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Pharmacogenetics and Drug Discovery for Anthracycline-Induced Cardiotoxicity Enabled by Sinoatrial Node-like Cells Derived from Human Pluripotent Stem Cells [SNP array]

ABSTRACT: The sinoatrial node (SAN) is the primary pacemaker of the heart. The human SAN is poorly understood due to limited primary tissue access and lack of robust in vitro derivation methods. We developed an efficient strategy, using a dual SHOX2:GFP; MYH6:mCherry knock-in reporter line, to generate and purify human pluripotent stem cell-derived SAN cells (hPSC-SAN), displaying molecular and electrophysiological characteristics of bona-fide nodal cells. We modeled cell type specific toxicity upon treatment with doxorubicin (DOXO) using hPSC-SAN generated from a library of induced pluripotent stem cells (iPSCs). We discovered 3 new genetic loci associated with increased sensitivity to DOXO-induced hPSC-SAN death. Genetic variants in these loci were associated with significantly higher early arrhythmia risk in patients receiving DOXO, confirmed by an unbiased PheWAS analysis. Finally, the in vitro DOXO assay enabled an unbiased drug screening platform and identification of physcion as a candidate therapeutic that can partially block DOXO-mediated cardiac toxicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118086 | GEO | 2021/07/01

REPOSITORIES: GEO

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Pharmacogenetics and Drug Discovery for Anthracycline-Induced Cardiotoxicity Enabled by Sinoatrial Node-like Cells Derived from Human Pluripotent Stem Cells [RNA-seq]

Project description:The sinoatrial node (SAN) is the primary pacemaker of the heart. The human SAN is poorly understood due to limited primary tissue access and lack of robust in vitro derivation methods. We developed an efficient strategy, using a dual SHOX2:GFP; MYH6:mCherry knock-in reporter line, to generate and purify human pluripotent stem cell-derived SAN cells (hPSC-SAN), displaying molecular and electrophysiological characteristics of bona-fide nodal cells. We modeled cell type specific toxicity upon treatment with doxorubicin (DOXO) using hPSC-SAN generated from a library of induced pluripotent stem cells (iPSCs). We discovered 3 new genetic loci associated with increased sensitivity to DOXO-induced hPSC-SAN death. Genetic variants in these loci were associated with significantly higher early arrhythmia risk in patients receiving DOXO, confirmed by an unbiased PheWAS analysis. Finally, the in vitro DOXO assay enabled an unbiased drug screening platform and identification of physcion as a candidate therapeutic that can partially block DOXO-mediated cardiac toxicity.

2021-07-01 | GSE118085 | GEO

Cell-surface proteomics identifies differences in signalling and adhesion protein expression between naive and primed human pluripotent stem cells

Project description:Naive and primed human pluripotent stem cells (hPSC) provide valuable models to study cellular and molecular developmental processes. The lack of detailed information about cell-surface protein expression in these two pluripotent cell types prevents an understanding of how the cells communicate and interact with their microenvironments. Here, we used plasma membrane profiling to directly measure cell-surface protein expression in naive and primed hPSC. This unbiased approach quantified over 1700 plasma membrane proteins including those involved in cell adhesion, signalling and cell interactions. Notably, multiple cytokine receptors upstream of JAK-STAT signalling were more abundant in naive hPSC. In addition, functional experiments showed that FOLR1 and SUSD2 proteins are highly expressed at the cell surface in naive hPSC but are not required to establish human naive pluripotency. This study provides a comprehensive stem cell proteomic resource that uncovers differences in signalling pathway activity and has identified new markers to define human pluripotent states.

2020-04-17 | PXD015359 | Pride

A safety screening platform for individualized cardiotoxicity assessment

Project description:Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin (DOXO), Aclarubicin (ACLA) and Amrubicin (AMR). DOXO and ACLA unlike AMR substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated with anthracyclines annually.

