October 6, 2008

Making “Safer” Stem Cells

Photo of cultured stem cells in a well plate cientists successfully converted adult mouse cells into versatile stem cells by adding genetically engineered cold viruses to the cultured cells.Justin Ide, Harvard News Office

By using a common cold virus to insert 4 genes into mouse cells, scientists have converted adult liver and other cells into versatile stem cells that can grow into a wide variety of cell types. The new technique sidesteps the cancer-causing potential of a previously developed method that used a different kind of virus.

Two years ago, scientists in Japan gained worldwide attention when they announced that they'd converted mouse tail cells into multipurpose stem cells by adding just 4 genes. Several research teams have since used similar techniques to create human pluripotent stem cells, which can give rise to many different human cell types. But these methods have a major drawback that limits their clinical usefulness: They all rely on retroviruses to deliver the transforming genes. Retroviruses randomly integrate their own viral DNA into the cell's genome, which can potentially cause cancer.

In a new study, reported in the September 25, 2008, advance online edition of Science, Dr. Konrad Hochedlinger of Massachusetts General Hospital and his colleagues found that they could bypass the problem of viral integration by using a different type of virus called an adenovirus. The research was funded in part by an NIH Director's New Innovator Award to Hochedlinger.

Adenoviruses generally cause mild respiratory diseases, like the common cold, or infections of the eyes or tonsils. Because they're able to infect a wide variety of cells, adenoviruses are often used to deliver new genes into cells. Unlike retroviruses, adenoviruses deliver their DNA without integrating it into the cell's genome. However, researchers had thought that the very low efficiency of cell reprogramming required the more robust integration of retroviruses.

Hochedlinger and his colleagues tested this idea by creating adenoviruses packed with the 4 transformative genes used by the Japanese researchers. They exposed cultures of mouse liver and connective tissue cells to the viruses and generated stable colonies of pluripotent stem cells. As expected, the scientists could detect viral DNA in the newly infected cells, but as the cells multiplied and transformed, the viral DNA dwindled away.

Several tests showed that the newly created stem cells shared many characteristics of pluripotent cells, including the ability to give rise to many different cell types. In one test, the researchers added molecular tags to the new stem cells and injected them into developing mouse embryos. The resulting mice and their offspring had the tagged cells throughout their bodies, showing that the new cells can behave like embryonic stem cells and give rise to a variety of cells and tissues. The new stem cells also affected coat color, causing an unusual pattern. The researchers noted that none of the 12 mice with patterned coats developed tumors a month or more after birth.

Adenovirus-induced stem cells are likely safer as a potential stem cell therapy than cells created using retroviruses, but their ultimate safety and clinical potential remain to be seen. The scientists are now working to convert adult human cells into pluripotent stem cells using the new method.

—by Vicki Contie

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