Measles vector as a multigene delivery platform facilitating iPSC reprogramming


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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  1. 1.

    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    CAS  Article  Google Scholar 

  2. 2.

    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    CAS  Article  Google Scholar 

  3. 3.

    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.

    CAS  Article  Google Scholar 

  4. 4.

    Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov. 2017;16:115–30.

    CAS  Article  Google Scholar 

  5. 5.

    Hu C, Li L. Current reprogramming systems in regenerative medicine: from somatic cells to induced pluripotent stem cells. Regen Med. 2016;11:105–32.

    Article  Google Scholar 

  6. 6.

    El-Khatib M, Ohmine S, Jacobus EJ, Tonne JM, Morsy SG, Holditch SJ, et al. Tumor-free transplantation of patient-derived induced pluripotent stem cells progeny for customized islet regeneration. Stem Cells Transl Med. 2016;5:694–702.

    CAS  Article  Google Scholar 

  7. 7.

    Kyodo. First iPS cell transplant patient makes progress one year on. In: Japan Times [online], 2015.

  8. 8.

    Kimbrel EA, Lanza R. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov. 2015;14:681–92.

    CAS  Article  Google Scholar 

  9. 9.

    Trounson A, DeWitt ND. Pluripotent stem cells progressing to the clinic. Nat Rev Mol Cell Biol. 2016;17:194–200.

    CAS  Article  Google Scholar 

  10. 10.

    Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med. 2017;376:1038–46.

    CAS  Article  Google Scholar 

  11. 11.

    Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods. 2011;8:409–12.

    CAS  Article  Google Scholar 

  12. 12.

    Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324:797–801.

    CAS  Article  Google Scholar 

  13. 13.

    Ban H, Nishishita N, Fusaki N, Tabata T, Saeki K, Shikamura M, et al. Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proc Natl Acad Sci USA. 2011;108:14234–9.

    CAS  Article  Google Scholar 

  14. 14.

    Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85:348–62.

    CAS  Article  Google Scholar 

  15. 15.

    Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7:618–30.

    CAS  Article  Google Scholar 

  16. 16.

    Kudva YC, Ohmine S, Greder LV, Dutton JR, Armstrong AS, Genebriera De Lamo J. et al. Transgene-free Disease-specific induced pluripotent stem cells from patients with type 1 and type 2 diabetes. Stem Cell Transl Med. 2012;1:451–61.

    CAS  Article  Google Scholar 

  17. 17.

    Schlaeger TM, Daheron L, Brickler TR, Entwisle S, Chan K, Cianci A, et al. A comparison of non-integrating reprogramming methods. Nat Biotechnol. 2015;33:58–63.

    CAS  Article  Google Scholar 

  18. 18.

    Thatava T, Kudva YC, Edukulla R, Squillace K, De Lamo JG, Khan YK, et al. Intrapatient variations in type 1 diabetes-specific iPS cell differentiation into insulin-producing cells. Mol Ther. 2013;21:228–39.

    CAS  Article  Google Scholar 

  19. 19.

    Moszynski P. Measles campaign’s “historic victory” for global public health. BMJ. 2007;334:177.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Driscoll CB, Tonne JM, El Khatib M, Cattaneo R, Ikeda Y, Devaux P. Nuclear reprogramming with a non-integrating human RNA virus. Stem Cell Res Ther. 2015;6:48.

    Article  Google Scholar 

  21. 21.

    Lamb RA, Parks GD. Paramyxoviridae: the viruses and their replication. In: Fields BN, Knipe DM, Howley PM editors. Fields virology, 5th ed. Lippincott-Raven: Philadelphia; 2007. p. 1305–40.

  22. 22.

    Bitzer M, Armeanu S, Lauer UM, Neubert WJ. Sendai virus vectors as an emerging negative-strand RNA viral vector system. J Gene Med. 2003;5:543–53.

    CAS  Article  Google Scholar 

  23. 23.

    Li HO, Zhu YF, Asakawa M, Kuma H, Hirata T, Ueda Y, et al. A cytoplasmic RNA vector derived from nontransmissible Sendai virus with efficient gene transfer and expression. J Virol. 2000;74:6564–9.

    CAS  Article  Google Scholar 

  24. 24.

    Robinson S, Galanis E. Potential and clinical translation of oncolytic measles viruses. Expert Opin Biol Ther. 2017;17:353–63.

    CAS  Article  Google Scholar 

  25. 25.

    Devaux P, von Messling V, Songsungthong W, Springfeld C, Cattaneo R. Tyrosine 110 in the measles virus phosphoprotein is required to block STAT1 protein phosphorylation. Virology. 2007;360:72–83.

    CAS  Article  Google Scholar 

  26. 26.

