Mouse Adult Skin Cells Reprogrammed to Embryonic State New reports by Japanese and American research teams show that mouse adult skin cells can be reprogrammed to acquire the properties of embryonic stem cells. Embryonic stem cells have thus far only been derived from early embryos. The reprogrammed cells are pluripotent; that means, like embryonic stem cells, they are capable of self-renewal and of generating all body cell types. The findings provide a new strategy for the generation of pluripotent stem cells, called induced pluripotent stem (iPS) cells, and have prompted efforts to adapt this approach for human cells. Previously, Yamanaka and Takahashi of Kyoto University reported that they had generated iPS cells by inserting into skin cells copies of four different genes known to be important in embryonic stem cells. These genes produce proteins that are known as transcription factors. These four transcription factors, when produced simultaneously, induce a cascade of activity of other genes. As a result, a fraction of the cells acquired key characteristics of embryonic stem cells. The engineered iPS cells, however, did not meet the “gold standard” of pluripotency – when injected into developing embryos, they were not able to generate all body cell types. Now, Yamanaka has improved the methodology so that the iPS cells now meet this gold standard. Two American teams composed of researchers from MIT, Harvard, and University of California also issued reports confirming the Kyoto group’s findings. The new reports assert that these reprogrammed iPS cells have most, if not all, properties of embryonic stem cells. Injection of the iPS cells into developing embryos resulted in the generation of “chimeric” mice- that is, mice that are a mix of cells from the original embryo and injected iPS cells. In the chimeric mice, these iPS cells were able to generate all the basic adult cell types. However, there was an important caveat: about 20 percent ofYamanaka’s chimeric mice developed tumors, attributed to the activity of one of the four inserted genes. These findings offer great promise for human stem cell research. Reprogramming of adult human cells would allow researchers to bypass some of the ethical and technical issues raised by the use of surplus human in vitro fertilization (IVF) embryos or by nuclear transfer. Furthermore, this approach could eventually allow the generation of “customized” patient-specific stem cells. Significant hurdles, however, remain. It is not clear that the same four genes that reprogram mouse adult cells will reprogram human adult cells. In addition, researchers will have to address ways to safely reprogram human cells without the risk of causing tumors. Yet, most scientists are optimistic that this research will open doors to novel therapeutic approaches using stem cells. Notes Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld, M., Yachechko, R., Tchieu, J., Jaenisch, R., et al. (2007). Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55-70 Okita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317. Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676. Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B. E., and Jaenisch, R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318-324. *Author affiliation Posted August 21, 2007
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