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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Article first published online: 5 APR 2011
Copyright © 2011 AlphaMed Press
Volume 29, Issue 4, pages 641–650, April 2011
How to Cite
Sasaki, N., Shinomi, M., Hirano, K., Ui-Tei, K. and Nishihara, S. (2011), LacdiNAc (GalNAcβ1-4GlcNAc) Contributes to Self-Renewal of Mouse Embryonic Stem Cells by Regulating Leukemia Inhibitory Factor/STAT3 Signaling. STEM CELLS, 29: 641–650. doi: 10.1002/stem.615
Disclosure of potential conflicts of interest is found at the end of this article.
N.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing. M.S.: collection and/or assembly of data, data analysis and interpretation. K.H.: collection and/or assembly of data. K.U.: provision of study material or patients. S.N.: conception and design, financial support, manuscript writing, final approval of manuscript.
First published online in STEM CELLSEXPRESS February 8, 2011.
- Issue published online: 5 APR 2011
- Article first published online: 5 APR 2011
- Accepted manuscript online: 8 FEB 2011 03:45PM EST
- Manuscript Accepted: 27 JAN 2011
- Manuscript Received: 15 NOV 2010
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Grant-in-Aid for Scientific Research. Grant Numbers: 20370051, S0901015
- Leukemia inhibitory factor/STAT3 signaling;
- Embryonic stem cell;
Self-renewal of mouse embryonic stem cells (mESCs) is maintained by leukemia inhibitory factor (LIF)/signal transducer and activator of transcription (STAT3) signaling. However, this signaling control does not function in neither mouse epiblast stem cells (mEpiSCs) nor human ESCs (hESCs) or human induced pluripotent stem cells (hiPSCs). To date, the underlying molecular mechanisms that determine this differential LIF-responsiveness have not been clarified. Here, we show that the cell surface glycan LacdiNAc (GalNAcβ1-4GlcNAc) is required for LIF/STAT3 signaling. Undifferentiated state mESCs expressed LacdiNAc at a higher level than differentiated state cells. Knockdown of β4GalNAc-T3 reduced LacdiNAc expression and caused a decrease in LIF/STAT3 signaling that lessened the rate of self-renewal of mESCs. A biochemical analysis showed that LacdiNAc expression on LIF receptor (LIFR) and gp130 was required for the stable localization of the receptors with lipid raft/caveolar components, such as caveolin-1. This localization is required for transduction of a sufficiently strong LIF/STAT3 signal. In primed state pluripotent stem cells, such as hiPSCs and mEpiSC-like cells produced from mESCs, LacdiNAc expression on LIFR and gp130 was extremely weak and the level of localization of these receptors on rafts/caveolae was also low. Furthermore, knockdown of β4GalNAc-T3 decreased LacdiNAc expression and reduced the efficiency of reversion of primed state mEpiSC-like cells into naïve state mESCs. These findings show that the different LIF-responsiveness of naïve state (mESCs) and primed state (mEpiSCs, hESCs, and hiPSCs) cells is dependent on the expression of LacdiNAc on LIFR and gp130 and that this expression is required for the induction and maintenance of the naïve state. STEM CELLS 2011;29:641–650