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Project description:RNA expression in the chick embryonic heart and sino-atrial node
| PRJNA449391 | ENA
Project description:The sinus node is a collection of highly specialized cells that constitute the natural pacemaker activity of our heart. The protein expression landscape of the sinus node differs from the surrounding cardiac tissue, although it is primarily comprised of myocytes and fibroblasts like the rest of the cardiac tissue, endowing it with its unique ability to regulate heart rate. Here we performed quantitative proteomics experiments to profile protein expression in the pacemaker of the heart, and compared it to protein expression in the neighbouring atrial muscle. In summary, the quantitative proteomics data presented here offer a highly detailed insight into the unique composition of the pacemaker of our heart.
2019-07-08 | PXD008736 | Pride
Project description:to study the effect of induced expression of TBX3 within the atrium of the heart Background: Treatment of congenital or acquired disorders of the sinus node or atrioventricular node requires insight into the molecular mechanisms for the development and homeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogram terminally differentiated working cardiomyocytes into pacemaker cells. This would be an attractive approach in biological pacemaker formation. Methods and results: TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na+ channel (NaV1.5; INa) and inwardly rectifying K+ ion channels (Kir-genes; IK1). Concordantly, we observed conduction slowing in these hearts, and reductions in INa and IK1 in cardiomyocytes isolated from these hearts. The reduction in IK1 resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current, If, were observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes. Conclusions: TBX3 partially reprograms terminally differentiated working cardiomyocytes into pacemaker-like cells and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce IK1 density to enable diastolic depolarization, are very promising TBX3 characteristics for biological pacemaker formation strategies. 5 TBX3 expressing left atrial appendage samples (Tamoxifen-treated Myh6MCM;CTBX3 adult male mice) and 6 controls ((Tamoxifen-treated Myh6MCM adult male mice)
2011-09-30 | E-GEOD-31969 | biostudies-arrayexpress
Project description:Sino Atrial Node (SAN) is part of the cardiac conduction system, which controls the rhythmic contraction of the vertebrate heart. SAN consists of a specialized pacemaker cell population that has the potential to generate electrical impulses. Although SAN pacemakers have been extensively studied in mammalian and teleost models, including the zebrafish, their molecular nature remains inadequately comprehended. Here, we utilized the zebrafish transgenic line sqet33mi59BEt to isolate cells of the sino-atrial ring (SAR) of developing zebrafish embryos and profiled their transcriptome. Our analyses identified novel candidate genes and well-known conserved signaling pathways (Wnt, BMP) involved in pacemaker development. We show that the zebrafish SAR expresses several mammalian SAN pacemaker signature genes, which include hcn4 and calcium and potassium gated channels. Moreover, genes encoding components of the BMP and Wnt signaling pathways, as well as members of the Tbx family, which have previously been implicated in pacemaker development, were also overexpressed in the SAR. Among SAR-overexpressed genes, 24 had human homologues implicated in 104 different ClinVar phenotype entries related to various forms of congenital heart diseases. Moreover, we show that loss-of-function of three SAR-overexpressed genes, pard6a, prom2, and atp1a1a.2, resulted in abnormal heart morphology and physiology. Our results suggest the relevance of our transcriptomics resource to studying human heart conditions.
2021-09-10 | GSE160398 | GEO
Project description:The sinus node is a collection of highly specialised cells constituting the heart’s pacemaker. It is keenly debated whether the so-called membrane or alternatively Ca2+ clocks provide the molecular substrate of pacemaking. By high-resolution mass spectrometry, we quantified >7,000 proteins from sinus node and neighbouring atrial muscle. The abundances of 575 proteins differed between the two tissues, including particular differences in metabolic profiles and extracellular matrix composition. Most notably, the data reveal significant differences between the tissues in the ion channels responsible for the membrane clock, but not in Ca2+ clock proteins, suggesting that the membrane clock underpins pacemaking. By performing single-nucleus RNA sequencing of sinus node biopsies, we attributed protein abundances to specific cell types. Consistent with these results, incorporation of the ion channel expression differences into a biophysically-detailed atrial action potential model resulted in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the pacemaker of the heart.
2019-05-04 | GSE130710 | GEO
Project description:to study the effect of induced expression of TBX3 within the atrium of the heart Background: Treatment of congenital or acquired disorders of the sinus node or atrioventricular node requires insight into the molecular mechanisms for the development and homeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogram terminally differentiated working cardiomyocytes into pacemaker cells. This would be an attractive approach in biological pacemaker formation. Methods and results: TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na+ channel (NaV1.5; INa) and inwardly rectifying K+ ion channels (Kir-genes; IK1). Concordantly, we observed conduction slowing in these hearts, and reductions in INa and IK1 in cardiomyocytes isolated from these hearts. The reduction in IK1 resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current, If, were observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes. Conclusions: TBX3 partially reprograms terminally differentiated working cardiomyocytes into pacemaker-like cells and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce IK1 density to enable diastolic depolarization, are very promising TBX3 characteristics for biological pacemaker formation strategies.
2011-10-01 | GSE31969 | GEO
Project description:The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its important function, the cellular and molecular composition of the human sinoatrial node is not resolved. Particularly, no cell surface marker to identify and isolate sinoatrial node pacemaker cells has been reported. Here we use single-nuclei/cell RNA sequencing of fetal and human pluripotent stem cell-derived sinoatrial node cells and show that they consist of three subtypes of pacemaker cells, including Core Pacemaker, Sinus Venosus, and Transitional Cells. Our study identifies a host of sinoatrial node pacemaker markers including MYH11, BMP4, and the cell surface antigen CD34. We demonstrate that sorting for CD34+ cells from stem cell differentiation cultures enriches for sinoatrial node cells with a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modelling, drug discovery, cell replacement therapies, as well as the delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.
2024-10-30 | GSE279631 | GEO
Project description:The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its important function, the cellular and molecular composition of the human sinoatrial node is not resolved. Particularly, no cell surface marker to identify and isolate sinoatrial node pacemaker cells has been reported. Here we use single-nuclei/cell RNA sequencing of fetal and human pluripotent stem cell-derived sinoatrial node cells and show that they consist of three subtypes of pacemaker cells, including Core Pacemaker, Sinus Venosus, and Transitional Cells. Our study identifies a host of sinoatrial node pacemaker markers including MYH11, BMP4, and the cell surface antigen CD34. We demonstrate that sorting for CD34+ cells from stem cell differentiation cultures enriches for sinoatrial node cells with a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modelling, drug discovery, cell replacement therapies, as well as the delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.
2024-10-30 | GSE279632 | GEO
Project description:The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its important function, the cellular and molecular composition of the human sinoatrial node is not resolved. Particularly, no cell surface marker to identify and isolate sinoatrial node pacemaker cells has been reported. Here we use single-nuclei/cell RNA sequencing of fetal and human pluripotent stem cell-derived sinoatrial node cells and show that they consist of three subtypes of pacemaker cells, including Core Pacemaker, Sinus Venosus, and Transitional Cells. Our study identifies a host of sinoatrial node pacemaker markers including MYH11, BMP4, and the cell surface antigen CD34. We demonstrate that sorting for CD34+ cells from stem cell differentiation cultures enriches for sinoatrial node cells with a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modelling, drug discovery, cell replacement therapies, as well as the delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.
2024-10-30 | GSE279630 | GEO
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
2015-02-06 | E-GEOD-65658 | biostudies-arrayexpress