Large-scale analysis of ion channel gene expression in the mouse heart during perinatal development

Harrell, Maddison D.; Harbi, Shaghayegh; Hoffman, Joan F; Zavadil, Jiří; Coetzee, William A.

doi:10.1152/physiolgenomics.00163.2006

Cited by 89 publications

(96 citation statements)

References 55 publications

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“…The peak amplitudes and repolarization rates varied among tCardiomyocytes. These varying electrophysiological characteristics suggests that each tCardiomyocyte might have a unique composition of ion channel types and abundances conferring differing electrical properties (11). In separate experiments, but in accordance with the action potential data, we also observed cytosolic Ca 2+ concentration changes in tCardiomyocytes (Fig.…”

Section: Reprogramming Of Global Gene Expression In Tcardiomyocytessupporting

confidence: 88%

Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes

Kim¹,

Sul²,

Peternko

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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We show that the transfer of the adult ventricular myocyte (AVM) transcriptome into either a fibroblast or an astrocyte converts the host cell into a cardiomyocyte. Transcriptome-effected cardiomyocytes (tCardiomyocytes) display morphologies, immunocytochemical properties, and expression profiles of postnatal cardiomyocytes. Cell morphology analysis shows that tCardiomyoctes are elongated and have a similar length-to-width ratio as AVMs. These global phenotypic changes occur in a time-dependent manner and confer electroexcitability to the tCardiomyocytes. tCardiomyocyte generation does not require continuous overexpression of specific transcription factors; for example, the expression level of transcription factor Mef2c is higher in tCardiomyocytes than in fibroblasts, but similar in tCardiomyocytes and AVMs. These data highlight the dominant role of the gene expression profile in developing and maintaining cellular phenotype. The transcriptomeinduced phenotype remodeling-generated tCardiomyocyte has significant implications for understanding and modulating cardiac disease development.C ardiomyocytes are among the most sought-after cells in regenerative medicine because they may help to repair an injured heart by replacing lost tissue (1, 2). Functional cardiomyocyte-like cells have been induced from embryonic stem cells (ESCs), induced from pluripotent stem cells (iPSCs), and generated from direct conversion of fibroblasts using defined transcription factor transduction (3-7). ESC-derived and iPSCderived cardiomyocytes exhibit many characteristics of cardiomyocytes, including electric activity, contractile movement, and up-regulation of cardiac genes; however, both stem cellderived cardiomyocytes are mixed populations of atrial, ventricular, and other cells, limiting their use in research and clinical application. In addition to heterogeneity of the cells, stem cellderived cardiomyocytes remain embryonic cardiomyocytes even after 2 mo under standard 2D culture conditions (5, 6). Transcription factor-induced cardiomyocytes also have many characteristics of neonatal cardiomyocytes (4). Furthermore, carcinogenesis and early senescence often develop in transcription factor-mediated induction of such phenotypic changes (8, 9).We have previously shown that the transfer of transcriptome (TIPeR) from a rat astrocyte into a rat neuron converts the electrically active neuron into an electrically quiescent tAstrocyte cell (10). We asked whether the change in expression profile (i.e., modulation of relative abundance of gene products) could transdifferentiate electrically quiescent cells into electrically excitable cells. Here we demonstrate the conversion of an electrically quiescent fibroblast directly into an electrically excitable tCardiomyocyte in a mouse system. We also show that another electrically quiescent cell, the astrocyte, can be converted into a tCardiomyocyte. This conversion was confirmed by a diverse set of single-cell phenotyping procedures. Results Generation of tCardiomyocytes from Fibroblasts by Trans...

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Section: Reprogramming Of Global Gene Expression In Tcardiomyocytessupporting

confidence: 88%

Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes

Kim¹,

Sul²,

Peternko

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…A fundamental characteristic of adult cardiomyocytes maturation is increased cell size; these characteristics have been linked to Kir2.1 expression in adult cardiomyocytes (6). To assess the effect of I K1 -enhancement on iPS-CM size, the whole cell membrane capacitance was determined from whole cell patchclamp electrophysiology measurements and the cell area was measured from imaging studies.…”

Section: H1614 Ips-cm Model For Investigating Complex Inherited Arrhymentioning

confidence: 99%

“…In addition to these electrophysiological functions, Kir2.1 is pivotal to fetal mouse cardiomyocyte maturation (6) and it is an important component for normal facial muscular/skeletal development and growth (32). Membrane hyperpolarization, induced by Kir2.1, is the key triggering event that initiates skeletal myotube differentiation and maturation (11).…”

