Decoding Aging in the Heart via Single Cell Dual Omics of Non-Cardiomyocytes (scATAC-Seq)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE277701 | GEO | 2024/11/01
REPOSITORIES: GEO
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Project description:(scRNA and scATAC) in profiling non-myocytes (non-CMs) from young, middle-aged, and elderly mice. Non-CMs, vital in heart development, physiology, and pathology, are understudied compared to cardiomyocytes. Our analysis revealed aging response heterogeneity and its dynamics over time among non-CM cell types. Immune cells, notably macrophages and neutrophils, showed significant aging alterations, while endothelial cells displayed moderate changes. We identified distinct aging signatures within the cell type, including differential gene expression and transcription factor activity, along with motif variation. Sub-cluster analysis revealed intra-cell type heterogeneity, characterized by diverse aging patterns. The senescence-associated secretory phenotype (SASP) emerged as a key aging-related phenotype. Moreover, aging significantly influenced cell-cell communication, especially impacting a fibroblast sub-cluster with high expression of Erbb4. This study elucidates the complex cellular and molecular landscape of cardiac aging in non-CMs, highlighting their importance in cardiac aging and offering guidance for future potential therapeutic avenues to treat aging-related heart diseases.
2024-11-01 | GSE277700 | GEO
Project description:Hypertrophic cardiomyopathy (HCM) is an important cause leading to heart failure. Preserving cardiac function particularly in cardiomyocytes (CMs) is essential for improving prognosis in HCM patients. Therefore, understanding single-cell transcriptome characteristics of CMs in HCM would be indispensable to investigate potential therapeutic targets. We applied single-cell tagged reverse transcription (STRT-seq) approach and obtained 338 CM transcriptomes. The human heart samples were collected from HCM patients who had extended septal myectomy and healthy donors. Our results revealed that in nonfailing HCM heart CMs could be categorized into three subsets: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of mitochondrial and electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (Cox7B), a subunit of Complex IV in ETC was positively correlated with CMs size. Further, after assessing Cox7B expression in HCM patients, we speculated that Cox7B was compensatory up-regulated at early-stage but down-regulated at end-stage of HCM. To test the hypothesis that Cox7B might play a cardioprotective role in the early-stage of HCM, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7B in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7B would accelerate heart failure progression and Cox7B overexpression could restore partial cardiac function in hypertrophy.
2024-02-07 | GSE227734 | GEO
Project description:Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (Ecs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of ERBB4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC–specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 weeks. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (Ang II) or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis and capillary density. In general, no major differences between EC–specific Erbb4 knockout mice and control littermates were observed. However, 8 weeks following TAC both myocardial hypertrophy and fibrosis were attenuated by EC–specific Erbb4 deletion, albeit these responses were normalized after 20 weeks. Similarly, 4 weeks after Ang II treatment myocardial fibrosis was less pronounced compared to control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatio-temporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.
2020-05-15 | GSE150619 | GEO
Project description:Human pluripotent stem cell-derived cardiomyocytes (CMs) are a promising tool for cardiac cell therapy. To optimize graft cells for cardiac reconstruction, we compared the engraftment efficiency of intramyocardially-injected undifferentiated-induced pluripotent stem cells (iPSCs), day4 mesodermal cells, and day8, day20, and day30 purified iPSC-CMs after initial differentiation by tracing the engraftment ratio (ER) using in vivo bioluminescence imaging. This analysis revealed the ER of day20 CMs was significantly higher compared to other cells. Transplantation of day20 CMs into the infarcted hearts of immunodeficient mice showed significant functional improvement. Moreover, the imaging signal and ratio of Ki67-positive CMs at 3 months post injection indicated engrafted CMs proliferated in the host heart. Although this graft growth reached a plateau at 3 months, histological analysis confirmed progressive maturation from 3 to 6 months. These results suggested that day20 CMs had very high engraftment, proliferation, and therapeutic potential in host mouse hearts. Differentiated cells, N=10 Undifferentiated pluripotent stem cells, N=1 Heart samples, N=6
2016-07-03 | E-GEOD-60634 | biostudies-arrayexpress
Project description:The mammalian heart is composed of a variety types of cells that can be roughly categorized into cardiomyocytes and non-myocytes. Instead of being bystanders of cardiac function, cardiac non-myocytes provide critical structural, mechanical and electrophysiological support to the working myocardium. However, the precise cellular identity and molecular features of the non-myocytes at single cell level remain elusive. Depiction of epigenetic landscape with transcriptomic signatures using the latest single cell multi-omics has the potential to unravel the molecular programs of cardiac non-myocytes underlying their cellular diversity. To characterize the molecular and cellular features of cardiac non-myocytes populations in the adult murine heart at single cell level. We applied single cell Assay for Transposase Aaccessible Chromatin using sequencing (scATAC-seq) in combination with high-throughput single cell RNA-seq (scRNA-seq) to map the epigenetic landscape and gene expression program of cardiac non-myocytes from adult murine heart. Through integrated dual-omics data analysis, we categorize the cardiac non-myocytes into 4 defined populations including endothelial cells, fibroblast, pericytes and immune cells with distinct chromatin accessibility patterns. Cis- and trans-regulatory factors for each cell type were identified. In particular, unbiased sub-clustering and functional annotation of the cardiac fibroblast (FB), indicated the heterogeneity and functionality of FB subtypes associated with cellular response, cytoskeleton organization and immune regulation. We further validated the expression and function of novel markers in major FB sub-populations and experimentally determined the distribution of the FB sub-populations in healthy and injured murine heart. In summary, we comprehensively characterized the non-myocyte cellular identity at the single-cell level and defined FB subpopulations by their functional states.
