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Overexpression of Map3k7 activates sinoatrial node-like differentiation in mouse ES-derived cardiomyocytes.

ABSTRACT: In vivo, cardiomyocytes comprise a heterogeneous population of contractile cells defined by unique electrophysiologies, molecular markers and morphologies. The mechanisms directing myocardial cells to specific sub-lineages remain poorly understood. Here we report that overexpression of TGFβ-Activated Kinase (TAK1/Map3k7) in mouse embryonic stem (ES) cells faithfully directs myocardial differentiation of embryoid body (EB)-derived cardiac cells toward the sinoatrial node (SAN) lineage. Most cardiac cells in Map3k7-overexpressing EBs adopt markers, cellular morphologies, and electrophysiological behaviors characteristic of the SAN. These data, in addition to the fact that Map3k7 is upregulated in the sinus venous-the source of cells for the SAN-suggest that Map3k7 may be an endogenous regulator of the SAN fate.

SUBMITTER: Brown K

PROVIDER: S-EPMC5744947 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Overexpression of Map3k7 activates sinoatrial node-like differentiation in mouse ES-derived cardiomyocytes.

Brown Kemar K Legros Stephanie S Ortega Francis A FA Dai Yunkai Y Doss Michael Xavier MX Christini David J DJ Robinson Richard B RB Foley Ann C AC

PloS one 20171227 12

In vivo, cardiomyocytes comprise a heterogeneous population of contractile cells defined by unique electrophysiologies, molecular markers and morphologies. The mechanisms directing myocardial cells to specific sub-lineages remain poorly understood. Here we report that overexpression of TGFβ-Activated Kinase (TAK1/Map3k7) in mouse embryonic stem (ES) cells faithfully directs myocardial differentiation of embryoid body (EB)-derived cardiac cells toward the sinoatrial node (SAN) lineage. Most cardi ...[more]

PMID: 29281682

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Pdx1 and Ngn3 overexpression enhances pancreatic differentiation of mouse ES cell-derived endoderm population.

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Mouse sinoatrial node transcriptome

Project description:RNA Sequencing of Mouse Sinoatrial Node Reveals an Upstream Regulatory Role for Islet-1 in Cardiac Pacemaker Cells Rationale: Treatment of sinus node disease with regenerative or cell-based therapies will require a detailed understanding of gene regulatory networks in cardiac pacemaker cells (PCs). Objective: To characterize the transcriptome of PCs using RNA sequencing, and to identify transcriptional networks responsible for PC gene expression. Methods and Results: We used laser capture micro-dissection (LCM) on a sinus node reporter mouse line to isolate RNA from PCs for RNA sequencing (RNA-Seq). Differential expression and network analysis identified novel SAN-enriched genes, and predicted that the transcription factor Islet-1 (Isl1) is active in developing pacemaker cells. RNA-Seq on SAN tissue lacking Isl1 established that Isl1 is an important transcriptional regulator within the developing SAN. Conclusions: (1) The PC transcriptome diverges sharply from other cardiomyocytes; (2) Isl1 is a positive transcriptional regulator of the PC gene expression program. There are 25 RNA-Sequencing Samples

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Mouse sinoatrial node transcriptome

2015-02-06 | GSE65658 | GEO

Deciphering cellular signals in adult mouse sinoatrial node cells.

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Project description:Emerging evidence from large animal models implicates Ca2+ regulation, particularly intracellular sarcoplasmic reticulum (SR) Ca2+ release, as essential for sinoatrial node (SAN) automaticity. However, despite the apparent importance of SR Ca2+ release to SAN cell function it is uncertain how SR Ca2+ release is controlled in SAN cells from mouse. Understanding mouse SAN SR Ca2+ release mechanism will allow improved understanding of results in studies on SAN from genetic mouse models of Ca2+ homeostatic proteins. Here we investigated the functional relationship between sarcolemmal Ca2+ influx and SR Ca2+ release at the level of single SAN cell, using simultaneous patch-clamp current recording and high resolution confocal Ca2+ imaging techniques. In mouse SAN cells, both Ca2+ channel currents and triggered SR Ca2+ transients displayed bell-shaped, graded function with the membrane potential. Moreover, the gain function for Ca2+-induced Ca2+ release (CICR) displayed a monotonically decreasing function with strong voltage dependence, consistent with a "local control" mechanism for CICR. In addition, we observed numerous discrete Ca2+ sparks at the voltage range of diastolic depolarization, in sharp contrast to the much lower frequency of sparks observed at resting potentials. We concluded that the "local control" mechanism of CICR is responsible for both local Ca2+ release during diastolic depolarization and the synchronized Ca2+ transients observed during action potential in SAN cells.

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Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue.

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Project description:The goal of this study was to assess the changes in protein expression in the human sinoatrial node (SAN) compared with working cardiomyocytes in order to identify specific SAN protein signatures. Four pair of samples (the SAN and working cardiomyocytes) were obtained post-mortem from four healthy human donors.

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Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways.

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