Journal
ACS SYNTHETIC BIOLOGY
Volume 10, Issue 11, Pages 2959-2967Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acssynbio.1c00214
Keywords
RNA virus; embryonic stem cells; riboswitch; aptazyme; vesicular stomatitis virus
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Funding
- Okinawa Institute of Science and Technology Graduate University
- Japan Society for the Promotion of Science (JSPS) KAKENHI [20K15669, 19H02855]
- Grants-in-Aid for Scientific Research [19H02855, 20K15669] Funding Source: KAKEN
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Mutated VSV vectors show improved stability and lower cytopathic effects in ESCs, allowing for chemical regulation of transgene expression through embedded riboswitches, maintaining pluripotency of cells and enabling the production of various differentiated cells without chromosomal alteration.
RNA viral vectors that replicate without DNA intermediates are attractive platforms for manipulation of cells for biomedical and veterinary applications because they have minimal risk of chromosomal integration. Vesicular stomatitis virus (VSV) vectors are among the most well-studied RNA viral vectors due to their low pathogenicity to humans and ability to express transgenes at high levels for weeks to months. However, their applications have been mostly limited to oncolytic and vaccine vectors due to their cytopathogenicity. We discovered two mutations in the VSV vector that synergistically confer improved stability in mouse embryonic stem cells (ESCs) with markedly lower cytopathic effects. We also demonstrated chemical regulation of transgene expression through embedded riboswitches. The ESCs infected with the mutant vector were shown to maintain pluripotency. This new vector sets the stage for precise regulation of gene expression in ESCs to produce a variety of differentiated cells without chromosomal alteration.
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