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Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4.

Lyssiotis, Costas A and Foreman, Ruth K and Staerk, Judith and Garcia, Michael and Mathur, Divya and Markoulaki, Styliani and Hanna, Jacob and Lairson, Luke L and Charette, Bradley D and Bouchez, Laure C and Bollong, Michael and Kunick, Conrad and Brinker, Achim and Cho, Charles and Schultz, Peter and Jaenisch, Rudolf (2009) Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proceedings of the National Academy of Sciences of the United States of America, 106 (22). pp. 8912-8917. ISSN 1091-6490

Abstract

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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: chemical biology; high-throughput screening; Nanog
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Date Deposited: 14 Dec 2009 13:49
Last Modified: 31 Jan 2013 00:57
URI: https://oak.novartis.com/id/eprint/1196

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