Immortality improves cell reprogramming

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Knocking out genes with a role in cancer prevention helps produce stem cells.

Switching off the p53 pathway helped researchers to make stem-like cells. Credit: Wikimedia Commons

Specialized adult cells made 'immortal' through the blockade of an antitumour pathway can be turned into stem-like cells quickly and efficiently.

The findings — which should make it easier to generate patient-specific cells from any tissue type, including certain diseased cells that have proved difficult to transform — suggest that cellular reprogramming and cancer formation are inextricably linked.

Since 2006, when Shinya Yamanaka of Japan's Kyoto University first created induced pluripotent stem (iPS) cells1 — which can develop into any cell type — many scientists have devised ways to make cells pluripotent. But the success rates of these techniques have remained frustratingly low — usually much fewer than 1% of adult cells are successfully reprogrammed to become iPS cells.

“Anything that we can do to increase the efficiency of reprogramming is a big step forward. George Daley , Children's Hospital Boston”

Now, five research teams, including Yamanaka's, have boosted their success rates by around a 100-fold by silencing the p53 pathway, which prevents mutations and preserves the sequence of the genome. After knocking out several genes to wipe out the p53 pathway, the teams successfully turned up to 10% of skin cells into bona fide iPS cells using viruses carrying the four commonly used reprogramming factors. What's more, disabling the p53 pathway improved success rates for techniques besides this four-factor method that are potentially safer but often much less efficient, including the use of viral vectors with only two or three factors, or plasmid vectors that don't modify the genome.

"Anything that we can do to increase the efficiency of reprogramming is a big step forward," says George Daley, a stem-cell expert at the Children's Hospital Boston in Massachusetts who was not involved with the new work.

Cancer link

The deluge of simultaneous publications in Nature today2,3,4,5,6 shows that there is "a consensus that this pathway plays an important role in reprogramming", says Konrad Hochedlinger, a stem-cell biologist at the Massachusetts General Hospital in Boston who headed one of the research teams. "By manipulating this pathway we can significantly enhance the efficiency and kinetics of the [reprogramming] process."

The studies also shed light on the mechanism of tumour formation, says study author Juan Carlos Izpisúa Belmonte, a developmental biologist at the Salk Institute for Biological Studies in La Jolla, California, and at the Center of Regenerative Medicine in Barcelona, Spain. Because it's now clear that p53 has a key role in both nuclear reprogramming and cancer development, Izpisúa Belmonte says, tumours can be thought of as cells that acquire more and more stem-cell-like characteristics — such as the ability to keep reproducing themselves forever. "If you connect the dots, you can say that cancer is really a de-differentiation problem," he says.

Quality control

Although the findings will make reprogramming easier — an important step for reliably generating iPS cells from diseased or older patients — the methods still involve genetic manipulation of genes associated with cancer, which would rule out their use in therapies, cautions Jacob Hanna, a stem-cell researcher at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who was not involved in the studies. "It's important, but it still does not eliminate concerns," he says. Izpisúa Belmonte says he is now screening chemicals that only transiently silence p53 to make iPS cells that are potentially safer.

Molecular biologist Maria Blasco of the Spanish National Cancer Research Center in Madrid who worked on two of the papers also warns against wiping out p53 when generating therapeutic iPS cells.

A working p53 pathway prevents the propagation of cells with heavy DNA damage, she says. With the p53 pathway intact, "the cells that are reprogrammed are cells that are healthy and do not carry any DNA damage". Nevertheless, stifling p53 to make DNA-damaged iPS cells could provide useful cellular models to aid the understanding of many diseases, she adds.

References

  1. 1

    Takahashi, K. & Yamanaka, S. Cell 126, 663-676 (2006).

  2. 2

    Hong, H. et al. Nature advance online publication doi:10.1038/nature08235 (2009).

  3. 3

    Utikal, J. et al. Nature advance online publication doi:10.1038/nature08285 (2009).

  4. 4

    Marión, R. M. et al. Nature advance online publication doi:10.1038/nature08287 (2009).

  5. 5

    Li, H. et al. Nature advance online publication doi:10.1038/nature08290 (2009).

  6. 6

    Kawamura, T. et al. Nature advance online publication doi:10.1038/nature08311 (2009).

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Video about creating iPS cells

Juan Carlos Izpisúa Belmonte

Maria Blasco

Konrad Hochedlinger

Manuel Serrano

Shinya Yamanaka

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Dolgin, E. Immortality improves cell reprogramming. Nature (2009) doi:10.1038/news.2009.809

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