A. et al. Nature 492, 438–442 (2012).

The co-author of the 2011 study, Yang Xu, a stem-cell scientist at the University of California, San Diego, is skeptical about this present study and says that the new work does not dispel all concerns about the immune response provoked by iPS cells. Xu pointed out that the skin and bone-marrow cells used in the latest study were not grown from iPS cells in culture, as they would be for clinical use. Instead, the researchers mixed iPS cells into early mouse embryos to make “chimeric” embryos. They then used skin and bone-marrow tissues that arose from iPS cells after the embryos grew into adult mice for their transplantation experiments. It is possible, says Xu, that the most immunogenic cells were rejected as the mice developed, which would explain why Abe and his colleagues observed a limited immune response. According to Xu, transplanting tissues from chimeric mice is “flawed.”

Chimeric embryo production is a standard technique for testing whether mouse iPS cells have been fully reprogrammed, says Jakub Tolar, a clinician at the University of Minnesota in Minneapolis. Tolar also noted that differentiating cells in culture outside the body is much harder. Tolar hopes to use iPS cells to treat the childhood skin disease epidermolysis bullosa, and added that iPS-cell therapies will use human cells, which could behave quite differently from mouse cells. “It’s helpful that they’ve done this, but it is absolutely different when you go to something that is cultured,” he says.

Hochedlinger believes that iPS cells show just as much promise for cell transplantation as ES cells, although many issues stand between the lab and the clinic. According to Hochedlinger, the differences between the two kinds of stem cell are minor compared with the differences in how individual cell lines grow and differentiate in culture.

“Based on what we know at this time from mice,” he says, “iPS cells are as good as ES cells, and should be as safe.” See Araki, R. et al. Nature 493, 145 (10 January 2013) doi:10.1038/493145a.