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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Molecular insights into reprogramming-initiation events mediated by the OSKM gene regulatory network
PLoS ONE, Volume 6, No. 8, Article e24351, Year 2011
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Description
Somatic cells can be reprogrammed to induced pluripotent stem cells by over-expression of OCT4, SOX2, KLF4 and c-MYC (OSKM). With the aim of unveiling the early mechanisms underlying the induction of pluripotency, we have analyzed transcriptional profiles at 24, 48 and 72 hours post-transduction of OSKM into human foreskin fibroblasts. Experiments confirmed that upon viral transduction, the immediate response is innate immunity, which induces free radical generation, oxidative DNA damage, p53 activation, senescence, and apoptosis, ultimately leading to a reduction in the reprogramming efficiency. Conversely, nucleofection of OSKM plasmids does not elicit the same cellular stress, suggesting viral response as an early reprogramming roadblock. Additional initiation events include the activation of surface markers associated with pluripotency and the suppression of epithelial-to-mesenchymal transition. Furthermore, reconstruction of an OSKM interaction network highlights intermediate path nodes as candidates for improvement intervention. Overall, the results suggest three strategies to improve reprogramming efficiency employing: 1) anti-inflammatory modulation of innate immune response, 2) pre-selection of cells expressing pluripotency-associated surface antigens, 3) activation of specific interaction paths that amplify the pluripotency signal. © 2011 Mah et al.
Authors & Co-Authors
Mah, Nancy
Germany, Berlin
Max Delbruck Center for Molecular Medicine
Wang, Ying
Germany, Berlin
Max Planck Institute for Molecular Genetics
Liao, Mei Chih
Germany, Berlin
Max Planck Institute for Molecular Genetics
Prigione, A.
Germany, Berlin
Max Planck Institute for Molecular Genetics
Jozefczuk, Justyna
Germany, Berlin
Max Planck Institute for Molecular Genetics
Lichtner, Björn
Germany, Berlin
Max Planck Institute for Molecular Genetics
Wolfrum, Katharina
Germany, Berlin
Max Planck Institute for Molecular Genetics
Haltmeier, Manuela
Germany, Munich
Genomatix ag
Flöttmann, Max
Germany, Berlin
Humboldt-universität zu Berlin
Schaefer, Martin
Germany, Berlin
Max Delbruck Center for Molecular Medicine
Hahn, Alexander
Germany, Munich
Genomatix ag
Mrowka, Ralf
Germany, Jena
Universitätsklinikum Jena Und Medizinische Fakultät
Klipp, Edda
Germany, Berlin
Humboldt-universität zu Berlin
Andrade-Navarro, Miguel A.
Germany, Berlin
Max Delbruck Center for Molecular Medicine
Adjaye, James A.
Germany, Berlin
Max Planck Institute for Molecular Genetics
Saudi Arabia, Riyadh
College of Medicine
Statistics
Citations: 75
Authors: 15
Affiliations: 6
Identifiers
Doi:
10.1371/journal.pone.0024351
e-ISSN:
19326203
Research Areas
Cancer
Genetics And Genomics
Study Design
Randomised Control Trial