Using mice, US scientists have found a safer way to make induced pluripotent stem cells (iPS cells) without using retroviruses which carry the risk of triggering cancer. They hope the method can be developed for human use, which would greatly increase the scope for creating non-embryonic stem cells to research and treat a wide range of serious diseases.

The discovery is reported in the journal Science and was led by a team of scientists at the Harvard Stem Cell Institute (HSCI) in Boston, Massachusetts.

Dr Konrad Hochedlinger and HSCI colleagues at Massachusetts General Hospital and Joslin Diabetes Center used adenoviruses to insert the four genes needed to cause an adult cell to transform into an iPS cell. Until now, the only way to make iPS cells was to use retroviruses to insert the four genes. However, retroviruses work by changing the DNA of their host cells, which can trigger cancer.

Fortunately, adenoviruses do not change the DNA of their host. They go into the nucleus of the host cell and work directly on the proteins and leave the chromosomes alone.

However, this latest discovery is a step, and not a leap, forward, because lots of problems remain, not least of which is how to improve the efficiency of the process. With retroviruses 1 in 10,000 skin cells is transformed into an iPS cell; with adenovirus gene insertion it is closer to 1 in a million.

Hochedlinger, an assistant professor in Harvard’s new inter-school Department of Stem Cell and Regenerative Biology (SCRB) said in a press statement that the adenoviruses infect the host cells, carrying the new genes with them, but after a few cell divisions, the host cell’s clearing up mechanism has eliminated them.

“This wouldn’t be harmful in any way because the DNA of the new cells remains unaffected,” said Hochedlinger.

Hochedlinger explained that when iPS cells were first made, scientists thought that the only way to get the four genes into the cells was to change the DNA of the host cells, but:

“We’ve shown that you don’t need integration of the virus into the genome to produce iPS cells,” he said.

With lead author Dr Mathias Stadtfeld and other colleagues, Hochedlinger used the new method to generate iPS cells from mouse skin cell, and mouse fetal and adult liver cells.

They have produced stem cell lines, “they are all pluripotent,” said Hochedlinger, which means they can become any type of cell, and they have no trace of the adenovirus left, and the mice carrying the new cells are showing no signs of developing tumors, unlike what frequently happens when mice carry iPS cells made with retroviruses.

Hochedlinger said he sees no reason why this won’t work in humans and the next step of this research is to test it with human cells.

HCSI researchers have also been looking at using chemicals instead of viruses as ways to introduce the four genes needed to make normal cells into iPS cells.

Shinya Yamanaka, at Kyoto University in Japan was the first to discover in 2006 that by inserting four genes into mouse skin cells they could be coaxed into regressing to an early stage cell that behaved very much like an embryonic stem cell, that is it had the potential to become nearly any other type of cell in the body. A year later, together with James Thomson, of the University of Wisconsin, Madison, Yamanaka used the same method to produce human iPS cells.

Human iPS cells have many potential uses. In research they could be used to find out how genes trigger diseases like cancer and Parkinson’s, and one day there may be drugs tailored to individual patients that cause their own bodies to prevent genetic diseases from being triggered, or even to regenerate damaged tissue, for instance brain cells damaged by neurodegenerative diseases. Drug companies are now starting to invest in stem cell research for this reason.

While iPS cells have many of the properties of embryonic stem cells, it is not yet clear whether they are as powerful, and Hochedlinger himself says this is an important question that remains unanswered.

This point was also made by Dr Kevin Eggan, an assistant professor of Stem Cell and Regenerative Biology and an assistant investigator of the Stowers Medical Institute at Harvard University. Eggan, who was not involved in the study, called this study a “landmark study”, but said nobody had yet managed to grow a mouse from a single iPS cell. He told the Washington Post that this was the gold standard for testing the pluripotency of a stem cell, and currently only embryonic stem cells pass that test.

“Induced Pluripotent Stem Cells Generated Without Viral Integration.”
Matthias Stadtfeld, Masaki Nagaya, Jochen Utikal, Gordon Weir, and Konrad Hochedlinger
Science, Published Online September 25, 2008
DOI: 10.1126/science.1162494

Click here for Abstract.

Source: Harvard Science, Washington Post, Science.

Written by: Catharine Paddock, PhD