Adult T-cells impair neonatal cardiac regeneration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE163277 | GEO | 2023/01/03
REPOSITORIES: GEO
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Project description:Heart failure (HF) is a leading cause of morbidity and mortality. As adult cardiomyocytes (CMs) have little regenerative capacity, after myocardial infarction (MI), resident cardiac fibroblasts (CFs) synthesize extracellular matrix to form scar tissues, resulting in myocardial remodeling and HF. Thus, both cardiac regeneration and fibrosis are therapeutic targets for chronic MI. We previously reported that fibroblasts were directly reprogrammed into induced CMs (iCMs) by overexpression of cardiogenic transcription factors in acute and chronic MI. Here we show that in vivo cardiac reprogramming improved cardiac function, and reversed cardiac remodeling in chronic MI using a novel transgenic mouse system. Transcriptome analysis revealed that in vivo cardiac reprogramming suppressed signs of fibrosis and inflammation. Thus, in vivo cardiac reprogramming may be a promising approach for chronic HF.
2024-07-01 | GSE240310 | GEO
Project description:Heart failure (HF) is a leading cause of morbidity and mortality. As adult cardiomyocytes (CMs) have little regenerative capacity, after myocardial infarction (MI), resident cardiac fibroblasts (CFs) synthesize extracellular matrix to form scar tissues, resulting in myocardial remodeling and HF. Thus, both cardiac regeneration and fibrosis are therapeutic targets for chronic MI. We previously reported that fibroblasts were directly reprogrammed into induced CMs (iCMs) by overexpression of cardiogenic transcription factors in vitro and in vivo in acute MI. Here we show that in vivo cardiac reprogramming generated iCMs from resident CFs, improved cardiac function, and reversed fibrosis in chronic MI using a novel transgenic mouse system. Transcriptome analysis revealed that in vivo cardiac reprogramming altered the interstitial cell landscape, suppressed signs of fibrosis and inflammation, and activated the angiogenic program. Thus, in vivo cardiac reprogramming may be a promising approach for chronic HF.
2022-12-12 | GSE183932 | GEO
Project description:Heart failure (HF) is a leading cause of morbidity and mortality. As adult cardiomyocytes (CMs) have little regenerative capacity, after myocardial infarction (MI), resident cardiac fibroblasts (CFs) synthesize extracellular matrix to form scar tissues, resulting in myocardial remodeling and HF. Thus, both cardiac regeneration and fibrosis are therapeutic targets for chronic MI. We previously reported that fibroblasts were directly reprogrammed into induced CMs (iCMs) by overexpression of cardiogenic transcription factors in vitro and in vivo in acute MI. Here we show that in vivo cardiac reprogramming generated iCMs from resident CFs, improved cardiac function, and reversed fibrosis in chronic MI using a novel transgenic mouse system. Single-cell transcriptome analysis revealed that cardiac reprogramming shifted matrix-producing CFs, matrifibrocytes, to a quiescent state and changed the interstitial cell landscape, suppressing fibrotic and inflammatory signatures and activating angiogenic program. Thus, in vivo cardiac reprogramming may be a promising approach for chronic HF.
2022-12-12 | GSE185265 | GEO
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. 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
2014-01-31 | E-GEOD-54530 | biostudies-arrayexpress
Project description:Background: The adult mammalian heart has limited ability to repair itself following injury. Zebrafish, newts and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown if hearts of young large mammals can regenerate. Methods: We examined the regenerative capacity of the pig heart in neonatal animals (ages: 2, 3 or 14 days postnatal) after myocardial infarction (MI) or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry and Western blotting were performed to study cell proliferation, sarcomere dynamics and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. Results: After MI, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls and did not recover function. Genome wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day old animals that was absent in 2-day old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the MI showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. Conclusions: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.
2018-09-12 | GSE115665 | GEO
Project description:Modulation of the heart's immune microenvironment is crucial for recovery after ischemic events such as myocardial infarction (MI). Endothelial cells (ECs) can have immune regulatory functions; however, interactions between ECs and the immune environment in the heart after MI remain poorly understood. We identified an EC-specific IFN responsive and immune regulatory gene signature in adult and pediatric heart failure (HF) tissues. Single-cell transcriptomic analysis of murine hearts subjected to MI uncovered an EC population (IFN-ECs) with immunologic gene signatures similar to those in human HF. IFN-ECs were enriched in regenerative-stage mouse hearts and expressed genes encoding immune responsive transcription factors (Irf7,Batf2, andStat1). Single-cell chromatin accessibility studies revealed an enrichment of these TF motifs at IFN-EC signature genes. Expression of immune regulatory ligand genes by IFN-ECs suggests bidirectional signaling between IFN-ECs and macrophages in regenerative-stage hearts. Our data suggest that ECs may adopt immune regulatory signatures after cardiac injury to accompany the reparative response. The presence of these signatures in human HF and murine MI models suggests a potential role for EC-mediated immune regulation in responding to stress induced by acute injury in MI and chronic adverse remodeling in HF.
2024-01-23 | GSE253984 | GEO
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
Project description:Fibrotic scarring drives the progression of heart failure after myocardial infarction (MI). Therefore, the development of specific treatment regimens to counteract fibrosis is of high clinical relevance. The transcription factor SOX9 functions as an important regulator during embryogenesis, but recent data point towards an additional causal role in organ fibrosis. We show here that SOX9 is upregulated in the scar after MI in mice. Fibroblast specific deletion of Sox9 ameliorated MI-induced left ventricular dysfunction, dilatation and myocardial scarring in vivo. Unexpectedly, deletion of Sox9 also potently eliminated persisting leukocyte infiltration of the scar in the chronic phase after MI. RNA-sequencing from the infarct scar revealed that Sox9 deletion in fibroblasts resulted in strongly downregulated expression of genes related to extracellular matrix, proteolysis and inflammation. Importantly, Sox9 deletion in isolated cardiac fibroblasts in vitro similarly affected gene expression as in the cardiac scar and prevented their activation and myofibroblast differentiation. Together, our data demonstrate that fibroblast SOX9 functions as a master regulator of cardiac fibrosis and inflammation and might constitute a novel therapeutic target during MI.
2019-07-25 | GSE132265 | GEO
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
Project description:Myocardial infarction models developed to understand fibrosis and promote myocardial regeneration towards ischemic heart disease (IHD) is challenged due to the low-throughput nature of in vivo models and the lack of humanized cardiac scarring in the in vitro models. We generated a novel 4D cardiac scarring model (4DCSM) mimicking the IHD in vitro based on the human engineered heart tissue(hEHT). To identify potential signaling dominating the fibrotic process, we characterized transcriptomics of 4DCSM at different scarring stages by bulk RNA sequencing. Taken together, our dataset is an informative resource to reveal the potential signaling dominating the fibrotic process and provides potential comparisons with public clinical data cohorts or other MI fibrosis model data.
2023-06-14 | GSE234715 | GEO