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  • 1
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    Immortalization eliminates a roadblock during cellular reprogramming into iPS cells (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-08-12
    Description: The overexpression of defined transcription factors in somatic cells results in their reprogramming into induced pluripotent stem (iPS) cells. The extremely low efficiency and slow kinetics of in vitro reprogramming suggest that further rare events are required to generate iPS cells. The nature and identity of these events, however, remain elusive. We noticed that the reprogramming potential of primary murine fibroblasts into iPS cells decreases after serial passaging and the concomitant onset of senescence. Consistent with the notion that loss of replicative potential provides a barrier for reprogramming, here we show that cells with low endogenous p19(Arf) (encoded by the Ink4a/Arf locus, also known as Cdkn2a locus) protein levels and immortal fibroblasts deficient in components of the Arf-Trp53 pathway yield iPS cell colonies with up to threefold faster kinetics and at a significantly higher efficiency than wild-type cells, endowing almost every somatic cell with the potential to form iPS cells. Notably, the acute genetic ablation of Trp53 (also known as p53) in cellular subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. Our results show that the acquisition of immortality is a crucial and rate-limiting step towards the establishment of a pluripotent state in somatic cells and underscore the similarities between induced pluripotency and tumorigenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987892/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987892/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Utikal, Jochen -- Polo, Jose M -- Stadtfeld, Matthias -- Maherali, Nimet -- Kulalert, Warakorn -- Walsh, Ryan M -- Khalil, Adam -- Rheinwald, James G -- Hochedlinger, Konrad -- DP2 OD003266/OD/NIH HHS/ -- England -- Nature. 2009 Aug 27;460(7259):1145-8. doi: 10.1038/nature08285. Epub 2009 Aug 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19668190" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Aging/*physiology ; Cell Differentiation ; Cell Division ; Cell Line ; Cells, Cultured ; Cellular Reprogramming/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/deficiency/genetics/metabolism ; Down-Regulation ; Fibroblasts/cytology/metabolism ; Gene Expression ; Humans ; Keratinocytes ; Kinetics ; Mice ; Mice, SCID ; Pluripotent Stem Cells/*cytology/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Induced pluripotent stem cells generated without viral integration (2008)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2008-09-27
    Description: Pluripotent stem cells have been generated from mouse and human somatic cells by viral expression of the transcription factors Oct4, Sox2, Klf4, and c-Myc. A major limitation of this technology is the use of potentially harmful genome-integrating viruses. We generated mouse induced pluripotent stem (iPS) cells from fibroblasts and liver cells by using nonintegrating adenoviruses transiently expressing Oct4, Sox2, Klf4, and c-Myc. These adenoviral iPS (adeno-iPS) cells show DNA demethylation characteristic of reprogrammed cells, express endogenous pluripotency genes, form teratomas, and contribute to multiple tissues, including the germ line, in chimeric mice. Our results provide strong evidence that insertional mutagenesis is not required for in vitro reprogramming. Adenoviral reprogramming may provide an improved method for generating and studying patient-specific stem cells and for comparing embryonic stem cells and iPS cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987909/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987909/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stadtfeld, Matthias -- Nagaya, Masaki -- Utikal, Jochen -- Weir, Gordon -- Hochedlinger, Konrad -- DP2 OD003266/OD/NIH HHS/ -- New York, N.Y. -- Science. 2008 Nov 7;322(5903):945-9. doi: 10.1126/science.1162494. Epub 2008 Sep 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, 185 Cambridge Street, Boston, MA 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18818365" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoviridae/*genetics/physiology ; Animals ; Cell Differentiation ; Cell Line ; *Cellular Reprogramming ; Chimera ; Cloning, Molecular ; Female ; Fibroblasts/*cytology/metabolism/virology ; Genes, myc ; *Genetic Vectors ; Hepatocytes/*cytology/metabolism/virology ; Kruppel-Like Transcription Factors/genetics/metabolism ; Liver/cytology/embryology ; Male ; Mice ; Mice, SCID ; Octamer Transcription Factor-3/genetics/metabolism ; *Pluripotent Stem Cells/cytology/metabolism/transplantation ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; SOXB1 Transcription Factors/genetics/metabolism ; Teratoma/etiology ; Transgenes ; Virus Integration
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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