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Reengineered Skin Cells Offer Hope for Alzheimer's Patients

In findings appearing online June 7 in Cell Stem Cell, researchers in the laboratory of Yadong Huang, M.D., Ph.D., at the Gladstone Institutes describe how they transferred a single gene called Sox2 into both mouse and human skin cells. Within days the skin cells transformed into early-stage brain stem cells, also called induced neural stem cells (iNSCs). These iNSCs began to self-renew, soon maturing into neurons capable of transmitting electrical signals. Within a month, the neurons had developed into neural networks.

"Many drug candidates&mdashespecially those developed for neurodegenerative diseases&mdashfail in clinical trials because current models don't accurately predict the drug's effects on the human brain," said Dr. Huang, who is also an associate professor of neurology at the University of California, San Francisco (UCSF). "Human neurons&mdashderived from reengineered skin cells&mdashcould help assess the efficacy and safety of these drugs, thereby reducing risks and resources associated with human trials."

Last year Sheng Ding, Ph.D., announced that he had used a combination of small molecules and genetic factors to transform skin cells directly into neural stem cells. Dr. Huang's approach, however, takes a new tack by using one genetic factor&mdashSox2&mdashto directly reprogram one cell type into another without reverting to an induced pluripotent state (iPS). In an iPS, four genetic factors are used to turn adult human skin cells into cells that act like embryonic stem cells that can then become virtually any cell in the body. The problem, however, is that they can sometimes produce tumors, too. Avoiding the pluripotent state lessens the danger of this occurring.

"We wanted to see whether these newly generated neurons could result in tumor growth after transplanting them into mouse brains," said Karen Ring, a graduate student at UCSF and the paper's lead author. "Instead we saw the reprogrammed cells integrate into the mouse's brain&mdashand not a single tumor developed."

The research also revealed the precise role of Sox2 as a master regulator that controls the identity of neural stem cells. Dr. Huang and his team next hope to identify similar regulators that guide the development of specific neural progenitors and subtypes of neurons in the brain.

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