Eggs of another species turns off the genes needed to make an embryo instead of turning them on Monday, 02 February 2009 Since the cloning of Dolly the Sheep over a decade ago, somatic cell nuclear transfer (SCNT) has been considered a promising way to generate human, patient-specific stem cells for therapeutic applications. The shortage of human donor eggs has led to efforts to substitute animal oocytes. However, a new study published online ahead of print in the Volume 11, Number 2, 2009 issue of Cloning and Stem Cells, demonstrates that animal oocytes lack the capacity to fully reprogram adult human cells. Robert Lanza, M.D. from Advanced Cell Technology (Worcester, MA), and colleagues compared the reprogramming of human cells using oocytes obtained from cows, rabbits, and humans. They report their findings in a paper entitled, "Reprogramming of Human Somatic Cells Using Human and Animal Oocytes." “Mixing human and animal cells does not appear to program the egg properly,” said Dr. Robert Lanza in an interview with Reuters. "For the last decade, we've carried out literally hundreds of experiments trying to create patient-specific stem cells using animal eggs," Lanza said. "We got beautiful little hybrid embryos, but it didn't work no matter how hard we tried." The ability to reprogram human cells using oocytes would enable the production of patient-specific stem cells that could then be differentiated to become any type of somatic cell and used for cell or tissue repair or placement therapy. This extensive reprogramming requires that the oocyte turn on, or up-regulate a large number of genes in the donor nucleus. Although previous reports have documented the formation of cloned embryos using both human and animal eggs, to date, there have been no data indicating to what extent the donor human DNA was reprogrammed. Lanza et al. show for the first time that human oocytes have the capacity to change these patterns of gene expression, and that interspecies (human-to-animal) cloning does not produce the same results. Although the human-bovine and human-rabbit clones looked similar to the human-human embryos, the human-animal hybrids did not exhibit the changes in gene expression seen in the human-human clones and normal embryos. A mouse-human hybrid petered out after just one division. The cow and rabbit human hybrids went further, but stopped at the point when maternal DNA is supposed to kick in and turn the ball of cells into a proper embryo, Lanza said. Lanza's team used a new method called global gene expression analysis to see which genes were turned on and off as the eggs grew. "We never had the tools before to actually look inside the cell and see what's going on," Lanza said. It appears that using the egg of another species turns off the genes needed to make an embryo instead of turning them on, he said. But the human-human clone did turn on the right genes, although it, too stopped dividing before it could produce stem cells, Lanza said. "We see exactly the same genes turned on in a normal embryo are actually turned on in a human clone," he said. “We examined the factors recently used to reprogram skin cells (to induce pluripotent stem cells),” said Robert Lanza. “At the center of cellular reprogramming lies the activation of the transcription factors Oct4, Sox2, and Nanog. These core factors were activated in both the normal and cloned human embryos. In striking contrast, the human-animal hybrids showed no difference or a down-regulation of these critical pluripotency genes −effectively silencing them — thus making the generation of stem cells impossible. Without appropriate reprogramming, these data call into question the potential use of animal egg sources to generate patient-specific stem cells. It also renders the moral controversy surrounding the use of human-animal hybrids mute.” Specifically, they did not achieve up-regulation of these critical pluripotency-associated genes needed for stem cell production. For example, human oocytes significantly up-regulated Oct-4, Sox-2, and Nanog (22-fold, 6-fold, and 12-fold, respectively), whereas the bovine and rabbit oocytes either showed no difference or a down-regulation of these critical pluripotency-associated genes, effectively silencing them. "This very important paper suggests that livestock oocytes are extremely unlikely to be suitable as recipients for use in human nuclear transfer. This is very disappointing because it would mean that production of patient-specific stem cells by this means would be impracticable," says Ian Wilmut, Ph.D., Editor-in-Chief of Cloning and Stem Cells and director of the Centre for Regenerative Medicine, in Edinburgh. Reference: Reprogramming of Human Somatic Cells Using Human and Animal Oocytes Young Chung, Colin E. Bishop, Nathan R. Treff, Stephen J. Walker, Vladislav M. Sandler, Sandy Becker, Irina Klimanskaya, Wan-Song Wun, Randall Dunn, Rebecca M. Hall, Jing Su, Shi-Jiang Lu, Marc Maserati, Young-Ho Choi, Richard Scott, Anthony Atala, Ralph Dittman, Robert Lanza Cloning and Stem Cells. ahead of print, doi:10.1089/clo.2009.0004 ......... ZenMaster
For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html
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