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AAV vector-mediated in vivo reprogramming into pluripotency

Author

Listed:
  • Elena Senís

    (Cluster of Excellence CellNetworks
    BioQuant, University of Heidelberg
    Cellular Plasticity and Cancer Group, Vall d’Hebron Institute of Oncology (VHIO))

  • Lluc Mosteiro

    (Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO))

  • Stefan Wilkening

    (National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ))

  • Ellen Wiedtke

    (Cluster of Excellence CellNetworks
    BioQuant, University of Heidelberg)

  • Ali Nowrouzi

    (National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ))

  • Saira Afzal

    (National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ))

  • Raffaele Fronza

    (National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ)
    GeneWerk GmbH)

  • Henrik Landerer

    (Cluster of Excellence CellNetworks
    BioQuant, University of Heidelberg
    University of Heidelberg)

  • Maria Abad

    (Cellular Plasticity and Cancer Group, Vall d’Hebron Institute of Oncology (VHIO))

  • Dominik Niopek

    (BioQuant, University of Heidelberg
    University of Heidelberg
    Theoretical Bioinformatics Division, German Cancer Research Center)

  • Manfred Schmidt

    (National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ)
    GeneWerk GmbH)

  • Manuel Serrano

    (Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO)
    Catalan Institution for Research and Advanced Studies (ICREA))

  • Dirk Grimm

    (Cluster of Excellence CellNetworks
    BioQuant, University of Heidelberg
    German Center for Infection Research (DZIF), Partner site Heidelberg)

Abstract

In vivo reprogramming of somatic cells into induced pluripotent stem cells (iPSC) holds vast potential for basic research and regenerative medicine. However, it remains hampered by a need for vectors to express reprogramming factors (Oct-3/4, Klf4, Sox2, c-Myc; OKSM) in selected organs. Here, we report OKSM delivery vectors based on pseudotyped Adeno-associated virus (AAV). Using the AAV-DJ capsid, we could robustly reprogram mouse embryonic fibroblasts with low vector doses. Swapping to AAV8 permitted to efficiently reprogram somatic cells in adult mice by intravenous vector delivery, evidenced by hepatic or extra-hepatic teratomas and iPSC in the blood. Notably, we accomplished full in vivo reprogramming without c-Myc. Most iPSC generated in vitro or in vivo showed transcriptionally silent, intronic or intergenic vector integration, likely reflecting the increased host genome accessibility during reprogramming. Our approach crucially advances in vivo reprogramming technology, and concurrently facilitates investigations into the mechanisms and consequences of AAV persistence.

Suggested Citation

  • Elena Senís & Lluc Mosteiro & Stefan Wilkening & Ellen Wiedtke & Ali Nowrouzi & Saira Afzal & Raffaele Fronza & Henrik Landerer & Maria Abad & Dominik Niopek & Manfred Schmidt & Manuel Serrano & Dirk , 2018. "AAV vector-mediated in vivo reprogramming into pluripotency," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05059-x
    DOI: 10.1038/s41467-018-05059-x
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