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Papers In Press, published online ahead of print September 19, 2005
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Cambridge, MA 02139
Corresponding Author: dhakuno{at}rics.bwh.harvard.edu
The signaling steps that induce cardiac differentiation in embryonic stem (ES) cells are incompletely understood. We examined the effect of adhesion signaling including Src and focal adhesion kinase (FAK) on cardiogenesis in mouse ES cells using alpha-myosin heavy chain (MHC) promoter-driven enhanced green fluorescent protein or luciferase as reporters. Cardiac transcription factors including Nkx2.5 and Tbx5 mRNA were first expressed at day 4 in hanging drop embryoid bodies, and adhesion of embryoid bodies to surfaces at or before that day strongly inhibited differentiation of ES cells to cardiomyocytes. Since adhesion signaling could suppress cardiogenesis through Src kinases, embryoid bodies were exposed to the small molecule PP2, known as a Src family kinase inhibitor. PP2 during embryoid body adhesion dramatically increased cardiomyocyte differentiation and decreased mRNA expression of neuronal cellular adhesion molecule and alpha-fetoprotein, neuroectodermal and endodermal markers, respectively. Surprisingly, although there was an interaction between Src and FAK in cardiogenesis, the pro-cardiogenic effect of PP2 appeared incompletely explained by Src kinase inhibition as another Src family kinase inhibitor SU6656 failed to induce cardiogenesis. Instead, PP2 specifically inhibited adhesion-induced FAK phosphorylation. In ES cells stably expressing FAK-related non-kinase, which functions as a dominant negative FAK, cell migration from embryoid bodies was inhibited, while alpha-MHC expression and myosin-stained cardiomyocytes were increased, suggesting that reducing cell motility may contribute to cardiogenesis. These data indicate that FAK is a key regulator of cardiogenesis in mouse ES cells, and that FAK signaling within embryoid bodies can direct stem cell lineage commitment.
J. Biol. Chem, 10.1074/jbc.M505575200
Submitted on May 23, 2005
Revised on January 1, 1998
Accepted on September 11, 2005
Focal adhesion kinase signaling regulates cardiogenesis of embryonic stem cells
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