Pluripotent mouse embryonic stem cells are able to differentiate into cardiomyocytes expressing chronotropic responses to adrenergic and cholinergic agents and Ca2+ channel blockers

Item Type:	Article
Title:	Pluripotent mouse embryonic stem cells are able to differentiate into cardiomyocytes expressing chronotropic responses to adrenergic and cholinergic agents and Ca2+ channel blockers
Creators Name:	Wobus, A.M. and Wallukat, G. and Hescheler, J.
Abstract:	A defined cultivation system was developed for the differentiation of pluripotent embryonic stem cells of the mouse into spontaneously beating cardiomyocytes, allowing investigations of chronotropic responses, as well as electrophysiological studies of different cardioactive drugs in vitro. The beta-adrenoceptor agonists (-)isoprenaline and clenbuterol, the mediators of cAMP metabolism, forskolin and isobutylmethylxanthine (IBMX), the alpha 1-adrenoceptor agonist (-)phenylephrine, and the heart glycoside digitoxin induced a positive, the muscarinic cholinoceptor agonist carbachol and L-type Ca2+ channel blockers nisoldipine, gallopamil and diltiazem induced a negative chronotropic response. In early differentiated cardiomyocytes beta 1-, alpha 1-, but not beta 2-adrenoceptors, cholinoceptors, as well as L-type Ca2+ channels participated in the chronotropic response. In terminally differentiated cardiomyocytes beta 2-adrenoceptors and digitoxin responses were also functionally expressed. The contractions of spontaneously beating cardiomyocytes were concomitant with rhythmic action potentials very similar to those described for embryonic cardiomyocytes and sinus-node cells. We conclude that cardiomyocytes differentiating from pluripotent embryonic stem cells are able to develop adrenoceptors and cholinoceptors and signal transduction pathways as well as L-type Ca2+ channels as a consequence of cell-cell interactions during embryoid body formation in vitro, independent of the development in living organisms. The cellular system described may be useful as in vitro assay for toxicological investigations of chronotropic drugs and a model system for studying commitment and cellular differentiation in vitro.
Keywords:	1-Methyl-3-isobutylxanthine, Atropine, Calcium Channel Blockers, Carbachol, Cell Differentiation, Cell Line, Drug Dose-Response Relationship, Mammalian Embryo, Nonmammalian Embryo, Forskolin, Heart, Heart Rate, Isoproterenol, Membrane Potentials, Myocardium, Parasympathomimetics, Phenylephrine, Prazosin, Stem Cells, Sympathomimetics, Animals
Source:	Differentiation
ISSN:	0301-4681
Publisher:	Blackwell Publishing
Volume:	48
Number:	3
Page Range:	173-182
Date:	1 December 1991
Official Publication:	https://doi.org/10.1111/j.1432-0436.1991.tb00255.x
PubMed:	View item in PubMed

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