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Novel Cell Lines Propel the Search for Safer Stem Cell Induction

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Whitehead Institute researchers have reliably produced mice and mouse cell lines with identical configurations of the specific factors needed to reprogram adult cells to an embryonic-stem-cell-like state. These so-called transgenic mice and mouse cell lines may be used to screen for potential drug substitutes for virally-inserted reprogramming genes and as a tool for unraveling how reprogramming works.

Currently, reprogramming adult cells usually requires one or more viruses to transfer the necessary reprogramming genes (Oct4, Sox2, Klf4 and c-Myc) into the cells’ DNA. Once activated, these genes convert the cells from their adult, differentiated status to an embryonic-like state.

Whitehead Member Rudolf Jaenisch sees this novel approach as an important step toward safely reprogramming cells for therapeutic use.

However, this method poses significant risks for potential use in humans. The viruses used in reprogramming are associated with cancer because they may insert DNA anywhere in a cell’s genome, thereby potentially triggering the expression of cancer-causing genes, or oncogenes. In addition, the reprogramming gene c-Myc is a known oncogene and its insertion into a cell’s genome can also cause cancer.

Before tapping into iPS cells’ vast potential to treat human diseases, researchers must find safe alternatives to reprogramming with such viruses and oncogenes. To this end, researchers have been attempting to stimulate cells’ innate reprogramming genes with drug-like molecules, thereby eliminating the use of both viruses and inserted programming genes.

To identify drugs potentially useful in reprogramming, researchers need cell lines with two attributes. First, the cells must lack one or more of the reprogramming factors that a candidate drug could replace. Second, the researchers need to know that the cells can in fact be reprogrammed if the drug successfully replaces the missing reprogramming genes.

To create such cell lines, Styliani Markoulaki and Jacob Hanna, postdoctoral researchers in Whitehead Member Rudolf Jaenisch’s laboratory, created mice from iPS cells and confirmed that their genomes contained all four reprogramming factors. These iPS-cell-derived mice were then mated with normal mice, and their progeny inherited various combinations of genes, ranging from all of the reprogramming factors to none of them.

When Markoulaki and Hanna systematically added the missing genes to the cells with various reprogramming gene combinations, the cells reverted to an embryonic stem-cell-like state, thereby indicating that the cells could be used reliably to screen for potential reprogramming drugs.