AAV vector-mediated in vivo reprogramming into pluripotency

Elena Senís, Lluc Mosteiro, Stefan Wilkening, Ellen Wiedtke, Ali Nowrouzi, Saira Afzal, Raffaele Fronza, Henrik Landerer, Maria Abad, Dominik Niopek, Manfred Schmidt, Manuel Serrano () and Dirk Grimm ()
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Elena Senís: Cluster of Excellence CellNetworks
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
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)
Henrik Landerer: Cluster of Excellence CellNetworks
Maria Abad: Cellular Plasticity and Cancer Group, Vall d’Hebron Institute of Oncology (VHIO)
Dominik Niopek: BioQuant, University of Heidelberg
Manfred Schmidt: National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ)
Manuel Serrano: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO)
Dirk Grimm: Cluster of Excellence CellNetworks

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05059-x

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