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Abstract
The use of small molecules to 'chemically direct' differentiation represents a powerful approach to promote specification of embryonic stem cells (ESCs) towards particular functional cell types for use in regenerative medicine and pharmaceutical applications. Here, we demonstrate a novel route for chemically directed differentiation of human ESCs (hESCs) into definitive endoderm (DE) exploiting a selective small-molecule inhibitor of glycogen synthase kinase 3 (GSK-3). This GSK-3 inhibitor, termed 1m, when used as the only supplement to a chemically defined feeder-free culture system, effectively promoted differentiation of ESC lines towards primitive streak (PS), mesoderm and DE. This contrasts with the role of GSK-3 in murine ESCs, where GSK-3 inhibition promotes pluripotency. Interestingly, 1m-mediated induction of differentiation involved transient NODAL expression and Nodal signalling. Prolonged treatment of hESCs with 1m resulted in the generation of a population of cells displaying hepatoblast characteristics, that is expressing. fetoprotein and HNF4 alpha. Furthermore, 1m-induced DE had the capacity to mature and generate hepatocyte-like cells capable of producing albumin. These findings describe, for the first time, the utility of GSK-3 inhibition, in a chemically directed approach, to a method of DE generation that is robust, potentially scalable and applicable to different hESC lines.
Original language | English |
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Pages (from-to) | 1992-2000 |
Number of pages | 9 |
Journal | Journal of Cell Science |
Volume | 124 |
Issue number | 12 |
Early online date | 23 May 2011 |
DOIs | |
Publication status | Published - 15 Jun 2011 |
Bibliographical note
The full article is freely available from http://dx.doi.org/10.1242/jcs.081679ID number: PMC3104033
Keywords
- embryonic stem cells
- hepatic differentiation
- directed differentiation
- glycogen synthase kinase 3 (GSK-3) inhibition
- definitive endoderm
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- 1 Finished
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GLYCOGEN SYNTHASE KINASE 3: A CRITICAL REGULATOR OF EMBYONI C STEM CELL SELF-RENEWAL?
Welham, M. J. (PI)
Biotechnology and Biological Sciences Research Council
1/06/05 → 31/12/08
Project: Research council