Five years after stunning the world with his announcement that adult cells could be reprogrammed to an embryonic stem cell-like state, Kyoto University’s Shinya Yamanaka took the stage today to defend the utility of his technique.
The cells he created, called induced pluripotent stem (iPS) cells, were hailed as a possible way to create patient-specific stem cells without using embryos. Companies and academic labs around the world rushed to model diseases ‘in a dish’ by creating iPS cell lines from patients with conditions ranging from Parkinson’s disease to autism.
Then, over the past year, a series of publications drew attention to troubling differences in gene expression and epigenetic markers between iPS cells and their embryonic counterparts. Last month, researchers also reported that mice rejected some iPS cell transplants even when the cells were generated from the recipient’s own tissue. (For more on the issues facing iPS cells, see ‘Stem cells: The growing pains of pluripotency’.)
But on 17 June at the International Society for Stem Cell Research (ISSCR) annual meeting in Toronto, Yamanaka presented unpublished data from his lab that suggested that the distinctions reported over the past year may not reflect fundamental differences between the two kinds of stem cells.
Yamanaka’s lab analyzed ten human embryonic stem cell lines and fifty iPS cell lines. He found that some – but not all – of the iPS cells indeed differed from embryonic stem cells. For example, some cell lines did have lower methylation of two genes, C9orf64 and TRIM4, as reported earlier this year. But methylation in other iPS cell lines was just as high as in the embryonic stem cell lines.
Yamanaka concluded that there is simply a wide degree of heterogeneity among iPS cells. He pointed out that a series of cell lines derived at Kyoto University had lower methylation than cells generated in other locations. “Maybe the water in Kyoto” is to blame, he speculated. But it’s not that the dividing line is drawn between embryonic stem cells and iPS cells: “It’s more like the difference between Japan – Kyoto – and the rest of the world.”
As for the immunogenicity reported last month, Yamanaka said he could not tell from the reported data if the differences seen were statistically significant.
During the same plenary session, Rudolf Jaenisch, whose lab at the Whitehead Institute in Cambridge, Massachusetts has also pioneered the iPS field, presented new data showing one way that iPS cell heterogeneity could come about. His lab, he noted, had difficulty reproducing results from iPS cells reported in a 2010 Nature paper from his former postdoc, Konrad Hochedlinger, now at the Massachusetts General Hospital in Boston. Yet the two groups generated their iPS cell lines using very similar techniques.
A little scientific sleuthing revealed that the discrepancy originated from the vectors used to shuttle in the four genes that, when overexpressed, can cause an adult cell to revert back to an embryonic state. The two labs used slightly different vectors, resulting in differences in the relative expression of the four genes. When those differences were corrected, the cells behaved similarly.
Image: stem cell cultures, NIH