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A more recent version of this article appeared on December 1, 2005
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Submitted on June 28, 2005
Revised on September 15, 2005
Accepted on September 16, 2005
Institute of Basic Medical Sciences, Department of Biochemistry, University of Oslo, 0317 Oslo, Norway
Monitoring Editor: Carl-Henrik Heldin
Functional reprogramming of a differentiated cell toward pluripotency may have long-term applications in regenerative medicine. We report the induction of dedifferentiation, associated with genome-wide programming of gene expression and epigenetic reprogramming of an embryonic gene, in epithelial 293T cells treated with an extract of undifferentiated human NCCIT carcinoma cells. 293T cells exposed for 1 h to extract of NCCIT cells, but not of 293T or Jurkat T-cells, form defined colonies which are maintained for at least 23 passages in culture. Microarray and quantitative analyses of gene expression reveal that the transition from a 293T to a pluripotent cell phenotype involves a dynamic upregulation of hundreds of NCCIT genes, concomitant with down-regulation of 293T genes and of indicators of differentiation such as A-type lamins. Up-regulated genes encompass embryonic and stem cell markers including OCT4, SOX2, NANOG and Oct4-responsive genes. OCT4 activation is associated with DNA demethylation in the OCT4 promoter and nuclear targeting of Oct4 protein. In fibroblasts exposed to extract of mouse embryonic stem cells, Oct4 activation is biphasic and RNA-PolII-dependent, with the first transient rise of Oct4 upregulation being necessary for the second, long-term activation of Oct4. Genes characteristic of multilineage differentiation potential are also up-regulated in NCCIT extract-treated cells, suggesting the establishment of ‘multilineage priming’. Retinoic acid triggers Oct4 down-regulation, de novo activation of A-type lamins and nestin. Furthermore, the cells can be induced to differentiate toward neurogenic, adipogenic, osteogenic and endothelial lineages. The data provide a proof-of-concept that an extract of undifferentiated carcinoma cells can elicit differentiation plasticity in an otherwise more developmentally restricted cell type.
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