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Comparison of gene expression in cardiac macrophages from P1 or P14 mice 3 days following MI

ABSTRACT: Myocardial infarction (MI) leads to cardiomyocyte death, which triggers an immune response that clears debris and restores tissue integrity. In the adult heart, the immune system facilitates scar formation, which repairs the damaged myocardium but compromises cardiac function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is lost by P7. The signals that govern neonatal heart regeneration are unknown. By comparing the immune response to MI in mice at P1 and P14, we identified differences in the magnitude and kinetics of monocyte and macrophage responses to injury. Using a cell-depletion model, we determined that heart regeneration and neoangiogenesis following MI depends on neonatal macrophages. Neonates depleted of macrophages were unable to regenerate myocardia and formed fibrotic scars, resulting in reduced cardiac function and angiogenesis. Immunophenotyping and gene expression profiling of cardiac macrophages from regenerating and nonregenerating hearts indicated that regenerative macrophages have a unique polarization phenotype and secrete numerous soluble factors that may facilitate the formation of new myocardium. Our findings suggest that macrophages provide necessary signals to drive angiogenesis and regeneration of the neonatal mouse heart. Modulating inflammation may provide a key therapeutic strategy to support heart regeneration. Total RNA was isolated from CD11b+Ly6G- cells sorted from hearts 3 days following ligation of LAD. 6 samples total: Triplicates of cells from P1 mice and from P14 mice

ORGANISM(S): Mus musculus

SUBMITTER: Arin Aurora

PROVIDER: E-GEOD-54530 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Comparison of gene expression in cardiac macrophages from P1 or P14 mice 3 days following MI

Project description:Myocardial infarction (MI) leads to cardiomyocyte death, which triggers an immune response that clears debris and restores tissue integrity. In the adult heart, the immune system facilitates scar formation, which repairs the damaged myocardium but compromises cardiac function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is lost by P7. The signals that govern neonatal heart regeneration are unknown. By comparing the immune response to MI in mice at P1 and P14, we identified differences in the magnitude and kinetics of monocyte and macrophage responses to injury. Using a cell-depletion model, we determined that heart regeneration and neoangiogenesis following MI depends on neonatal macrophages. Neonates depleted of macrophages were unable to regenerate myocardia and formed fibrotic scars, resulting in reduced cardiac function and angiogenesis. Immunophenotyping and gene expression profiling of cardiac macrophages from regenerating and nonregenerating hearts indicated that regenerative macrophages have a unique polarization phenotype and secrete numerous soluble factors that may facilitate the formation of new myocardium. Our findings suggest that macrophages provide necessary signals to drive angiogenesis and regeneration of the neonatal mouse heart. Modulating inflammation may provide a key therapeutic strategy to support heart regeneration.

2014-01-31 | GSE54530 | GEO

Genome-wide analysis of gene expression changes in miR-214 KO mouse hearts and skeletal muscle

Project description:Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abrupt increases in intracellular Ca2+ during myocardial reperfusion cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Cardiac IR is accompanied by dynamic changes in expression of microRNAs (miRNAs), which inhibit specific mRNA targets. miR-214 is up-regulated during ischemic injury and heart failure in mice and humans, but its potential role in these processes is unknown. We show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury. The microarray contains 6 samples, each containing cDNA pooled from 3 mice per group. There are no replicates. The array was designed to make 3 different pairwise comparisons between the following: P14 WT and miR-214 KO hearts; adult WT and miR-214 KO skeletal muscle; adult WT and miR-214 KO hearts

2012-01-31 | E-GEOD-35421 | biostudies-arrayexpress

Functionally conserved non-coding regulators of cardiomyocyte proliferation and regeneration in mouse and human

Project description:The adult mammalian heart has little regenerative capacity after myocardial infarction (MI) while neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI. Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and non-coding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two thirds of each of the mRNAs, lncRNAs and microRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these microRNAs, miR-144-3p, miR-195a-5p, miR-451a and miR-6240 showed evidence of functional conservation in human cardiomyocytes. The sets of mRNAs, miRNAs and lncRNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.

