KCNQ1/KCNE1 K+ Channels Associated with Long QT Syndrome are Expressed in Early Stage Human Embryonic Stem Cell-Derived Cardiomyocytes

Abstract

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are not only a potential source of functional cardiac tissue that can be utilized as a drug screening platform or agents for cell-based therapy but also offer great potential in studies of heritable cardiac arrhythmias known as channelopathies. Many major cardiac ion channels have been reported to be expressed in hESC-CMs. However, the presence of KCNQ1/KCNE1 (IKs) K+ channels critical to cardiac repolarization particularly during sympathetic nerve stimulation and associated with the most common variant of congenital Long QT syndrome (LQT1), to date has not been reported. Here we report investigation of the cellular electrophysiological properties of hESC-CMs during the first 34 days of cytokine directed differentiation with a focus on IKs channels. All beating hESC-CMs studied had action potentials with cardiac phenotypes and expressed L-type calcium channels (n=26) and pacemaker channels (n=27) while 68% of cells (n=11 out of 16) expressed IKr, the potassium current associated with LQT2, defined as E4031-sensitive outward current measured during prolonged depolarization. IKs, the potassium current associated with LQT1, was identified by its biophysical and pharmacological properties: recorded in 29% of cells (n=5 out of 17), IKs was defined as an outward current slowly activating during prolonged depolarization, insensitive to E4031 (5 μM) and blocked by Chromanol 293B (30 μM). qPCR experiments confirmed the presence of IKs channels α- (KCNQ1) and β- (KCNE1) subunits in these hESC-CMs. This is the first report of IKs channel expression in hESC-CMs providing strong evidence in support of their use in mechanistic and pharmacological investigations of LQT1 and other heritable arrhythmia syndromes linked to mutations in the genes coding for IKs channel subunits and/or accessory proteins.