The possibility of reprogramming adult cells to behave like embryonic stem cells without overexpressing cancer genes or relying on hard-to-control viruses has gotten a bit closer. Publishing in Science, Shinya Yamanaka and colleagues from Kyoto University, in Japan (see From skin cells to stem cells), show that the reprogramming techniques he previously demonstrated on cultured mouse skin cells also work on two other mouse cell types: those that line the stomach and those from the liver1.

Because far fewer than 1 in 100 treated cells are successfully reprogrammed, several stem cell scientists had raised concerns that reprogramming does not work on fully differentiated cells but rather on rare stem cells residing undetected within the culture. That would make the reprogrammed cells less interesting scientifically and, potentially, therapeutically. To address this concern, Yamanaka used a genetic marking system that permanently labeled liver cells once they differentiated enough to express albumin, and he found that these cells could be reprogrammed to so-called induced pluripotent stem (iPS) cells that can contribute to all cell types in an adult mouse.

“The old question in cloning was exactly the same: was Dolly derived from a fully differentiated cell?” said Rudolf Jaenisch of the Whitehead Institute, in Cambridge, Massachusetts, who showed that mice can be cloned from terminally differentiated cells such as neurons. Yamanaka provides “good evidence” that reprogramming works in differentiated cells, said Jaenisch, but that conclusion assumes both a reliable labeling system and that only mature cells express the albumin gene. Yamanaka himself stopped short of calling the initial cells fully differentiated: “Our data showed that lineage-committed albumin-producing cells can be reprogrammed.”

Perhaps more interesting, Yamanaka also shows that the epithelial cells lining the stomach can generate iPS cells using a less rigorous screening system than that used with cultured skin cells or fibroblasts. Reprogramming currently uses viruses to insert several copies of three or more pluripotency genes into cells, one of which is particularly implicated in cancer. Tumours develop in about a third of mice created using iPS cells derived from fibroblasts; no tumours were found in mice created from iPS cells derived from stomach and liver cells. Though viruses were less efficient at infecting the stomach-lining cells with the necessary genes, the cells that were transformed contained fewer copies of the transgenes compared with fibroblasts, perhaps because epithelial cells are more similar to embryonic stem cells than fibroblasts are. (These mice were more likely to die in utero, but live-born mice appeared healthy.)

Yamanaka found that the transgenes do not need to be inserted into specific sites within the genome for liver and stomach cells to be reprogrammed. “This is encouraging to those of us who are seeking a nonviral means of generating iPS cells,” said George Daley of Children’s Hospital Boston, who recently compared the efficiencies of reprogramming human fibroblasts from different sources.

References

1. Aoi, T. et al. Generation of pluripotent stem cells from adult mouse liver and stomach cell. Science published online 14 February 2008; doi:10.1126/science.1154884