Document Detail


Insulin inhibits cardiac mesoderm, not mesendoderm, formation during cardiac differentiation of human pluripotent stem cells and modulation of canonical Wnt signaling can rescue this inhibition.
MedLine Citation:
PMID:  23193013     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The study of the regulatory signaling hierarchies of human heart development is limited by a lack of model systems that can reproduce the precise developmental events that occur during human embryogenesis. The advent of human pluripotent stem cell (hPSC) technology and robust cardiac differentiation methods affords a unique opportunity to monitor the full course of cardiac induction in vitro. Here, we show that stage-specific activation of insulin signaling strongly inhibited cardiac differentiation during a monolayer-based differentiation protocol that used transforming growth factor β superfamily ligands to generate cardiomyocytes. However, insulin did not repress cardiomyocyte differentiation in a defined protocol that used small molecule regulators of canonical Wnt signaling. By examining the context of insulin inhibition of cardiomyocyte differentiation, we determined that the inhibitory effects by insulin required Wnt/β-catenin signaling and that the cardiomyocyte differentiation defect resulting from insulin exposure was rescued by inhibition of Wnt/β-catenin during the cardiac mesoderm (Nkx2.5+) stage. Thus, insulin and Wnt/β-catenin signaling pathways, as a network, coordinate to influence hPSC differentiation to cardiomyocytes, with the Wnt/β-catenin pathway dominant to the insulin pathway. Our study contributes to the understanding of the regulatory hierarchies of human cardiomyocyte differentiation and has implications for modeling human heart development.
Authors:
Xiaojun Lian; Jianhua Zhang; Kexian Zhu; Timothy J Kamp; Sean P Palecek
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  31     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-26     Completed Date:  2014-01-07     Revised Date:  2014-03-20    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  447-57     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 AlphaMed Press.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Differentiation / drug effects
Humans
Insulin / pharmacology*
Mesoderm / cytology,  drug effects,  metabolism
Mice
Myocardium / cytology*
Myocytes, Cardiac / drug effects*,  metabolism
Signal Transduction / drug effects
Wnt Signaling Pathway / drug effects*
Grant Support
ID/Acronym/Agency:
P30 CA014520/CA/NCI NIH HHS; R01 EB007534/EB/NIBIB NIH HHS; R01 EB007534/EB/NIBIB NIH HHS; R01 HL084615/HL/NHLBI NIH HHS; R01 HL084615/HL/NHLBI NIH HHS; U01 HL099773/HL/NHLBI NIH HHS; U01 HL099773/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Insulin
Comments/Corrections

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