Induced pluripotent stem cells may not be good disease models after all

A study funded by the EU under its ESTOOLS research programme has delivered the disappointing finding that induced pluripotent stem (iPS) cells may not provide such important disease models as first hoped.

Researchers at the Hebrew University of Jerusalem and the Children’s Hospital in Boston have shown that although disease genes are present in stem cells produced by reprogramming adult somatic cells, the genes themselves are not active. This undermines the wide potential that was foreseen for generating induced pluripotent stem cells representing disease genotypes for use in drug discovery.

The results of the study will be presented next week in Lisbon at the International Symposium “Stem Cells in Biology and Disease” organised by ESTOOLS, a European consortium of researchers studying human embryonic stem cells, which includes the Jerusalem group as a partner.

ESTOOLS, coordinated by Sheffield University, UK, was the first programme to be awarded EU funding to studying human iPS cells.

Human iPS cells were discovered in 2007. Like embryonic stem cells, iPS cells can self-renew and turn into any cell or tissue type, but are obtained by genetically reprogramming the somatic cells of an individual, raising hopes for their use in research and regenerative medicine without the practical and ethical limitations of embryonic stem cells. iPS cells also provide models for diseases that would be difficult or impossible to study in humans.

While human embryonic and iPS cells show remarkable similarities, there is controversy over whether iPS cells will be able to fully replace embryonic stem cells in basic research and in clinical applications.

The researchers obtained iPS cells from the skin cells of individuals affected by fragile X syndrome, the most common form of inherited mental retardation in boys, and compared their properties with that of embryonic stem cells isolated from embryos with the same genetic defect.

The fragile X gene, called FMR1, was active in embryonic stem cells but not in iPS cells. “We saw a difference between iPS and embryonic stem cells, although they have the same mutation,” said Nissim Benvenisty, director of the Stem Cell Unit at the Hebrew University of Jerusalem and a leading author of the study.

Three years ago, the Jerusalem group showed that FMR1 was active in human stem cells but not in adult tissues: when stem cells differentiate and turn into mature tissues, epigenetic modifications of the DNA lock down the FMR1 gene, silencing its activity.

Researchers expected that reprogramming adult skin cells back into iPS cells would reset the epigenetic blocks, reactivating FMR1; instead, they found out that the FMR1 gene resisted reprogramming, and remained inactive in iPS cells, which then failed to faithfully model the natural process.

However, the same iPS cells may be a useful model for studying neurons affected by fragile X, which do not express the gene, researchers said.

It is possible that other genes may likewise escape the reprogramming process leading to iPS cells. “Our findings might underline a more general phenomenon of epigenetic differences between human embryonic and induced pluripotent stem cells,” Benvenisty said. “Until we understand better the differences between these two types of cells, the optimal approach might be to model human genetic disorders using both systems, whenever possible.”

Peter Andrews, the Co-ordinator of ESTOOLS and Director of the Centre for Stem Cell Biology at the University of Sheffield said. “These results from Nissim Benvenisty’s group show that human ES cells and iPS cells are complementary tools that in some cases may give different insights into fundamental disease processes. They emphasise the importance of continued research with both types of pluripotent human stem cells. The results also confirm the value and importance of European funding of research consortia like ESTOOLS.”