2021-04-21 | GSE157445 | GEO
Project description:The mammalian heart is composed of a variety types of cells that can be roughly categorized into cardiomyocytes and non-myocytes. Instead of being bystanders of cardiac function, cardiac non-myocytes provide critical structural, mechanical and electrophysiological support to the working myocardium. However, the precise cellular identity and molecular features of the non-myocytes at single cell level remain elusive. Depiction of epigenetic landscape with transcriptomic signatures using the latest single cell multi-omics has the potential to unravel the molecular programs of cardiac non-myocytes underlying their cellular diversity. To characterize the molecular and cellular features of cardiac non-myocytes populations in the adult murine heart at single cell level. We applied single cell Assay for Transposase Aaccessible Chromatin using sequencing (scATAC-seq) in combination with high-throughput single cell RNA-seq (scRNA-seq) to map the epigenetic landscape and gene expression program of cardiac non-myocytes from adult murine heart. Through integrated dual-omics data analysis, we categorize the cardiac non-myocytes into 4 defined populations including endothelial cells, fibroblast, pericytes and immune cells with distinct chromatin accessibility patterns. Cis- and trans-regulatory factors for each cell type were identified. In particular, unbiased sub-clustering and functional annotation of the cardiac fibroblast (FB), indicated the heterogeneity and functionality of FB subtypes associated with cellular response, cytoskeleton organization and immune regulation. We further validated the expression and function of novel markers in major FB sub-populations and experimentally determined the distribution of the FB sub-populations in healthy and injured murine heart. In summary, we comprehensively characterized the non-myocyte cellular identity at the single-cell level and defined FB subpopulations by their functional states.
2021-04-21 | GSE157444 | GEO
Project description:Like all receptor tyrosine kinases (RTKs), ErbB4 signals through a canonical signaling involving phosphorylation cascades. However, ErbB4 can also signal through a non-canonical mechanism whereby the intracellular domain is released into the cytoplasm by regulated intermembrane proteolysis (RIP) and translocates to the nucleus where it regulates transcription. These different signaling mechanisms depend on the generation of alternative spliced isoforms, a RIP cleavable ErbB4-JMa and an uncleavable ErbB4-JMb. Non-canonical signaling by ErbB4-JMa has been implicated in the regulation of brain, heart, mammary gland, lung, and immune cell development. However, most studies on non-canonical ErbB4 signaling have been performed in vitro due to the lack of an adequate mouse model. We created an ErbB4-JMa specific knock out mouse and demonstrate that RIP-dependent, non-canonical signaling by ErbB4-JMa is required for the regulation of GFAP expression during cortical development. We also show that ErbB4-JMa signaling is not required for the development of the heart, mammary glands, sensory ganglia. Furthermore, we identify genes whose expression during cortical development is regulated by ErbB4, and show that the expression of two of them, CRYM and DBi, depend on ErbB4-JMa. Thus, we provide the first animal model to study the roles of non-canonical RTK in vivo.
