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

被引：113

作者：

Kleger, Alexander ^{[2
,6
,7
]}

Seufferlein, Thomas ^{[8
]}

Malan, Daniela ^{[9
]}

Tischendorf, Michael ^{[2
]}

Storch, Alexander ^{[10
,11
]}

Wolheim, Anne ^{[13
]}

Latz, Stephan

Protze, Stephanie ^{[12
]}

Porzner, Marc ^{[8
]}

Proepper, Christian ^{[1
]}

Brunner, Cornelia ^{[3
]}

Katz, Sarah-Fee ^{[6
,7
]}

Pusapati, Ganesh Varma ^{[2
]}

Bullinger, Lars ^{[4
]}

Franz, Wolfgang-Michael ^{[14
]}

Koehntop, Ralf ^{[2
]}

Giehl, Klaudia ^{[2
]}

Spyrantis, Andreas ^{[2
]}

Wittekindt, Oliver ^{[5
]}

Lin, Qiong ^{[15
]}

Zenke, Martin ^{[15
]}

Fleischmann, Bernd K. ^{[9
]}

Wartenberg, Maria ^{[13
]}

Wobus, Anna M. ^{[16
]}

Boeckers, Tobias M. ^{[1
]}

Liebau, Stefan ^{[1
,13
]}

机构：

[1] Univ Ulm, Inst Anat & Cell Biol, D-89081 Ulm, Germany

[2] Univ Ulm, Dept Internal Med 1, D-89081 Ulm, Germany

[3] Univ Ulm, Inst Physiol Chem, D-89081 Ulm, Germany

[4] Univ Ulm, Dept Internal Med 3, D-89081 Ulm, Germany

[5] Univ Ulm, Dept Gen Physiol, D-89081 Ulm, Germany

[6] Inst Mol Med, Ulm, Germany

[7] Max Planck Res Grp Stem Cell Aging, Ulm, Germany

[8] Univ Halle Wittenberg, Dept Internal Med 1, Saale, Germany

[9] Univ Bonn, Inst Physiol 1, Life & Brain Ctr, D-53115 Bonn, Germany

[10] Tech Univ Dresden, Dept Neurol, D-8027 Dresden, Germany

[11] Tech Univ Dresden, Ctr Regenerat Therapies Dresden, D-8027 Dresden, Germany

[12] Tech Univ Dresden, Dept Pharmacol & Toxicol, D-8027 Dresden, Germany

[13] Univ Jena, Dept Internal Med 1, Jena, Germany

[14] Univ Munich, Klinikum Grosshadern, Med Clin 1, Dept Cardiol, D-8000 Munich, Germany

[15] Dept Cell Biol, Inst Biomed Engn, Aachen, Germany

[16] Leibniz Inst Plant Genet & Crop Plant Res, Gatersleben, Germany

来源：

CIRCULATION | 2010年 / 122卷 / 18期

关键词：

embryology; cells; genes; developmental; ion channels; stem cells; CA2+-ACTIVATED K+ CHANNEL; ACUTE MYOCARDIAL-INFARCTION; INTERMEDIATE-CONDUCTANCE; ELECTROPHYSIOLOGICAL PROPERTIES; FUNCTIONAL ROLES; PROGENITOR-CELL; ES CELLS; DIFFERENTIATION; EXPRESSION; ATRIAL;

D O I：

10.1161/CIRCULATIONAHA.110.971721

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-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 Ca2+ -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. Methods and Results-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. Conclusions-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. (Circulation. 2010;122:1823-1836.)

引用

页码：1823 / +

页数：39

共 54 条

[1] Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4 [J].