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A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3


Reference:

Bone, H. K., Nelson, A. S., Goldring, C. E., Tosh, D. and Welham, M. J., 2011. A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3. Journal of Cell Science, 124 (12), pp. 1992-2000.

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http://dx.doi.org/10.1242/jcs.081679

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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.

Details

Item Type Articles
CreatorsBone, H. K., Nelson, A. S., Goldring, C. E., Tosh, D. and Welham, M. J.
DOI10.1242/jcs.081679
Related URLs
URLURL Type
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104033PubMedCentral
Uncontrolled Keywordsembryonic stem cells, hepatic differentiation, directed differentiation, glycogen synthase kinase 3 (gsk-3) inhibition, definitive endoderm
DepartmentsFaculty of Science > Biology & Biochemistry
Faculty of Science > Pharmacy & Pharmacology
Research CentresCentre for Regenerative Medicine
RefereedYes
StatusPublished
ID Code24196
Additional InformationThe full article is freely available from http://dx.doi.org/10.1242/jcs.081679 ID number: PMC3104033

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