2023-10-01 | GSE232331 | GEO

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

2015-02-06 | E-GEOD-65658 | biostudies-arrayexpress

Mouse sinoatrial node transcriptome

2015-02-06 | GSE65658 | GEO

Comparative iTRAQ analysis of proteomic expression in human sinoatrial node and working cardiomyocytes

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.

2018-03-05 | PXD004109 | Pride

Nicotinamide Mononucleotide administration prevents doxorubicin-induced cardiotoxicity and loss in physical activity in mice.

Project description:In this study we investigated whether nicotinamide mononucleotide (NMN) could protect against Doxorubicin-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic. In the acute study, C57BL6/J (B6) mice were injected intraperitoneally (i.p.) once with Doxo (20 mg/kg) and NMN (180 mg/kg/day, i.p.) was administered daily for five days before and after the Doxo injection. In the chronic study, B6 mice received a cumulative dose of 20 mg/kg Doxo administered in fractionated doses for five days. NMN (500 mg/kg/day) was supplied in the mice’s drinking water beginning five days before the first injection of Doxo and continuing for 60 days after.

2023-01-11 | GSE221003 | GEO

Unbiased Proteomics Benchmarking of Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes

Project description:Rationale: Human pluripotent stem cells-derived cardiomyocytes (hPSC-CMs) exhibit the properties of fetal CMs, which limit their applications. Various methods have been used to promote maturation of hPSC-CMs; however, there is a lack of an unbiased and comprehensive method for accurate benchmarking of hPSC-CM maturation. Objective: We aim to develop an unbiased proteomics method integrating high-throughput top-down targeted proteomics and bottom-up global proteomics for accurate and comprehensive assessment of hPSC-CM maturation. Methods and Results: Utilizing hPSC-CMs from early- and late-stage two-dimensional monolayer culture and three-dimensional engineered cardiac tissue, we demonstrated high reproducibility and reliability of the top-down proteomics method, which enabled simultaneous quantification of contractile protein isoform expressions and their PTMs. This method allowed for the detection of known maturation-associated contractile protein alterations, and for the first time, identified contractile protein PTMs as promising new markers of maturation. By employing a global proteomics strategy, we identified candidate maturation markers important for sarcomere organization, cardiac excitability, and Ca2+ homeostasis; and validated these markers in the developing mouse cardiac ventricles. Conclusions: We established an unbiased proteomics method that can provide accurate and specific benchmarking of hPSC-CM maturation, and identified new markers of maturation. Furthermore, this integrated proteomics strategy laid a strong foundation for uncovering molecular basis underlying cardiac development and disease using hPSC-CMs.

| MSV000082985 | MassIVE

Transcriptome profile of the zebrafish sinoatrial ring

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

Epigenetic Profiling of Cardiac Pacemaker Cells Reveals a Conserved Isl1 Enhancer That Regulates Sinoatrial Node Development and Function

Project description:Cardiac pacemaker cells (PCs) in the sinoatrial node (SAN) have a distinct gene expression program that allows them to fire automatically and initiate the heartbeat. Although critical SAN transcription factors, including Isl1, have been identified, the cis-regulatory architecture that governs PC-specific gene expression is not understood, and discrete enhancers required for gene regulation in the SAN have not been identified. We used ATAC-Seq on sorted neonatal mouse SAN to define regions of open chromatin in PCs and neighboring right atrial cardiomyocytes. PC-specific ATAC-seq peaks were located near established SAN genes and were enriched for distinct sets of transcription factor binding sites. In-vivo testing of a novel ATAC-seq peak at the Isl1 locus defined a regulatory element that was active specifically in the cardiac inflow at E8.5 and throughout later SAN development and maturation. Deletion of the enhancer uncovered a role for this cis-regulatory element in SAN development and function. The mouse SAN enhancer also directed reporter activity to the inflow tract in developing zebrafish hearts, demonstrating deep conservation of its upstream regulatory network. Finally, single nucleotide polymorphisms in the human genome that occur near the region syntenic to the mouse enhancer exhibit significant associations with resting heart rate in human populations.

2020-10-12 | GSE148515 | GEO

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