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Nuclear transfer appears superior for creating embryonic stem cells

OHSU study in Nature shows iPS method produces epigenetic abnormalities

Scientists at Oregon Health & Science University have found that a process called "somatic cell nuclear transfer" is much better and more accurate at reprogramming human skin cells to become embryonic stem cells — capable of transforming into any cell type in the body — than an alternative process that produces cells similar to embryonic stem cells, but with many more epigenetic abnormalities.

The findings come from a team led by OHSU's Shoukhrat Mitalipov, Ph.D., with collaborators from the University of California, San Diego School of Medicine and the Salk Institute for Biological Studies. The findings, which will be published online July 2 in the journal Nature, could have major implications for how science continues to develop better embryonic stem cells and stem cell therapies — which many hope could someday revolutionize how medicine treats and cures a wide range of diseases.

Scientists believe stem cell therapies hold the promise of replacing human cells damaged through injury or illness, meaning embryonic stem cells could someday treat or cure Parkinson's disease, multiple sclerosis, spinal cord injuries and many other diseases and conditions.

Mitalipov, director of OHSU’s Center for Embryonic Cell and Gene Therapy, has been an international leader in embryonic stem cell research, especially since he and his team’s breakthrough in May 2013 when they announced they had successfully used somatic cell nuclear transfer to convert human skin cells into embryonic stem cells. In 2007, Mitalipov's team successfully transformed monkey skin cells into embryonic stem cells.

The somatic cell nuclear transfer process Mitalipov and his team use involves transplanting the nucleus of one cell, containing an individual's DNA, into an egg cell that has had its genetic material removed. The unfertilized egg then develops and eventually produces stem cells.

Since 2006, however, many scientists have been focused on a different process to convert adult somatic cells — for instance, skin cells — into something very much like embryonic stem cells. The process happens through the introduction of four specific genes into the adult cell and produces transformed cells called induced pluripotent stem cells — or iPS cells. These cells, like embryonic stem cells, are capable of transforming into any type of cell in the body. The iPS process was pioneered by Japanese scientist Shinya Yamanaka in 2006, who shared the 2012 Nobel Prize for his work.

Since Yamanaka’s discovery, however, it's been known that iPS cells do not match exactly to genuine embryonic stem cells. That could affect how they can be used in stem cell research or therapies.

The current research is the first to more deeply compare the somatic cell nuclear transfer and iPS methods — and to analyze how the SCNT and iPS methods worked when they each started with the same set of skin cells.

The study found that stem cells produced from the skin cells by the SCNT method were almost identical to embryonic stem cells produced through in vitro fertilized eggs — which are considered the "gold standard." The iPS cells made from the same skin cells, in contrast, retained a large number of the skin cells’ characteristics, referred to as “memory.”

“We think the difference is remarkable,” Mitalipov said. “The SCNT method faithfully erases the memory of the skin cell and converts it into an embryonic stem cell. The iPS method produces a cell with significant differences and abnormalities.”

“If you believe that gene expression is important, which we do, then the closer you get to the gene expression patterns of embryonic stem cells, the better,” said co-author Joseph R. Ecker, Ph.D., professor and director of Salk's Genomic Analysis Laboratory and co-director of The Center of Excellence for Stem Cell Genomics. “Right now, nuclear transfer cells look closer to the embryonic stem cells than do the iPS cells.”

“If we can figure out how the egg manages to do a better job at reprogramming compared to the iPS method, it may help us develop a better iPS method,” says co-author Louise C. Laurent, assistant professor in the Department of Reproductive Medicine at the University of California, San Diego.

Until then, Mitalipov said, he believes the SCNT method is a much better candidate for cell replacement therapies. “And we hope science can continue to develop stem cell therapies — so that somebody they can help us battle and defeat diseases that are defeating us today.”

The research was funded by OHSU, the Leducq Foundation, the Howard Hughes Medical Institute, the Salk International Council Chair endowment fund and the Mary K. Chapman Foundation.

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