Bringing iPS cells closer to the clinic

One of this year’s most promising stem cell developments has been the refinement of the methods used to produce induced pluripotent (iPS) cells, which closely resemble human embryonic stem cells but do not require the use of embryos.

Until now, the excitement over the ability to create iPS cells has been tempered by the fact that the four genes used to ‘turn back the clock’ on adult cells and return them to an embryonic-like state have been inserted using retroviruses, which have the potential to trigger tumor growth. In addition, two of the four genes used are themselves known to cause cancer.

But a number of recent papers by HSCI research groups suggest that these problems are not insurmountable.

Konrad Hochedlinger, PhD, has shown that it is possible to create mouse iPS cells using an adenovirus in place of the retroviruses previously used.

HSCI faculty member Konrad Hochedlinger, PhD, and colleagues have recently shown that it is possible to create mouse iPS cells using an adenovirus, which does not integrate into the cells’ DNA and would therefore not be cancer-causing. This approach disproves the previous belief that the viruses carrying the four genes had to be integrated into the genome of the adult cells in order for reprogramming to take place.

The iPS cells created in the study have no traces of the adenovirus and, thus far, none of the mice carrying the new cell lines have shown any signs of developing tumors, which had been reported in mice carrying the cell lines created using retroviruses.

And as Hochedlinger and his colleagues have been working to find viral alternatives for the retroviruses in the production of iPS cells, other HSCI researchers have also been looking for chemicals that might be used to replace the viruses altogether.

In a paper published this October, HSCI Co-Director Douglas Melton, PhD, Danwei Huangfu, PhD, a postdoctoral fellow in Melton’s lab, and colleagues describe a method for creating iPS cells in which two of the four genes used in the reprogramming technique are replaced by a chemical. This publication marks Huangfu’s second success using chemicals in reprogramming. Last year, working with mouse cells, Huangfu used a chemical to improve the efficiency of the gene-induced reprogramming process.

In this latest experiment – using human cells – the team used a chemical to eliminate the need for two of the four genes now routinely used in reprogramming experiments. What is even more significant in terms of hastening the day when stem cells may be used to treat disease is that the two genes Huangfu eliminated were c-Myc and K1f4, both of which are cancer genes.

Valproic acid, the chemical used in the reprogramming experiment, has been used for a number of years as a medication to treat seizure disorders. “On at least a superficial level, it appears to be safe,” Huangfu said.

“The exciting thing about Danwei’s work is you can see how one might be able to sprinkle chemicals on cells and make stem cells,” said Melton. What is not known at this point is whether chemicals can replace all four genes used in reprogramming. However, Huangfu believes the right chemical or combination of chemicals should be possible to find.

iPS cells have many potential benefits, including the production of disease-specific cell lines from a patient with a particular disease, and the use of these cells in high-throughput screens to identify potential therapeutics or to study disease mechanisms. But before this potential can be fully realized, the fundamental challenges facing reprogramming must be addressed. These two studies show the progress that HSCI faculty have made in overcoming these challenges – through the creation of adenoiPS cells and the chemical replacement of some of the genes – thereby bringing this exciting technology one step closer to clinical application.