Abstract
Human induced pluripotent stem cells (hiPSCs) with the ability to form all somatic cells can generate pacemaking cardiomyocytes (CMs) for engineering of biological pacemakers. However, differentiation efficiency of hiPSCs into pacemaking cardiomyocytes is merely at 5% of the total CMs. Membrane potential of a cell can alter cell fate. Activation of small conductance Ca2+-activated K+ channels (SKs) has been shown to induce membrane hyperpolarization. In this study, we demonstrated that SKs are present and functional in hiPSCs and their differentiation progeny. Addition of SK activator (EBIO or CyPPA) hyperpolarized hiPSCs and differentiating hiPSCs 2 and 5 days post-differentiation by -2.5±0.97, -22.7±1.8 and -13.6±3.3 mV, respectively. The magnitude of hyperpolarization exhibited dose-dependency to SK activator in differentiating hiPSCs 2 days post-differentiation. Activation of SK channels by EBIO or CyPPA on day 2-3 from the onset of differentiation significantly upregulated the expression of Islet (Isl)1, a marker for a subset of cardiac progenitor cells that are known to form the sinoatrial node where the pacemaking cardiomyocyte reside. The number of Isl1-positive cells in differentiating hiPSCs with SK activation on day 2-3 has also increased relative to control. Our findings indicate that the activation of SK channels at an appropriate treatment time and length results in a facilitated increase in the differentiation of hiPSCs to pacemaking cardiomyocyte precursors.
Published Version
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