Development of electrical activity in cardiac myocyte aggregates derived from mouse embryonic stem cells

Banach, Kathrin; Halbach, Marcel; Hu, Peng; Hescheler, Juergen; Egert, Ulrich

doi:10.1152/ajpheart.01106.2001

Cited by 102 publications

(100 citation statements)

References 45 publications

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“…Several lines of arguments could explain this effect. For example, it was recently shown that larger beating areas of embryoid bodies display a higher beating frequency (Banach et al, 2003). As Tbx5 overexpression results in an increase in cardiomyocyte formation this might directly result in an increased beating frequency.…”

Section: Discussionmentioning

confidence: 99%

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Herrmann

Bundschu

Kühl

et al. 2011

Developmental Dynamics

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The T-box transcription factor Tbx5 is involved in several developmental processes including cardiogenesis. Early steps of cardiac development are characterised by the formation of two cardiogenic lineages, the first (FHF) and the second heart field (SHF) lineage, which arise from a common cardiac progenitor cell population. To further investigate the function of Tbx5 during cardiogenesis, we generated a murine embryonic stem cell line constitutively overexpressing Tbx5. Differentiation of these cells is characterised by an earlier and increased appearance of contracting cardiomyocytes that beat with a higher frequency than control cells. In semi-quantitative and quantitative RT-PCR analyses, we observed an up-regulation of cardiac marker genes such as Troponin T, endogenous Tbx5, and Nkx2.5 and a down-regulation of others like BMP4 and Hand2. Similar data were gained in Xenopus laevis arguing for a conserved function of Tbx5. Furthermore, markers of the conduction system and atrial cardiomyocytes were increased.

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Section: Discussionmentioning

confidence: 99%

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Herrmann

Bundschu

Kühl

et al. 2011

Developmental Dynamics

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“…Stem cell-derived myocytes grown in vitro can recapitulate the development and differentiation of cardiomyocytes very closely [92][93][94]. The accessibility of these cells and the relative ease by which they can be genetically manipulated (compared to myocytes in early embryos) has led them to be used for many studies of cardiac development.…”

Section: Ip 3 Signaling In Cardiac Developmentmentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

169

149

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Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

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“…multichannelsystems.com) [22][23][24]. For this aim, beating areas were mechanically removed and plated on MEA plates.…”

Section: Microelectrode Mappingmentioning

confidence: 99%

Generation and Characterization of Functional Cardiomyocytes from Rhesus Monkey Embryonic Stem Cells

et al. 2006

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Embryonic stem cells (ESCs) from mice and humans (hESCs) have been shown to be able to efficiently differentiate toward cardiomyocytes (CMs). Because murineESCs and hESCs do not allow for establishment of preclinical allogeneic transplantation models, the aim of our study was to generate functional CMs from rhesus monkey ESCs (rESCs). Although formation of ectodermal and neuronal/glial cells appears to be the default pathway of the rESC line R366.4, we were able to change this commitment and to direct generation of endodermal/mesodermal cells and further differentiation toward CMs. Differentiation of rESCs resulted in an average of 18% of spontaneously contracting embryoid bodies (EBs) from rESCs. Semiquantitative reverse transcription-polymerase chain reaction analyses demonstrated expression of marker genes typical for endoderm, mesoderm, cardiac mesoderm, and CMs, including brachyury, goosecoid, Tbx-5, Tbx-20, Mesp1, Nkx2.5, GATA-4, FOG-2, Mlc2a, MLC2v, ANF, and ␣-MHC in rESC-derived CMs. Immunohistological and ultrastructural studies showed expression of CM-typical proteins, including sarcomeric actinin, troponin T, titin, connexin 43, and cross-striated muscle fibrils. Electrophysiological studies by means of multielectrode arrays revealed evidence of functionality, electrical coupling, and ␤-adrenergic signaling of the generated CMs. This is the first study demonstrating generation of functional CMs derived from rESCs. In contrast to hESCs, rESCs allow for establishment of preclinical allogeneic transplantation models. Moreover, rESC-derived CMs represent a cell source for the development of high-throughput assays for cardiac safety pharmacology.

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Development of electrical activity in cardiac myocyte aggregates derived from mouse embryonic stem cells

Cited by 102 publications

References 45 publications

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Generation and Characterization of Functional Cardiomyocytes from Rhesus Monkey Embryonic Stem Cells

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