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| Status |
Public on Nov 13, 2009 |
| Title |
Heparan Sulfation Dependent FGF Signalling Maintains ES Cells Primed for Differentiation in a Heterogeneous State |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous LIF and BMP4 perpetuate a pluripotent state, less is known about factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical co-receptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and 2, two enzymes required for N-sulfation of proteoglycans, blocked differentiation. This phenotype was rescued by HS presented in trans or by soluble heparin. NaClO3-, which reduces sulfation of proteoglycans, potently blocked differentiation of wild type cells. Mechanistically, N-sulfation was identified to be critical for functional autocrine FGF4 signalling. Micro array analysis identified the pluripotency maintaining transcription factors Nanog, KLF2/4/8, Tbx3 and Tcf3 to be negatively regulated, whereas markers of differentiation such as Gbx2, Dnmt3b, FGF5 and Brachyury were induced by sulfation-dependent-FGFR signalling. We show that several of these genes are heterogeneously expressed in ES cells and targeting of heparan sulfation or FGFR-signalling facilitated a homogenous Nanog/KLF4/Tbx3 positive ES cell state. This finding suggests that the recently discovered heterogeneous state of ES cells is regulated by HS-dependent FGFR signalling. Similarly, culturing blastocysts with NaClO3- eliminated GATA6 positive primitive endoderm progenitors generating a homogenous Nanog positive inner cell mass. Functionally, reduction of sulfation robustly improved de novo ES cell derivation efficiency. We conclude that N-sulfated HS is required for FGF4 signalling to maintain ES cells primed for differentiation in a heterogeneous state. Inhibiting this pathway facilitates a more naïve ground state.
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| Overall design |
Four groups with three biological replicates and a technical duplicate in each
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| Contributor(s) |
Lanner F, Sohl ML, Lee KL, Holmborn K, Yang H, Wilbertz J, Poellinger L, Rossant J, Farnebo F |
| Citation(s) |
19937756 |
| Submission date |
May 06, 2009 |
| Last update date |
Jun 14, 2018 |
| Contact name |
Kian Leong LEE |
| E-mail(s) |
kianleong.lee@duke-nus.edu.sg
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| Phone |
+(65) 6601 3685
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| Organization name |
National University of Singapore (NUS)
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| Department |
Duke-NUS Medical School
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| Lab |
Cancer & Stem Cell Biology Program (CSCB)
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| Street address |
#07-21, 8 College Road
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| City |
Singapore |
| State/province |
Singapore |
| ZIP/Postal code |
169857 |
| Country |
Singapore |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (16)
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| GSM400305 |
Wild type CCE ES cells Control rep1 |
| GSM400306 |
Wild type CCE ES cells Control rep2 |
| GSM400307 |
Wild type CCE ES cells Control rep3 |
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| Relations |
| BioProject |
PRJNA115557 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE15974_RAW.tar |
3.1 Mb |
(http)(custom) |
TAR |
| GSE15974_non-normalized.txt.gz |
2.7 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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