Referenced in: none

Automatically associated channels: Kv10.1

Title: Modulation of Calcium-Activated Potassium Channels Induces Cardiogenesis of Pluripotent Stem Cells and Enrichment of Pacemaker-Like Cells.

Authors: Alexander Kleger, Thomas Seufferlein, Daniela Malan, Michael Tischendorf, Alexander Storch, Anne Wolheim, Stephan Latz, Stephanie Protze, Marc Porzner, Christian Proepper, Cornelia Brunner, Sarah-Fee Katz, Ganesh Varma Pusapati, Lars Bullinger, Wolfgang-Michael Franz, Ralf Koehntop, Klaudia Giehl, Andreas Spyrantis, Oliver Wittekindt, Quiong Lin, Martin Zenke, Bernd K Fleischmann, Maria Wartenberg, Anna M Wobus, Tobias M Boeckers, Stefan Liebau

Journal, date & volume: , 2010 Oct 18 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20956206

Abstract
Ion channels are key determinants for the function of excitable cells, but little is known about their role and involvement during cardiac development. Earlier work identified Ca(2+)-activated potassium channels of small and intermediate conductance (SKCas) as important regulators of neural stem cell fate. Here we have investigated their impact on the differentiation of pluripotent cells toward the cardiac lineage.We have applied the SKCa activator 1-ethyl-2-benzimidazolinone on embryonic stem cells and identified this particular ion channel family as a new critical target involved in the generation of cardiac pacemaker-like cells: SKCa activation led to rapid remodeling of the actin cytoskeleton, inhibition of proliferation, induction of differentiation, and diminished teratoma formation. Time-restricted SKCa activation induced cardiac mesoderm and commitment to the cardiac lineage as shown by gene regulation, protein, and functional electrophysiological studies. In addition, the differentiation into cardiomyocytes was modulated in a qualitative fashion, resulting in a strong enrichment of pacemaker-like cells. This was accompanied by induction of the sino-atrial gene program and in parallel by a loss of the chamber-specific myocardium. In addition, SKCa activity induced activation of the Ras-Mek-Erk signaling cascade, a signaling pathway involved in the 1-ethyl-2-benzimidazolinone-induced effects.SKCa activation drives the fate of pluripotent cells toward mesoderm commitment and cardiomyocyte specification, preferentially into nodal-like cardiomyocytes. This provides a novel strategy for the enrichment of cardiomyocytes and in particular, the generation of a specific subtype of cardiomyocytes, pacemaker-like cells, without genetic modification.