Many research labs around the world are focused on finding the most effective ways to reprogram an adult cell (a skin cell, for example) into induced pluripotent stem cells (iPSCs)—that is, cells that have the ability to develop into other tissues in the body. These cells not only offer researchers powerful tools to study a particular patient’s individual disease, but they have the potential to therapeutically replace diseased or damaged tissue in the patient from whom the cells originated.
Most experiments to reprogram adult cells employ viruses as vehicles to carry four particular genes—called reprogramming factors—into the nucleus of a cell. But genetic engineering carries its own risks, including the chance that these cells will continue replicating, eventually forming a tumor. What’s more, scientists are not exactly sure what the reprogramming factors do, on the molecular level, to promote the generation of iPSCs.
Could there be a safer and more predictable way to alter the expression of genes in cells, thereby reprogramming their DNA so they revert to their earlier, more malleable state?
Last February, Sanford-Burnham’s Dr. Tariq Rana and his team developed one new way to make the transition from skin cell to iPSC more efficient. Now, in a paper published in the journal Stem Cells, the researchers uncover two new compounds that have the power to dial up some genes and tone down others in order to promote the generation of iPSCs—all in the absence of two of the traditional reprogramming factors. Neither of these compounds is entirely new. One of the drugs, called Nabumetone, is commonly used as a nonsteroidal anti-inflammatory drug (NSAID) to treat osteoarthritis and rheumatoid arthritis. The other is 4-hydroxytamoxifen, the active ingredient in the breast cancer drug Tamoxifen.
In their study, the researchers, led by graduate student Chao-Shun Yang, first analyzed genomic datasets to identify genes in mouse skin cells that act as barriers to reprogramming. Armed with this knowledge, they employed genetic material called small interfering RNA, or siRNA, to stifle those genes.
The siRNA experiments helped the researchers narrow down the number of compounds to screen, so they could more rapidly zero in on the ones that would promote the conversion to iPSCs. Using sophisticated computer programs and genomics analysis, Dr. Rana and his colleagues further narrowed down the number of compounds to screen to just 17. They found that Nabumetone and 4-hydroxytamoxifen could generate iPSCs in the absence of one of the reprogramming factors, called Sox-2. Furthermore, Nabumetone could produce iPSCs in the absence of Sox-2 and also a second reprogramming factor called c-Myc—without compromising the cells’ pluripotency (their ability to specialize into other cell types) or their ability to self-renew (make more stem cells).
“The exciting part is both of these compounds are already FDA-approved,” Dr. Rana says. “You take Motrin—a non-steroidal anti-inflammatory drug—for a headache all the time.”
Work is continuing on testing the compounds with other types of cells, and Dr. Rana says his goal is to develop a way to safely create iPSCs from patients without having to use risky viral vectors to deliver reprogramming factors.
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Original paper:
Yang CS, Lopez CG, & Rana TM (2011). Discovery of nonsteroidal anti-inflammatory drug and anticancer drug enhancing reprogramming and induced pluripotent stem cell generation. Stem cells (Dayton, Ohio), 29 (10), 1528-36 PMID: 21898684
