One-Gene Method Makes Safer Human Stem Cells, Max Planck Institute Study

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Researchers have regressed human stem cells to an embryonic state using just a single transcription factor, as opposed to the four factors previously needed to induce pluripotency in human cells, according to a study published online today (August 28) in Nature.

Human embryonic stem cells
Image: Wikimedia commons,
Nissim Benvenisty

“This is another important milestone of [stem cell] research,” linkurl:Kwang-Soo Kim,; a stem cell researcher at McLean Hospital of Harvard Medical School, wrote in an email to The Scientist. “This elegant work further advances the already fast-moving field and demonstrates that human [induced pluripotent stem (iPS)] cells can be generated with [a] minimal number of retroviral vectors,” added Kim, who was not involved in the work. Earlier this year, linkurl:Hans Schöler; of the Max Planck Institute for Molecular Biomedicine in Münster, Germany, and his colleagues succeeded in using just a single transcription factor, OCT4, to revert mouse adult neural stem cells to a pluripotent form, capable of producing other cell types, including germ cells that could be transmitted to the next generation. Now, Schöler’s group has found that the same factor can induce pluripotency in human cells as well. The researchers infected human fetal neural stem cells with retroviruses carrying either human OCT4 or both OCT4 and KLF4 — two of the four factors Kyoto University’s Shinya Yamanaka used to create iPS cells from adult mouse fibroblasts in 2006, and from adult human skin cells in 2007. Sure enough, 10 to 11 weeks after the infection, the team noticed cell cultures that resembled human embryonic stem (ES) cells in both experimental conditions. Further examination revealed that these colonies expressed human ES cell markers, and global gene expression resembled that of human ES cells. Rigorous tests of pluripotency in vitro confirmed the cells’ ability to form all three germ layers, and in vivo, the cells developed into a variety of cell types, including respiratory epithelium, skeletal muscle, cartilage, and neural epithelium. “Demonstrating OCT4 is sufficient for reprogramming in a human cell type is a major step and further validated the earlier conceptually similar finding in the mouse,” linkurl:Sheng Ding; of the Scripps Research Institute in La Jolla, Calif., said in an email. Eliminating viral transgenes from this process, particularly oncogenes such as c-Myc (one of the four transcription factors used by Yamanaka), which frequently causes tumors in mice, is a step in the right direction for creating safer stem cell therapies, Kim said. However, the retroviral vector used to deliver the one remaining factor integrates into the cell’s genome, which could “pose potential problems for future clinical applications,” he noted. One possible alternative to using retroviruses is to express the transcription factors as proteins, first author Jeong Beom Kim of the Max Planck Institute for Molecular Biomedicine told The Scientist, which can be added directly to the cells, but so far this method requires all four factors. Furthermore, the cells used in this study were derived from fetal brain tissue, as opposed to adult tissues, which would be the source of cells used therapeutically. And the reprogramming efficiency and time required to induce pluripotency are “suboptimal in this study,” Kwang-Soo Kim added. Important areas of future research include the application of this technique to other cell types, and determining how to increase the efficiency and shorten the time scale of the process, he said. An additional goal of the stem cell community is to further whittle the number of factors needed to create iPS cells — down to zero, said Ding. “This will undoubtedly promote additional research effort toward studying and replacing the ‘last-standing’ Oct in cellular reprogramming to pluripotency.”
**__Related stories:__***linkurl:Patient-ready iPS cells?;
[28th May 2009]*linkurl:Purely protein pluripotency;
[23rd April 2009]*linkurl:Single-factor stem cells;
[5th February 2009]

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