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Chinese Scientists Generate Superior and Safer Stem Cells with Gene Editing

Author: Update time: 2017-07-11

Stem cell replacement therapy holds great promise towards providing therapeutic means to combat stem cell exhaustion and dysfunction due to injury and aging. However, two main challenges including aging-associated functional decay and neoplastic transformation of human stem cells or their derivatives must be overcome before stem cell replacement therapies can be effectively and safely implemented in the clinical setting. Recent advances in targeted gene editing technologies are facilitating the development of cell therapy. For example, generation of healthy autologous cells via the correction of disease-causing mutations in patient-derived cells. In a new study recently published in Cell Research, a collaborative group headed by Chinese scientists developed genetic enhancement strategies to obtain superior and safer stem cells.

In the current study, researchers first performed gero-protective chemical screening and identified the activators of NRF2, a master safeguard against stress, could rescue the proliferation of Werner syndrome-specific premature senescent human mesenchymal stem cells (hMSCs). Since previous studies on lower organisms and animals have discovered that the deficiency of NRF2 shortens life span, whereas constitutive activation of NRF2 delays the aging process. Also, the same research groups have demonstrated that the decline of NRF2 accompanied cellular senescence and activation of NRF2 retarded the senescence of progeria hMSCs, Researchers hypothesized that manipulation of NRF2 pathway is a plausible way to produce genetically enhanced stem (GES) cells. To activate NRF2 in a stable and controllable manner while retaining NRF2’s native biological function with minimal genomic change, researchers introduced a single nucleotide variation (A245G) of NRF2 gene in human embryonic stem cells (hESCs) via targeted gene editing. This variation results in a glutamic acid to glycine switch at amino acid 82 in the NRF2 protein and lead to NRF2 stabilization and transcriptional activation of its target cytoprotective genes.

Subsequently, researchers found the engineered hESC-derived human mesenchymal stem cells (hMSCs) exhibited improved self-renewal and strong resistance to stress and cellular senescence in vitro. Likewise, the genetically enhanced human vascular endothelial cells (hVECs) specifically resisted oxidative stress. Encouragingly, GES-hMSCs exhibited significant improvements in survival, engraftment and injury repair compared to wild-type hMSCs in an ischemic in vivo niche, indicating the therapeutic potential of these GES cells.

Last but not least, researchers performed safety evaluation on these GES cells. Despite more robust proliferation and alleviated senescence associated with genetically enhanced hMSCs, tumor susceptibility was not elevated in genetically enhanced hMSCs after long-term transplantation in immunodeficient mice. Moreover, these genetically enhanced hMSCs could maintain genomic stability and resist tumor formation even in the presence of strong oncogenic insults. Interestingly, genetically edited hESCs generated much smaller teratomas in vivo, supporting a possibility that even if residual undifferentiated hESCs are present in their MSC derivatives, the teratoma-forming ability of these transplanted cells should be minimalized. This will pose even less risk for teratoma formation, a major concern for cell replacement therapies using hESC derivatives.

In summary, this study provides an experimental proof-of-concept on how recoding a single nucleotide within NRF2 gene renders cultured hMSCs with an increased self-renewal activity, enhanced stress resistance, delayed cellular senescence and functional decay, better engraftment efficiency and functional regeneration in vivo, as well as greater resistance to oncogenic transformation, and thereby, allows for the generation of superior and safer GES for regenerative medicine therapies.

The article entitled Genetic enhancement in cultured human adult stem cells conferred by a single nucleotide recoding was published online in Cell Research on July 7, 2017. Dr. LIU Guang-hui from Institute of Biophysics, Chinese Academy of Sciences, Dr. TANG Fuchou from Peking University and Dr. QU Jing from Institute of Zoology, Chinese Academy of Sciences collaborate in this work.

This work was supported by National Basic Research Program of China (973 Program), the Strategic Priority Research Program of the Chinese Academy of Sciences, Beijing Natural Science Foundation, National High Technology Research and Development Program of China, National Natural Science Foundation of China, Program of Beijing Municipal Science and Technology Commission, Key Research Program of the Chinese Academy of Sciences, and the Thousand Young Talents program of China.


LIU Guanghui

National Laboratory of Biomacromolecules, IBP





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