Measles vector as a multigene delivery platform facilitating iPSC reprogramming

Abstract

Induced pluripotent stem cells (iPSCs) provide a unique platform for individualized cell therapy approaches. Currently, episomal DNA, mRNA, and Sendai virus-based RNA reprogramming systems are widely used to generate iPSCs. However, they all rely on the use of multiple (three to six) components (vectors/plasmids/mRNAs) leading to the production of partially reprogrammed cells, reducing the efficiency of the systems. We produced a one-cycle measles virus (MV) vector by substituting the viral attachment protein gene with the green fluorescent protein (GFP) gene. Here, we present a highly efficient multi-transgene delivery system based on a vaccine strain of MV, a non-integrating RNA virus that has a long-standing safety record in humans. Introduction of the four reprogramming factors OCT4, SOX2, KLF4, and cMYC via a single, “one-cycle” MV vector efficiently reprogrammed human somatic cells into iPSCs, whereas MV vector genomes are rapidly eliminated in derived iPSCs. Our MV vector system offers a new reprogramming platform for genomic modification-free iPSCs amenable for clinical translation.

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Acknowledgements

We thank Andrew Badley, Roberto Cattaneo, Eva Galanis, and Jason Tonne for reading the manuscript. We thank Megan Rasmussen, Christopher Driscoll, Jason Tonne for technical assistance. We thank Debra Schultz from the Mayo Clinic Medical Genome Facility Gene Expression Core for performing the microarray and Vivekananda Sarangi from the Mayo Clinic Bioinformatics Core for helping with the gene expression analysis. We thank the Mayo Clinic Cancer Center for the use of the Cytogenetics Core, which provided karyotyping analysis services. Mayo Clinic Cancer Center is supported in part by an NCI Cancer Center Support Grant 5P30 CA15083-45. We also thank Todd DanDeWalker, Tony Goble, and Patricia T Greipp for cytogenetic analysis.

Funding

This work was supported by Mayo Center for Regenerative Medicine (PD), Mayo Graduate School, and the National Institutes of Health (R21AI105233 to PD). This publication was also made possible by CTSA Grant Number UL1TR000135 and UL1TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

Author contributions

PD: study design and direction, data acquisition and analysis, manuscript writing, discussion, and editing; QW: data acquisition and analysis, figures preparation, manuscript writing, and discussion; AV: data acquisition; YI: data analysis, provision of materials, manuscript discussion, revising, and editing. All authors read and approved the final manuscript.

Data availability

The datasets used and/or analyzed during the current study are available from GEO DataSets, Boston, MA: GSE122790.

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Correspondence to Patricia Devaux.

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PD and YI are inventors on a patent application (WO2018064460A1) for the content of the manuscript. The remaining authors declare that they have no conflict of interest.

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Wang, Q., Vossen, A., Ikeda, Y. et al. Measles vector as a multigene delivery platform facilitating iPSC reprogramming. Gene Ther 26, 151–164 (2019). https://doi.org/10.1038/s41434-019-0058-7

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