Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 22, Pages 8912-8917Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0903860106
Keywords
chemical biology; high-throughput screening; Nanog
Categories
Funding
- National Science Foundation Predoctoral Fellowship
- Human Frontier Science Program Long-Term Fellowship
- Canadian Institute for Health Research Post-Doctoral Fellowship
- Skaggs Institute of Chemical Biology of The Scripps Research Institute
- Novartis Research Foundation
- National Institute of Health [RO1-HD045022, R37-CA084198]
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Ectopic expression of defined transcription factors can reprogram somatic cells to induced pluripotent stem (iPS) cells, but the utility of iPS cells is hampered by the use of viral delivery systems. Small molecules offer an alternative to replace virally transduced transcription factors with chemical signaling cues responsible for reprogramming. In this report we describe a small-molecule screening platform applied to identify compounds that functionally replace the reprogramming factor Klf4. A series of small-molecule scaffolds were identified that activate Nanog expression in mouse fibroblasts transduced with a subset of reprogramming factors lacking Klf4. Application of one such molecule, kenpaullone, in lieu of Klf4 gave rise to iPS cells that are indistinguishable from murine embryonic stem cells. This experimental platform can be used to screen large chemical libraries in search of novel compounds to replace the reprogramming factors that induce pluripotency. Ultimately, such compounds may provide mechanistic insight into the reprogramming process.
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