mentioning

confidence: 99%

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

Vaidyanathan

Markandeya

Kamp

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Vaidyanathan R, Markandeya YS, Kamp TJ, Makielski JC, January CT, Eckhardt LL. IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes. Am J Physiol Heart Circ Physiol 310: H1611-H1621, 2016. First published April 8, 2016; doi:10.1152/ajpheart.00481.2015.-Currently available induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) do not ideally model cellular mechanisms of human arrhythmic disease due to lack of a mature action potential (AP) phenotype. In this study, we create and characterize iPS-CMs with an electrically mature AP induced by potassium inward rectifier (IK1) enhancement. The advantages of IK1-enhanced iPS-CMs include the absence of spontaneous beating, stable resting membrane potentials at approximately Ϫ80 mV and capability for electrical pacing. Compared with unenhanced, IK1-enhanced iPS-CMs calcium transient amplitudes were larger (P Ͻ 0.05) with a typical staircase pattern. IK1-enhanced iPS-CMs demonstrated a twofold increase in cell size and membrane capacitance and increased DNA synthesis compared with control iPS-CMs (P Ͻ 0.05). Furthermore, IK1-enhanced iPS-CMs expressing the F97C-CAV3 long QT9 mutation compared with wild-type CAV3 demonstrated an increase in AP duration and late sodium current. I K1-enhanced iPSCMs represent a more mature cardiomyocyte model to study arrhythmia mechanisms. arrhythmia; potassium ion channel; LQTS; iPS-CM NEW & NOTEWORTHY Ik1-enhanced induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) more closely represent the cell size, structure, multinucleation, electrophysiology, and calcium handling properties of adult human cardiomyocytes. These I K1-enhanced iPS-CMs will permit advanced studies of arrhythmia mechanisms such as rotor and reentry generation in plated iPS-CMs or drug safety testing due to the mature cellular phenotype.INDUCED PLURIPOTENT STEM (iPS) cells have opened new avenues to investigate many human diseases (33). Patient-specific iPSderived cardiomyocytes (iPS-CMs) have been used to investigate inherited arrhythmia syndromes such as long QT syndrome (LQTS) and catecholeminergic polymorphic ventricular tachycardia (9,21,31,34). These proof of concept studies have recapitulated some characteristic features of human disease (8, 23). However, despite advances in differentiation and culturing techniques, currently available iPS-CMs have several features of immature cardiomyocytes, which limit their application for modeling cellular arrhythmia mechanisms and inherited arrhythmic disease. The electrophysiological limitations occur predominately due to action potential (AP) diastolic properties including a relatively depolarized resting membrane potential and spontaneous automaticity due to a small inward rectifier (I K1 ) density and unopposed pacemaker current (I f ) (5, 18). In turn, this results in partial inactivation of ion channels such as the cardiac sodium channel to reduce current (I Na ) amplitude. Automaticity also interferes w...

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“…Decreased extracellular concentration of Na, an indirect measure of increased intracellular retention, is in accordance with Na/K/ATPase pump failure under hypoxic conditions (Palpant et al, 2008;Kawai et al, 1996). Intracellular alteration of Na and calcium concentrations following ATP depletion is associated with activation of inwardly rectifier K channels (KIR) of high conductance, to facilitate cell membrane re-polarization (Lien et al, 2003;Mintert et al, 2007;Harrell et al, 2007;Pouget, 2008). During hypoxia, ischemia or metabolic inhibition, ATP-dependent K channels (K ATP ) open, which facilitate K influx and shortening of action potential duration (Harrell, 2007;Pouget, 2008;Lebuffe et al, 2003;Cameron et al, 2003;Lascano et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Intracellular alteration of Na and calcium concentrations following ATP depletion is associated with activation of inwardly rectifier K channels (KIR) of high conductance, to facilitate cell membrane re-polarization (Lien et al, 2003;Mintert et al, 2007;Harrell et al, 2007;Pouget, 2008). During hypoxia, ischemia or metabolic inhibition, ATP-dependent K channels (K ATP ) open, which facilitate K influx and shortening of action potential duration (Harrell, 2007;Pouget, 2008;Lebuffe et al, 2003;Cameron et al, 2003;Lascano et al, 2002). Therefore, reduced extracellular K concentration, following ATP depletion seems to be due to the activation of ATPdependent KIR channels, located in the membrane of endothelial cells (Cameron et al, 2003;Hu et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide level and von Willebrand factor (vWF) secretion are not candidate markers of endothelial cell dysfunction in adenosine triphosphate (ATP) depleted endothelial cells

Behjati¹,

Hashemi²,

Kazemi³

et al. 2011

Afr. J. Biotechnol.

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Large-scale analysis of ion channel gene expression in the mouse heart during perinatal development

Abstract: Harrell MD, Harbi S, Hoffman JF, Zavadil J, Coetzee WA. Largescale analysis of ion channel gene expression in the mouse heart during perinatal development.

Cited by 89 publications

References 55 publications

Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes

Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

Nitric oxide level and von Willebrand factor (vWF) secretion are not candidate markers of endothelial cell dysfunction in adenosine triphosphate (ATP) depleted endothelial cells

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