2018-02-02 | E-MTAB-6272 | biostudies-arrayexpress

Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair

Project description:The adult mammalian heart heals after myocardial infarction (MI) by deposition of scar tissue, leading to downstream arrhythmia, remodelling and heart failure1. In contrast, adult zebrafish and neonatal mouse hearts are capable of regenerating after injury. Macrophages are key mediators of tissue repair and appear to be required for both regeneration and healing by scar formation, but the mechanisms underlying these distinct roles are poorly understood2-4. Here we investigated how macrophages differentially influence the mode of repair by determining their responses in scar-free versus scar-induced healing, comparing ventricular resection with cryo-injured adult zebrafish hearts and neonatal versus adult mouse hearts after MI. Unbiased transcriptomics revealed molecular programmes implicating macrophages in the initiation and resolution of inflammation to dictate the kinetics of scarring during zebrafish regeneration and the activation of direct and indirect pathways to drive fibrosis in the adult mouse heart. Most notably we observed up-regulation of collagen isoforms in both zebrafish and mouse macrophages following injury. Adoptive transfer of macrophages, from resected zebrafish hearts into cryo-injured hosts and splenic monocyte-derived macrophages from adult mouse donors into neonatal hearts, enhanced scar formation and induced fibrosis, respectively, via cell autonomous production of collagen. In zebrafish, macrophage-specific targeting of collagen 4a binding protein and cognate collagen 4a1 followed by transfer led to significantly reduced scarring in cryo-injured hosts, as further evidence of a direct macrophage contribution to collagen deposition and scar formation. These findings contrast with the current model of scarring, whereby collagen is laid down exclusively by myofibroblasts, and implicate macrophages as critical regulators of heart repair.

2019-12-18 | GSE126772 | GEO

Epigenome profiling of neonatal heart regeneration

Project description:Background: The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and non-regenerative mouse hearts over a 7-day time period following myocardial infarction. Methods: RNA-Seq, H3K27ac ChIP-Seq and H3K27me3 ChIP-Seq were performed on ventricular samples from regenerative P1 or non-regenerative P8 mouse hearts at +1.5d, +3d and +7d after MI or Sham surgery to assemble the transcriptome, active chromatin and repressed chromatin landscapes during neonatal heart regeneration. Dynamic enhancer landscapes from mouse hearts during cardiac development were analyzed using data from ENCODE. Effects on cardiomyocyte proliferation and cardiac function from selected factors identified in this study were tested using BrdU/EdU pulse-labeling or mouse models coupled with immunohistochemistry and echocardiography. Results: By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and an embryonic cardiogenic gene program that remains active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Conclusions: Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that might be modulated to promote heart regeneration.

2019-07-15 | GSE123867 | GEO

Transcriptome profiling of neonatal heart regeneration

2019-07-15 | GSE123863 | GEO

Transcriptional re-programming of primary human macrophages by IRF-3 and IRF-7

Project description:This SuperSeries is composed of the following subset Series: GSE11926: Transcriptional profiles of Ad-F3 and Ad-F7 transduced macrophages. GSE12002: Transcriptional profiles of Ad-F7 transduced macrophages in the presence of neutralizing antibody for the type I interferon receptor (IFNAR2) or control isotype (IgG). Refer to individual Series

2008-11-29 | E-GEOD-12120 | biostudies-arrayexpress

Evaluating the effects of cardiac telomerase re-activation after myocardial infarction in adult mice

Project description:Coronary heart disease is a main cause of death in the developed world and treatment success remains modest with high mortality rates within one year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases including heart disease. Here, we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific Tert expression in a mouse model of MI. We find that upon MI, hearts expressing Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared to controls. Furthermore, Tert treatment results in elongated telomeres, increased numbers of Ki67 and pH3-positive cardiomyocytes and a gene expression switch towards a regeneration signature of neonatal mice. Our work highlights telomerase activation as a novel therapeutic strategy to prevent heart failure after MI.

2014-12-15 | GSE62973 | GEO

Transcriptional response to intracellular DNA in cells lacking AIM2-like receptors

Project description:Analysis of ALR-deficient cells indicates that ALRs are not required for the IFN response to intracellular DNA. To explore whether AIM2-like receptors activated another innate signaling pathway upon DNA detection, we performed microarray analysis comparing ALR+/+, ALR-/-, and AIM2-/- macrophages and fibroblasts 4 or 8 hours after transfection with calf-thymus DNA. Total RNA was isolated from ALR+/+, ALR-/-, and AIM2-/- bone marrow-derived macrophages (BMMs) or fibroblasts (MEFs) mock-treated (lipofectamine alone) or transfected with 5ug CT-DNA for 4 or 8 hours.

2016-05-31 | E-GEOD-80766 | biostudies-arrayexpress

Cardiac conduction system regeneration prevents arrhythmias after myocardial infarction

Project description:Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. The cardiac conduction system is implicated in arrhythmias, but how it is altered following MI is poorly understood. We demonstrate complete conduction system restoration during neonatal mouse heart regeneration, versus pathological remodelling at non-regenerative stages. Tissue-cleared whole-organ imaging identified disorganised bundling of conduction fibres after MI, global His/Purkinje disruption and regional loss of connexin-40. Single-cell RNA-sequencing revealed that Purkinje cells undergo specific molecular changes to regenerate the network, versus sustained aberrant electrical alterations during fibrotic repair. This manifested functionally as transition from normal rhythm to pathological conduction delay beyond the regenerative window. Modelling the non-regenerative phenotype in the infarcted human heart implicated these changes as causative for bundle branch block and ventricular dyssynchrony, as observed in patients. These findings elucidate the mechanisms underpinning conduction system regeneration versus repair and reveal the consequences of MI-induced damage for clinical arrhythmogenesis.

2024-10-31 | GSE245872 | GEO

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