Document Detail


Heparan sulfate facilitates FGF and BMP signaling to drive mesoderm differentiation of mouse embryonic stem cells.
MedLine Citation:
PMID:  22556407     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Heparan sulfate (HS) has been implicated in regulating cell fate decisions during differentiation of embryonic stem cells (ESCs) into advanced cell types. However, the necessity and the underlying molecular mechanisms of HS in early cell lineage differentiation are still largely unknown. In this study, we examined the potential of EXT1(-/-) mouse ESCs (mESCs), that are deficient in HS, to differentiate into primary germ layer cells. We observed that EXT1(-/-) mESCs lost their differentiation competence and failed to differentiate into Pax6(+)-neural precursor cells and mesodermal cells. More detailed analyses highlighted the importance of HS for the induction of Brachyury(+) pan-mesoderm as well as normal gene expression associated with the dorso-ventral patterning of mesoderm. Examination of developmental cell signaling revealed that EXT1 ablation diminished FGF and BMP but not Wnt signaling. Furthermore, restoration of FGF and BMP signaling each partially rescued mesoderm differentiation defects. We further show that BMP4 is more prone to degradation in EXT1(-/-) mESCs culture medium compared with that of wild type cells. Therefore, our data reveal that HS stabilizes BMP ligand and thereby maintains the BMP signaling output required for normal mesoderm differentiation. In summary, our study demonstrates that HS is required for ESC pluripotency, in particular lineage specification into mesoderm through facilitation of FGF and BMP signaling.
Authors:
Daniel C Kraushaar; Sumit Rai; Eduard Condac; Alison Nairn; Siyuan Zhang; Yu Yamaguchi; Kelley Moremen; Stephen Dalton; Lianchun Wang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-09-11     Revised Date:  2014-06-13    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  22691-700     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticoagulants / pharmacology
Bone Morphogenetic Protein 4 / metabolism*,  pharmacology
Cell Differentiation / drug effects,  physiology
Cell Lineage / drug effects,  physiology
Cells, Cultured
Culture Media / pharmacology
Ectoderm / cytology,  drug effects
Embryonic Stem Cells / cytology*,  drug effects
Fetal Proteins / genetics,  metabolism
Fibroblast Growth Factor 2 / metabolism*,  pharmacology
Heparin / pharmacology
Heparitin Sulfate / metabolism*,  pharmacology
Mesoderm / cytology,  drug effects
Mice
Mice, Mutant Strains
N-Acetylglucosaminyltransferases / genetics,  metabolism
Neural Plate / cytology,  drug effects
Pluripotent Stem Cells / cytology,  drug effects
RNA, Messenger / metabolism
T-Box Domain Proteins / genetics,  metabolism
Wnt Signaling Pathway / drug effects,  physiology*
Grant Support
ID/Acronym/Agency:
5P01GM085354/GM/NIGMS NIH HHS; P41 RR005351/RR/NCRR NIH HHS; R01 HL093339/HL/NHLBI NIH HHS; R01HL093339/HL/NHLBI NIH HHS; RR005351/GM103390/GM/NIGMS NIH HHS; RR018502/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Anticoagulants; 0/Bmp4 protein, mouse; 0/Bone Morphogenetic Protein 4; 0/Brachyury protein; 0/Culture Media; 0/Fetal Proteins; 0/RNA, Messenger; 0/T-Box Domain Proteins; 103107-01-3/Fibroblast Growth Factor 2; 9005-49-6/Heparin; 9050-30-0/Heparitin Sulfate; EC 2.4.1.-/N-Acetylglucosaminyltransferases; EC 2.4.1.224/exostosin-1
Comments/Corrections

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