    Parks CL, Lerch RA, Walpita P, Wang HP, Sidhu MS, Udem SA. Analysis of the noncoding regions of measles virus strains in the Edmonston vaccine lineage. J Virol. 2001;75:921–33.

    CAS  Article  Google Scholar 

  27. 27.

    Parks CL, Lerch RA, Walpita P, Wang HP, Sidhu MS, Udem SA. Comparison of predicted amino acid sequences of measles virus strains in the Edmonston vaccine lineage. J Virol. 2001;75:910–20.

    CAS  Article  Google Scholar 

  28. 28.

    del Valle JR, Devaux P, Hodge G, Wegner NJ, McChesney MB, Cattaneo R. A vectored measles virus induces hepatitis B surface antigen antibodies while protecting macaques against measles virus challenge. J Virol. 2007;81:10597–605.

    Article  Google Scholar 

  29. 29.

    Duprex WP, McQuaid S, Hangartner L, Billeter MA, Rima BK. Observation of measles virus cell-to-cell spread in astrocytoma cells by using a green fluorescent protein-expressing recombinant virus. J Virol. 1999;73:9568–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Kärber G. Beitrag zur kollektiven Behandlung pharmakologischer Reihenversuche. Arch Exp Pathol Pharmakol. 1931;162:480–3.

    Article  Google Scholar 

  31. 31.

    Toth AM, Devaux P, Cattaneo R, Samuel CE. Protein kinase PKR mediates the apoptosis induction and growth restriction phenotypes of C protein-deficient measles virus. J Virol. 2009;83:961–8.

    CAS  Article  Google Scholar 

  32. 32.

    Lin T, Ambasudhan R, Yuan X, Li W, Hilcove S, Abujarour R, et al. A chemical platform for improved induction of human iPSCs. Nat Methods. 2009;6:805–8.

    CAS  Article  Google Scholar 

  33. 33.

    Cattaneo R, Rebmann G, Schmid A, Baczko K, ter Meulen V, Billeter MA. Altered transcription of a defective measles virus genome derived from a diseased human brain. EMBO J. 1987;6:681–8.

    CAS  Article  Google Scholar 

  34. 34.

    Lundstrom K. Viral vectors in gene therapy. Diseases 2018;6:42–62.

    Article  Google Scholar 

  35. 35.

    Billeter MA, Naim HY, Udem SA. Reverse genetics of measles virus and resulting multivalent recombinant vaccines: applications of recombinant measles viruses. Curr Top Microbiol Immunol. 2009;329:129–62.

    CAS  PubMed  Google Scholar 

  36. 36.

    Fujie Y, Fusaki N, Katayama T, Hamasaki M, Soejima Y, Soga M, et al. New type of Sendai virus vector provides transgene-free iPS cells derived from chimpanzee blood. PLoS ONE. 2014;9:e113052.

    Article  Google Scholar 

  37. 37.

    Park A, Hong P, Won ST, Thibault PA, Vigant F, Oguntuyo KY, et al. Sendai virus, an RNA virus with no risk of genomic integration, delivers CRISPR/Cas9 for efficient gene editing. Mol Ther Methods Clin Dev. 2016;3:16057.

    Article  Google Scholar 

  38. 38.

    Takeda M, Nakatsu Y, Ohno S, Seki F, Tahara M, Hashiguchi T, et al. Generation of measles virus with a segmented RNA genome. J Virol. 2006;80:4242–8.

    CAS  Article  Google Scholar 

  39. 39.

    Hiramoto T, Tahara M,  Miura Y, Nakatsu Y, Kubota T, Kurita R, et al. Newly developed measles viral vector can efficiently transduce multiple genes into naïve T cells. Blood. 2014;124:4798.

  40. 40.

    Hiramoto T, Tahara M, Sakamoto C, Nakatsu Y, Kubota T, Ono H, et al. 5. Newly developed measles virus vector can simultaneously transfer multiple genes into human hematopoietic cells and induce ground state like pluripotent stem cells. In: The American society of gene & cell therapy. New Orleans, LA: Elsevier Inc.; 2015. p. pS2–S3.

  41. 41.

    Garber K. RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nat Biotechnol. 2015;33:890–1.

    CAS  Article  Google Scholar 

  42. 42.

    Pera MF. Stem cells: the dark side of induced pluripotency. Nature. 2011;471:46–7.

    CAS  Article  Google Scholar 

  43. 43.

    Normile D. iPS cell therapy reported safe. Science. 2017;355:1109–10.

    CAS  Article  Google Scholar 

  44. 44.

    Pless RP, Bentsi-Enchill AD, Duclos P. Monitoring vaccine safety during measles mass immunization campaigns: clinical and programmatic issues. J Infect Dis. 2003;187(Suppl 1):S291–8.

    Article  Google Scholar 

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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.


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).

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