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

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

doi:10.1161/circulationaha.110.971721

Cited by 104 publications

(107 citation statements)

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“…Overall, our data are consistent with recent studies showing that the SK4 channels are critical players in determining the cardiac pacemaker fate in embryonic stem cells and induced pluripotent stem cells from mice [183−185] and humans [186] . Treatment with 1-ethyl-2-benzimidazolinone (EBIO), the SK4 channel opener, differentiates mouse embryonic stem cells into cardiomyocytes, with a strong enrichment of the pacemaker-like cells [183] . This differentiation is accompanied by the induction of SAN-specific genes and by a loss of the ventricular-specific gene program [183] .…”

Section: Future Directionmentioning

confidence: 99%

“…Treatment with 1-ethyl-2-benzimidazolinone (EBIO), the SK4 channel opener, differentiates mouse embryonic stem cells into cardiomyocytes, with a strong enrichment of the pacemaker-like cells [183] . This differentiation is accompanied by the induction of SAN-specific genes and by a loss of the ventricular-specific gene program [183] . Notably, the SK4 channel blocker clotrimazole inhibits EBIO-induced cardiogenesis and the up-regulation of the pacemaker transcripts [183] .…”

Section: Future Directionmentioning

confidence: 99%

“…This differentiation is accompanied by the induction of SAN-specific genes and by a loss of the ventricular-specific gene program [183] . Notably, the SK4 channel blocker clotrimazole inhibits EBIO-induced cardiogenesis and the up-regulation of the pacemaker transcripts [183] . In addition, a transcriptional analysis showed a ninefold upregulation of the SK4 mRNA in the developing conduction system compared with SK1-3 [187] .…”

Section: Future Directionmentioning

confidence: 99%

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Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cellderived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca 2+ -activated K + channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

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Section: Future Directionmentioning

confidence: 99%

Section: Future Directionmentioning

confidence: 99%

Section: Future Directionmentioning

confidence: 99%

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Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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“…To [36]. The potentiometric signal detection of Di-8-ANNEPS presented a stable fluorescent signal pattern following stimulation of cells with ADP as well as ATP, indicating that the membrane potential remained in a Bsteady-state^during purinoceptor-induced [Ca 2+ ] i signaling.…”

Section: Adp/atp-mediated Intracellular [Ca 2+ ]I Transientsmentioning

confidence: 91%

“…Membrane potential-dependent fluorescence emission of Di-8-ANEPPS was measured by two spectral bands: band pass filter (BP) 530-600 nm; low pass filter (LP) >615 nm. The ratio signal was calculated as follows: ratio signal=BP signal/ LP signal [36,37].…”

Section: Di-8-anepps Membrane Potential Imagingmentioning

confidence: 99%

Cardiomyogenesis of embryonic stem cells upon purinergic receptor activation by ADP and ATP

Mazrouei

Sharifpanah

Bekhite

et al. 2015

Purinergic Signalling

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Purinergic signaling may be involved in embryonic development of the heart. In the present study, the effects of purinergic receptor stimulation on cardiomyogenesis of mouse embryonic stem (ES) cells were investigated. ADP or ATP increased the number of cardiac clusters and cardiac cells, as well as beating frequency. Cardiac-specific genes showed enhanced expression of α-MHC, MLC2v, α-actinin, connexin 45 (Cx45), and HCN4, on both gene and protein levels upon ADP/ATP treatment, indicating increased cardiomyogenesis and pacemaker cell differentiation. Real-time RT-PCR analysis of purinergic receptor expression demonstrated presence of P2X1, P2X4, P2X6, P2X7, P2Y1, P2Y2, P2Y4, and P2Y6 on differentiating ES cells. ATP and ADP as well as the P2X agonists β,γ-methylenadenosine 5′-triphosphate (β,γ-MetATP) and 8-bromoadenosine 5′-triphosphate (8- Br

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Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration

et al. 2021

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Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3-null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5 + liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in Dkk3-null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog-signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling.

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

Cited by 104 publications

References 50 publications

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

Cardiomyogenesis of embryonic stem cells upon purinergic receptor activation by ADP and ATP

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration

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