Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers

Levin, Mark; Lü, Min; Petrenko, Nataliya; Hawkins, Brian T.; Gupta, Tara H.; Lang, Deborah; Buckley, Peter T.; Jochems, Jeanine; Liu, Fang; Spurney, Christopher F.; Yuan, Li; Jacobson, Jason T.; Brown, Christopher B.; Huang, Li; Beermann, Friedrich; Margulies, Kenneth B.; Madesh, Muniswamy; Eberwine, James; Epstein, Jonathan A.; Patel, Vickas V.

doi:10.1172/jci39109

Cited by 61 publications

(83 citation statements)

References 67 publications

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“…Developmentally too, in the mouse model, cells constituting PV tissue have demonstrated properties akin to the AV node. 30 In support of the latter hypothesis, in some patients undergoing AF ablation where frequent spontaneous PV depolarizations have been identified, using a combination of circular mapping and a quadripolar ablation catheter, we have noted decremental conduction across the PVs such that the more closely coupled PV depolarizations manifest a longer exit time out of the vein. In these patients, isoproterenol infusion appears to facilitate PV conduction [ Figure 1 …”

Section: Are the Pulmonary Veins Arrhythmogenic By Design?supporting

confidence: 56%

Is Isolation of Arrhythmogenic Pulmonary Veins sufficient for The Long-term Efficacy of Atrial Fibrillation Ablation?

Dixit¹

2010

J.A.F.I.B

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Section: Are the Pulmonary Veins Arrhythmogenic By Design?supporting

confidence: 56%

Is Isolation of Arrhythmogenic Pulmonary Veins sufficient for The Long-term Efficacy of Atrial Fibrillation Ablation?

Dixit¹

2010

J.A.F.I.B

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“…Patch clamp recordings were performed using the patch clamp technique in the whole-cell configuration as described previously (29). In brief, GΩ seals were achieved using pipettes fashioned from borosilicate glass (WPI) with resistances of 2-3 MΩ after fire polishing.…”

Section: Methodsmentioning

confidence: 99%

“…Given this scenario, it is easy to envision disease processes that occur in part by pushing the preexisting indigenous transcriptome to an another profile, thereby weakening the cells' ability to function appropriately and initiating a cascade of disease-related consequences (29). This idea has therapeutic implications.…”

Section: Reprogramming Of Global Gene Expression In Tcardiomyocytesmentioning

confidence: 99%

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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“…Although melanocyte-like cells in the heart were also identified as non-myocardial triggers contributing to AF (Levin et al, 2009), factors that promote ectopic pacemaker fate in the PV myocardium remain to be identified.…”

Section: Introductionmentioning

confidence: 99%

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

et al. 2015

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In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. The genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. It was noted previously that Nkx2-5, which is expressed in the PV myocardium and reinforces a chamber-like myocardial identity in the PV, is lacking in the SAN. Here we present evidence that in mice Shox2 antagonizes the transcriptional output of Nkx2-5 in the PV myocardium and in a functional Nkx2-5 + domain within the SAN to determine cell fate. Shox2 deletion in the Nkx2-5 + domain of the SAN caused sick sinus syndrome, associated with the loss of the pacemaker program. Explanted Shox2 + cells from the embryonic PV myocardium exhibited pacemaker characteristics including node-like electrophysiological properties and the capability to pace surrounding Shox2 − cells. Shox2 deletion led to Hcn4 ablation in the developing PV myocardium. Nkx2-5 hypomorphism rescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in the PV myocardium in Nkx2-5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. A similar mechanism is also adopted in differentiated embryoid bodies. We found that Shox2 interacts with Nkx2-5 directly, and discovered a substantial genomewide co-occupancy of Shox2, Nkx2-5 and Tbx5, further supporting a pivotal role for Shox2 in the core myogenic program orchestrating venous pole and pacemaker development.

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Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers

Cited by 61 publications

References 67 publications

Is Isolation of Arrhythmogenic Pulmonary Veins sufficient for The Long-term Efficacy of Atrial Fibrillation Ablation?

Is Isolation of Arrhythmogenic Pulmonary Veins sufficient for The Long-term Efficacy of Atrial Fibrillation Ablation?

Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

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