| Endogenous Wnt/beta-catenin signaling is required for cardiac differentiation in human embryonic stem cells. | |
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MedLine Citation:
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PMID: 20559569 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Wnt/beta-catenin signaling is an important regulator of differentiation and morphogenesis that can also control stem cell fates. Our group has developed an efficient protocol to generate cardiomyocytes from human embryonic stem (ES) cells via induction with activin A and BMP4. METHODOLOGY/PRINCIPAL FINDINGS: We tested the hypothesis that Wnt/beta-catenin signals control both early mesoderm induction and later cardiac differentiation in this system. Addition of exogenous Wnt3a at the time of induction enhanced cardiac differentiation, while early inhibition of endogenous Wnt/beta-catenin signaling with Dkk1 inhibited cardiac differentiation, as indicated by quantitative RT-PCR analysis for beta-myosin heavy chain (beta-MHC), cardiac troponin T (cTnT), Nkx2.5, and flow cytometry analysis for sarcomeric myosin heavy chain (sMHC). Conversely, late antagonism of endogenously produced Wnts enhanced cardiogenesis, indicating a biphasic role for the pathway in human cardiac differentiation. Using quantitative RT-PCR, we show that canonical Wnt ligand expression is induced by activin A/BMP4 treatment, and the extent of early Wnt ligand expression can predict the subsequent efficiency of cardiogenesis. Measurement of Brachyury expression showed that addition of Wnt3a enhances mesoderm induction, whereas blockade of endogenously produced Wnts markedly inhibits mesoderm formation. Finally, we show that Wnt/beta-catenin signaling is required for Smad1 activation by BMP4. CONCLUSIONS/SIGNIFICANCE: Our data indicate that induction of mesoderm and subsequent cardiac differentiation from human ES cells requires fine-tuned cross talk between activin A/BMP4 and Wnt/beta-catenin pathways. Controlling these pathways permits efficient generation of cardiomyocytes for basic studies or cardiac repair applications. |
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Authors:
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Sharon L Paige; Tomoaki Osugi; Olga K Afanasiev; Lil Pabon; Hans Reinecke; Charles E Murry |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-06-15 |
Journal Detail:
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Title: PloS one Volume: 5 ISSN: 1932-6203 ISO Abbreviation: PLoS ONE Publication Date: 2010 |
Date Detail:
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Created Date: 2010-06-18 Completed Date: 2010-09-01 Revised Date: 2010-09-30 |
Medline Journal Info:
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Nlm Unique ID: 101285081 Medline TA: PLoS One Country: United States |
Other Details:
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Languages: eng Pagination: e11134 Citation Subset: IM |
Affiliation:
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Department of Pathology, University of Washington, Seattle, Washington, United States of America. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Bone Morphogenetic Protein 4
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physiology Cell Differentiation* Embryonic Stem Cells / metabolism* Humans Mesoderm / cytology Myocardium / cytology* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction* Smad Proteins / metabolism Wnt Proteins / metabolism* beta Catenin / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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F30HL095343/HL/NHLBI NIH HHS; P01 GM081719/GM/NIGMS NIH HHS; P01 HL03174/HL/NHLBI NIH HHS; R01 HL084642/HL/NHLBI NIH HHS; R01 HL64387/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bone Morphogenetic Protein 4; 0/Smad Proteins; 0/Wnt Proteins; 0/beta Catenin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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