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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Article first published online: 26 JUL 2011
Copyright © 2011 AlphaMed Press
Volume 29, Issue 8, pages 1196–1205, August 2011
How to Cite
Hasegawa, Y., Takahashi, N., Forrest, A. R. R., Shin, J. W., Kinoshita, Y., Suzuki, H. and Hayashizaki, Y. (2011), CC Chemokine Ligand 2 and Leukemia Inhibitory Factor Cooperatively Promote Pluripotency in Mouse Induced Pluripotent Cells. STEM CELLS, 29: 1196–1205. doi: 10.1002/stem.673
Author contributions: Y.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; N.T.: collection and/or assembly of data, data analysis and interpretation; A.R.R.F. and J.W.S.: manuscript writing, data analysis and interpretation; Y.K.: collection and/or assembly of data; H.S.: conception and design, administrative support, manuscript writing, final approval of manuscript; Y.H.: financial support, administrative support.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS June 16, 2011.
- Issue published online: 26 JUL 2011
- Article first published online: 26 JUL 2011
- Accepted manuscript online: 16 JUN 2011 10:34AM EST
- Manuscript Accepted: 25 APR 2011
- Manuscript Received: 10 JAN 2011
- Research grant for RIKEN Omics Science Center from MEXT
- Innovative Cell Biology by Innovative Technology (Cell Innovation Program from the MEXT, Japan)
- Strategic programs for R&D (Presidents discretionary fund)
- Pluripotent stem cells;
- Transcription factors;
The pluripotency of mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can be maintained by feeder cells, which secrete leukemia inhibitory factor (LIF). We found that feeder cells provide a relatively low concentration (25 unit/ml) of LIF, which is insufficient to maintain the ESCs/iPSCs pluripotency in feeder free conditions. To identify additional factors involved in the maintenance of pluripotency, we carried out a global transcript expression profiling of mouse iPSCs cultured on feeder cells and in feeder-free (LIF-treated) conditions. This identified 17 significantly differentially expressed genes (adjusted p value <0.05) including seven chemokines overexpressed in iPSCs grown on feeder cells. Ectopic expression of these chemokines in iPSCs revealed that CC chemokine ligand 2 (Ccl2) induced the key transcription factor genes for pluripotency, Klf4, Nanog, Sox2, and Tbx3. Furthermore, addition of recombinant Ccl2 protein drastically increased the number of Nanog–green fluorescent protein–positive iPSCs grown in low-LIF feeder free conditions. We further revealed that pluripotency promotion by Ccl2 is mediated by activating the Stat3-pathway followed by Klf4 upregulation. We demonstrated that Ccl2-mediated increased pluripotency is independent of phosphoinositide 3-kinase and mitogen-activated protein kinase pathways and that Tbx3 may be upregulated by Klf4. Overall, Ccl2 cooperatively activates the Stat3-pathway with LIF in feeder-free conditions to maintain pluripotency for ESCs/iPSCs. STEM CELLS 2011;29:1196–1205