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        Cell Res:Major breakthrough!

        Number of visits: Date:2017-07-18

          From improve crop resistance, to in situ editing animal genetic code, and then to destroy the targeted mutation of mitochondria, and specific genes in the cells of patients with correct mutations, the rapid development of gene editing technology is to bring different levels of change for human health and life. The day before, the Research Institute of Biophysics, Peking University, Liu Guanghui research group soup rich reward group and the Chinese Academy of Sciences Institute of animal research group Qu Jing carried out jointly to further expand the scope of application of gene editing technology. The researchers used gene editing rewrite human genome single nucleotide genetic code, for the first time in the laboratory has obtained genetic enhancement of the "super" stem cells (Genetically Enhanced Stem cells, GES cells). The GES cell can produce double resistance to cell senescence and tumorigenicity, so it provides a possible solution for safe and effective stem cell therapy. The research work in July 7, 2017 to "Genetic enhancement in cultured human adult stem cellsconferred a single nucleotide recoding" as the title published in Cell Research by.
          There are two important scientific problems to be solved in the field of regenerative medicine: (1) the effectiveness of stem cell therapy, which is how to obtain more high quality available for transplantation in the treatment of human stem cells, how to give these cells graft stronger self-renewal, survival, and differentiation of transplanted environment (such as aging and stress) tolerance, in order to make it play a more lasting therapeutic effect in vivo. (2) the safety of stem cell therapy, that is, how to effectively reduce the risk of cell graft formation in vivo. The latest published this research work focused on the two important issues, expectations of key genes and signaling pathways of intracellular precise regulation by gene editing means, so as to realize the stem cell activity increase and decreased tumorigenicity. At the same time, finally get the quality and safety of human stem cell graft.
          By screening small molecules that slow down stem cell aging, researchers have discovered that the antioxidant transcription factor NRF2 agonist slows the aging of human mesenchymal stem cells in human early life. In previous studies of low model organisms, the deletion of NRF2 leads to shortened life span of organisms, whereas overexpression contributes to life extension. The Institute of biophysics research team study published in the 2016 article on Cell and this will further reveal human mesenchymal stem cell aging is accompanied by significantly reduced NRF2 protein level; in turn, the function of NRF2 enhanced and can improve the aging of mesenchymal stem cells activity. Therefore, the researchers hypothesized that increasing NRF2 activity at the coding gene level may retard the aging of human stem cells. To prove this, they use the third generation of adenovirus vector mediated HDAdV gene editing technology in human embryonic stem cells in the replacement of exon second of NRF2 gene single nucleotide in the (A245G). This single base substitution causes the NRF2 protein in the cell to break from the binding of its inhibitory protein, KEAP1, and, by translocation to the nucleus, activate a range of antioxidant and cytoprotective genes.
        Then, the researchers will gene editing of human embryonic stem cells differentiate into a therapeutic potential of mesenchymal stem cells, and found that the mesenchymal stem cell self-renewal and cell senescence and stress resistance ability were significantly enhanced. In addition, vascular endothelial cells induced by this embryonic stem cell show strong resistance to oxidative damage. These results indicate that the genetic enhancement strategy can give human stem cells and their differentiation derivatives stronger activity and self-protection ability.
          At the same time, the researchers also examined whether GES cells would have stronger viability, integration and tissue repair after transplantation in vivo. The results showed that the GES cells transplanted into mice can show the survival and integration ability is stronger, and could significantly promote the ischemic injury in mice model of hindlimb blood flow recovery, proved that GES cells can express better than ordinary stem cell regeneration after transplantation.
          The researchers also carried out according to the safety evaluation methods of genetic enhancement, found that although GES cells have stronger self-renewal capacity and in vitro life, but in the transplantation into immunodeficient mice did not form tumors. It is exciting that GES cells also exhibit strong resistance to cancer induced malignant transformation of cells. In many cases of oncogene activation, GES cells remain highly genomic stable and transplanted into immunodeficient mice without tumor formation. More interestingly, genetically enhanced human embryonic stem cells produced only a much smaller number of teratomas in immunodeficient mice than in control embryonic stem cells. The results suggest that, even if GES cell grafts remain in a small number of undifferentiated pluripotent stem cells, the ability to form teratomas in vivo has been greatly weakened, which further reduces the risk of security enhanced stem cell cell transplantation using genetic.

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