Researchers Report Stem Cell Advance

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By Jeffrey Perkel
HealthDay Reporter

THURSDAY, Sept. 25 (HealthDay News) -- Researchers report that they have sidestepped a major technical hurdle in the generation of pluripotent stem cells from adult cells.

A team of Boston scientists developed a way to generate induced pluripotent stem cells (iPS) -- which are functionally similar to embryonic stem cells, but which can be produced from adult cells, rather than via the creation or destruction of an embryo -- more safely than ever.

Should the findings, which involved mouse cells, be repeated with humans, they could pave the way for using iPS to delve into the biology of a wide range of genetic diseases. Longer term, they could lead to patient-specific stem-cell therapies.

"I think it's a really important, landmark study," said Kevin Eggan, an assistant professor of Stem Cell and Regenerative Biology and an assistant investigator of the Stowers Medical Institute at Harvard University. He was not involved in the study.

The results were published in the Sept. 25 online edition of Science.

Shinya Yamanaka, of Kyoto University, Japan, first demonstrated in 2006 that adult mouse cells -- for instance, skin cells -- could be reprogrammed into something akin to an embryonic stem cell by the introduction of four specific genes. According to the lead author of this latest study, Matthias Stadtfeld, that "was like a gigantic, essentially quantum leap for biology." The following year, Yamanaka and James Thomson, of the University of Wisconsin, Madison, demonstrated the same approach could create human iPS cells.

Normally, the four genes -- all of which can induce cancer if left unchecked -- are delivered using retroviruses, which integrate their viral DNA into the cells' chromosomes; the worry is that these random insertions will introduce mutations into the cells that would alter their behavior, thus minimizing the cells' potential usefulness as research tools. Should these cells ever be used to generate tissues that were transplanted into human patients, researchers fear they could inadvertently lead to cancer.

Konrad Hochedlinger, of Massachusetts General Hospital and the Harvard Stem Cell Institute, his postdoctoral fellow Stadtfeld, and their colleagues circumvented this problem by delivering the genes using adenoviruses instead, which do not insert their viral DNA into a cell's chromosomes. iPS cells generated by this new approach appear indistinguishable from other iPS cells, carry some of the molecular hallmarks of embryonic stem cells, and can form multiple cell types when transplanted into mice (that is, they are pluripotent).

"My conclusion is that viral integration is not necessary for reprogramming to a pluripotent state, which is an important step toward safer patient-specific iPS cells, if it can be translated into humans," said Stadtfeld.

Human iPS cells have several potential applications. On a research level, they may be used to study how particular genetic defects lead to disease. Pharmaceutical companies might be able to use these cells to design drugs that alter, circumvent or repair these behaviors. Ultimately, iPS cells could be used clinically to develop patient-specific transplants, for instance, of genetically repaired neurons in patients with neurodegenerative diseases.

Before any of that can happen, however, this new method must be optimized. Only about one in 1 million skin cells actually developed into an iPS by Stadtfeld's method, compared to one in 10,000 using retroviruses. Using liver cells (hepatocytes), the efficiency was about one in 50,000 -- better, but still worse than with retroviruses.

"For this to be translated into humans, we have to find ways to make the process more efficient and properly make it work in cell types which are more easily accessible than hepatocytes, such as skin cells, for example," said Stadtfeld.

Dr. Rudolf Jaenisch, of the Whitehead Institute and Massachusetts Institute of Technology, who studies iPS cells, called the findings "clearly an advance."