2022-08-02 | GSE202063 | GEO
Project description:Background: We had shown that cardiomyocytes (CMs) were more efficiently differentiated from human induced pluripotent stem cells (hiPSCs) when the hiPSCs were reprogrammed from cardiac fibroblasts rather than dermal fibroblasts or blood mononuclear cells. Here, we continued to investigate the relationship between somatic-cell lineage and hiPSC-CM production by comparing the yield and functional properties of CMs differentiated from iPSCs reprogrammed from human atrial or ventricular cardiac fibroblasts (AiPSC or ViPSC, respectively). Methods: Atrial and ventricular heart tissues were obtained from the same patient, reprogrammed into AiPSCs or ViPSCs, and then differentiated into CMs (AiPSC-CMs or ViPSC-CMs, respectively) via established protocols. Results: The time-course of expression for pluripotency genes (OCT4, NANOG, and SOX2), the early mesodermal marker Brachyury, the cardiac mesodermal markers MESP1 and Gata4, and the cardiovascular progenitor-cell transcription factor NKX2.5 were broadly similar in AiPSC-CMs and ViPSC-CMs during the differentiation protocol. Flow-cytometry analyses of cardiac troponin T expression also indicated that purity of the two differentiated hiPSC-CM populations (AiPSC-CMs: 88.23±4.69%, ViPSC-CMs: 90.25±4.99%) was equivalent. While the field-potential durations were significantly longer in ViPSC-CMs than in AiPSC-CMs, measurements of action potential duration, beat period, spike amplitude, conduction velocity, and peak calcium-transient amplitude did not differ significantly between the two hiPSC-CM populations. Yet, our cardiac-origin iPSC-CM showed higher ADP and conduction velocity than previously reported iPSC-CM derived from non-cardiac tissues. Transcriptomic data comparing iPSC and iPSC-CMs showed similar gene expression profiles between AiPSC-CMs and ViPSC-CMs with significant differences when compared to iPSC-CM derived from other tissues. This analysis also pointed to several genes involved in electrophysiology processes to be responsible for the physiological differences observed between cardiac and non-cardiac-derived cardiomyocytes. ¬ Conclusions: AiPSC and ViPSC were differentiated into CMs with equal efficiency. Detected differences in electrophysiological properties, calcium handling activity, and transcription profiles between cardiac and non-cardiac derived cardiomyocytes demonstrated that 1) tissue of origin matters to generate a better-featured iPSC-CMs, 2) the sublocation within the cardiac tissue has marginal effects on the differentiation process.
2023-02-03 | GSE221268 | GEO
Project description:Contrary to adult mammals, zebrafish are able to regenerate their heart after cardiac injury. This regenerative response relies, in part, on the endogenous ability of cardiomyocytes (CMs) to dedifferentiate and proliferate to replenish the lost muscle. However, CM heterogeneity and population dynamics during development and regeneration remain poorly understood. Through comparative transcriptomic analyses of the developing and adult zebrafish heart, we identified tnnc2 and tnni4b.3 expression as markers for CMs at early and late developmental stages, respectively. Using newly developed reporter lines for these genes, we investigated their expression dynamics during development and regeneration, and observed interesting expression patterns. tnnc2 reporter lines label most CMs at embryonic stages, and this labeling declines rapidly during larval stages; in adult hearts expression is only detectable in a subset of CMs. Conversely, expression of a tnni4b.3 reporter is initially visible in outer curvature CMs at larval stages, and it is subsequently present in a vast majority of the CMs in adult hearts. Interestingly, we find that the adult CMs labeled by the embryonic reporter display higher levels of Tg(tp1:EGFP) expression, which indicates active Notch signaling. To further characterize this CM population, we performed transcriptomic analysis and found that it expresses genes encoding components of the Notch signaling pathway as well as markers of immature CMs. Moreover, during heart regeneration, proliferating CMs in the injured area activate the embryonic CM reporter. Overall, our findings provide further evidence of cardiomyocyte heterogeneity in the adult zebrafish heart.
2021-05-03 | GSE157662 | GEO
Project description:The heart is a complex organ composed of multiple cell and tissue types. During early developmental stages, heart cells from different regions of the heart exhibit different patterns of gene expression, which are thought to significantly contribute to heart development and morphogenesis. Until recently, the lack of adequate tools prevented our ability to systematically profile gene expression in a cell type and anatomically-specific manner during heart development. Single cell RNA sequencing has emerged as a powerful approach that allows genome-wide analysis of gene expression in single cells. Using microfluidic-chip and droplet-based single-cell RNA sequencing platforms, we analyze cardiac cells during the early stages of heart development. We found, by principle component analysis, that the expression of cell cycle genes represents a major determinant of transcriptional variation in all analyzed cardiac cell types. Interestingly, when single cardiomyocytes (CMs) from different heart chambers were analyzed, we found that atrial ventricular canal derived CMs have reduced cell cycle activity compare with CMs from the left and right ventricular chambers. In addition, CMs in the trabecular myocardium exhibit reduced cell cycle activity than CMs in the compact myocardium. When CMs within the same chamber were segregated by their cell cycle phase, we found that CMs in the G2/M phase downregulate their sarcomeric and cytoskeletal markers. Finally, we revealed the expression of a signaling ligand from the endocardium that may repress trabecular CM proliferation, and an epicardial-derived ligand that can promote compact CM proliferation. Together these data highlight the variations in cell cycle activity to selectively promote cardiac chamber growth during development and the profound transcriptional shift within the same cell at different phases of cell cycle. Identifying alterations in the expression of key signaling molecules that drive CM proliferation may lead to greater understanding of the onset or progression of congenital heart disease.
2019-05-30 | GSE122403 | GEO