Small molecule Wnt inhibitors enhance the efficiency of BMP-4-directed cardiac differentiation of human pluripotent stem cells.
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Small molecule Wnt inhibitors enhance the efficiency of BMP-4-directed cardiac differentiation of human pluripotent stem cells. / Ren, Yongming; Lee, Min Young; Schliffke, Simon; Paavola, Jere; Amos, Peter J; Ge, Xin; Ye, Mingyu; Zhu, Shenjun; Senyei, Grant; Lum, Lawrence; Ehrlich, Barbara E; Qyang, Yibing.
in: J MOL CELL CARDIOL, Jahrgang 51, Nr. 3, 3, 2011, S. 280-287.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Small molecule Wnt inhibitors enhance the efficiency of BMP-4-directed cardiac differentiation of human pluripotent stem cells.
AU - Ren, Yongming
AU - Lee, Min Young
AU - Schliffke, Simon
AU - Paavola, Jere
AU - Amos, Peter J
AU - Ge, Xin
AU - Ye, Mingyu
AU - Zhu, Shenjun
AU - Senyei, Grant
AU - Lum, Lawrence
AU - Ehrlich, Barbara E
AU - Qyang, Yibing
PY - 2011
Y1 - 2011
N2 - Human induced pluripotent stem (iPS) cells potentially provide a unique resource for generating patient-specific cardiomyocytes to study cardiac disease mechanisms and treatments. However, existing approaches to cardiomyocyte production from human iPS cells are inefficient, limiting the application of iPS cells in basic and translational cardiac research. Furthermore, strategies to accurately record changes in iPS cell-derived cardiomyocyte action potential duration (APD) are needed to monitor APD-related cardiac disease and for rapid drug screening. We examined whether modulation of the bone morphogenetic protein 4 (BMP-4) and Wnt/?-catenin signaling pathways could induce efficient cardiac differentiation of human iPS cells. We found that early treatment of human iPS cells with BMP-4 followed by late treatment with small molecule Wnt inhibitors led to a marked increase in production of cardiomyocytes compared to existing differentiation strategies. Using immunocytochemical staining and real-time intracellular calcium imaging, we showed that these induced cardiomyocytes expressed typical sarcomeric markers, exhibited normal rhythmic Ca(2+) transients, and responded to both ?-adrenergic and electric stimulation. Furthermore, human iPS cell-derived cardiomyocytes demonstrated characteristic changes in action potential duration in response to cardioactive drugs procainamide and verapamil using voltage-sensitive dye-based optical recording. Thus, modulation of the BMP-4 and Wnt signaling pathways in human iPS cells leads to highly efficient production of cardiomyocytes with typical electrophysiological function and pharmacologic responsiveness. The use of human iPS cell-derived cardiomyocytes and the application of calcium- and voltage-sensitive dyes for the direct, rapid measurement of iPS cell-derived cardiomyocyte activity promise to offer attractive platforms for studying cardiac disease mechanisms and therapeutics.
AB - Human induced pluripotent stem (iPS) cells potentially provide a unique resource for generating patient-specific cardiomyocytes to study cardiac disease mechanisms and treatments. However, existing approaches to cardiomyocyte production from human iPS cells are inefficient, limiting the application of iPS cells in basic and translational cardiac research. Furthermore, strategies to accurately record changes in iPS cell-derived cardiomyocyte action potential duration (APD) are needed to monitor APD-related cardiac disease and for rapid drug screening. We examined whether modulation of the bone morphogenetic protein 4 (BMP-4) and Wnt/?-catenin signaling pathways could induce efficient cardiac differentiation of human iPS cells. We found that early treatment of human iPS cells with BMP-4 followed by late treatment with small molecule Wnt inhibitors led to a marked increase in production of cardiomyocytes compared to existing differentiation strategies. Using immunocytochemical staining and real-time intracellular calcium imaging, we showed that these induced cardiomyocytes expressed typical sarcomeric markers, exhibited normal rhythmic Ca(2+) transients, and responded to both ?-adrenergic and electric stimulation. Furthermore, human iPS cell-derived cardiomyocytes demonstrated characteristic changes in action potential duration in response to cardioactive drugs procainamide and verapamil using voltage-sensitive dye-based optical recording. Thus, modulation of the BMP-4 and Wnt signaling pathways in human iPS cells leads to highly efficient production of cardiomyocytes with typical electrophysiological function and pharmacologic responsiveness. The use of human iPS cell-derived cardiomyocytes and the application of calcium- and voltage-sensitive dyes for the direct, rapid measurement of iPS cell-derived cardiomyocyte activity promise to offer attractive platforms for studying cardiac disease mechanisms and therapeutics.
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Biological Markers/metabolism
KW - Gene Expression Regulation, Developmental/drug effects
KW - Calcium/metabolism
KW - Action Potentials/drug effects
KW - Bone Morphogenetic Protein 4/pharmacology
KW - Cell Differentiation/drug effects
KW - Embryonic Stem Cells/cytology/drug effects/metabolism
KW - Induced Pluripotent Stem Cells/cytology/drug effects/metabolism
KW - Mesoderm/drug effects/metabolism
KW - Myocytes, Cardiac/cytology/drug effects/metabolism
KW - Wnt Proteins/antagonists & inhibitors
KW - beta Catenin/genetics/metabolism
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Biological Markers/metabolism
KW - Gene Expression Regulation, Developmental/drug effects
KW - Calcium/metabolism
KW - Action Potentials/drug effects
KW - Bone Morphogenetic Protein 4/pharmacology
KW - Cell Differentiation/drug effects
KW - Embryonic Stem Cells/cytology/drug effects/metabolism
KW - Induced Pluripotent Stem Cells/cytology/drug effects/metabolism
KW - Mesoderm/drug effects/metabolism
KW - Myocytes, Cardiac/cytology/drug effects/metabolism
KW - Wnt Proteins/antagonists & inhibitors
KW - beta Catenin/genetics/metabolism
M3 - SCORING: Journal article
VL - 51
SP - 280
EP - 287
JO - J MOL CELL CARDIOL
JF - J MOL CELL CARDIOL
SN - 0022-2828
IS - 3
M1 - 3
ER -