A subset of temporary resident cardiac macrophages induced by myocardial infarction limits adverse ventricular remodeling [scRNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE216211 | GEO | 2023/10/20
REPOSITORIES: GEO
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Project description:We provided an mRNA-seq analysis of mouse macrophage heterogeneity in the heart after MI.
2023-10-20 | GSE230811 | GEO
Project description:We provided an analysis of mouse macrophage heterogeneity in the heart after MI using spatial transcriptome sequencing.
2023-10-20 | GSE219116 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-10-20 | GSE219117 | GEO
Project description:Despite substantial declines in mortality following myocardial infarction (MI), subsequent left ventricular remodelling (LVRm) remains a significant long-term complication. Extracellular small non-coding RNAs (exRNAs) have been associated with cardiac inflammation and fibrosis and we hypothesized that they are associated with post-MI LVRm phenotypes. RNA sequencing of exRNAs was performed on plasma samples from patients with “beneficial” (decrease LVESVI ≥20%, n=11) and “adverse” (increase LVESVI ≥15%, n=11) LVRm. Selected differentially expressed exRNAs were validated by RT-qPCR (n=331) and analyzed for their association with LVRm determined by cardiac MRI. Principal components of exRNAs were associated with LVRm phenotypes post-MI; specifically, LV mass, LV ejection fraction, LV end systolic volume index, and fibrosis. We then investigated the temporal regulation and cellular origin of exRNAs in murine and cell models and found that: 1) plasma and tissue miRNA expression was temporally regulated; 2) the majority of the miRNAs were increased acutely in tissue and at sub-acute or chronic time-points in plasma; 3) miRNA expression was cell-specific; and 4) cardiomyocytes release a subset of the identified miRNAs packaged in exosomes into culture media in response to hypoxia/reoxygenation. In conclusion, we find that plasma exRNAs are temporally regulated and are associated with measures of post-MI LVRm.
2019-04-01 | GSE112690 | GEO
Project description:Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4+LYVE1+MHC-IIloCCR2- resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4-LYVE1-MHC-IIhiCCR2- macrophages and fully replaced TIMD4-LYVE1-MHC-IIhiCCR2+ macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4+ and TIMD4- resident macrophage abundance, whereas CCR2+ monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.
| S-EPMC6565365 | biostudies-literature
Project description:Mononuclear phagocytes promote injury and repair following myocardial infarction but discriminating functions within mixed populations remains challenging. We utilized fate mapping and single cell RNA-sequencing to delineate fate specification trajectories of heterogeneous cardiac macrophage subpopulations. In steady state, TIMD4 expression tracked with a dominant resident cardiac macrophage subset that persisted via in situ self-renewal with minimal monocyte input. Following ischemic injury, monocytes displayed significant plasticity, ultimately adopting transcriptional states similar to resident macrophages, but also multiple unique states. Ischemic injury reduced resident macrophage abundance within infarct tissue, and despite transcriptional similarity, TIMD4 expression distinguished resident from recruited macrophages. Specific lineage-based depletion of resident cardiac macrophages resulted in depressed cardiac function and adverse remodeling primarily within the peri-infarct zone, the only region of the myocardium where resident macrophages expanded numerically following injury. Together, these data highlight a non-redundant, cardioprotective role of resident cardiac macrophages, and the diverse transcriptional fates recruited monocytes can adopt.
2018-12-15 | GSE119355 | GEO
Project description:Background. Accumulation of extracellular matrix in the myocardium attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Connective tissue growth factor (CTGF) is a matricellular protein that has been shown to promote development of cardiac fibrosis. Objectives. To investigate for the potential of CTGF monoclonal antibody (CTGF mAb) in protecting from development of cardiac fibrosis following myocardial infarction (MI), and to evaluate its effect during infarct repair and acute cardiac ischemia-reperfusion (I/R) injury. Methods. Mice were subjected to MI or to I/R injury and treated with either control IgG or CTGF mAb. Cultured human cardiac fibroblasts were used to investigate the signalling mechanisms modulated by CTGF mAb. Results. Treatment with CTGF mAb for four days from day three after MI improved survival, attenuated infarct expansion, and resulted in better preserved left ventricular (LV) systolic function. CTGF mAb therapy for six weeks from day seven after MI reduced the MI-induced increase in cardiomyocyte size, heart weight to body weight ratio and remote LV fibrosis. RNA sequencing analysis of LV samples showed that CTGF mAb induced expression of cardiac repair/developmental genes and normalized the MI-induced increase in expression of inflammatory/profibrotic genes. CTGF mAb induced c-Jun N-terminal kinase (JNK) phosphorylation in vivo and in vitro, and inhibition of JNK abrogated the reduced collagen production in CTGF mAb treated fibroblasts. Conclusions. Treatment with CTGF mAb induces expression of cardiac repair/developmental genes and inhibits expression of inflammatory/pro-fibrotic genes in MI hearts providing benefit during post-MI cardiac repair and reducing post-MI cardiac fibrosis.
2019-04-02 | GSE129134 | GEO
Project description:Microvascular malperfusion after myocardial infarction leads to infarct expansion, adverse remodeling, and functional impairment. Native reparative mechanisms exist but are inadequate to vascularize ischemic myocardium. We hypothesized that a 3-dimensional human fibroblast culture (3DFC) functions as a sustained source of angiogenic cytokines, thereby augmenting native angiogenesis and limiting adverse effects of myocardial ischemia.Lewis rats underwent ligation of the left anterior descending coronary artery to induce heart failure; experimental animals received a 3DFC scaffold to the ischemic region. Border-zone tissue was analyzed for the presence of human fibroblast surface protein, vascular endothelial growth factor, and hepatocyte growth factor. Cardiac function was assessed with echocardiography and pressure-volume conductance. Hearts underwent immunohistochemical analysis of angiogenesis by co-localization of platelet endothelial cell adhesion molecule and alpha smooth muscle actin and by digital analysis of ventricular geometry. Microvascular angiography was performed with fluorescein-labeled lectin to assess perfusion.Immunoblotting confirmed the presence of human fibroblast surface protein in rats receiving 3DFC, indicating survival of transplanted cells. Increased expression of vascular endothelial growth factor and hepatocyte growth factor in experimental rats confirmed elution by the 3DFC. Microvasculature expressing platelet endothelial cell adhesion molecule/alpha smooth muscle actin was increased in infarct and border-zone regions of rats receiving 3DFC. Microvascular perfusion was also improved in infarct and border-zone regions in these rats. Rats receiving 3DFC had increased wall thickness, smaller infarct area, and smaller infarct fraction. Echocardiography and pressure-volume measurements showed that cardiac function was preserved in these rats.Application of a bioengineered 3DFC augments native angiogenesis through delivery of angiogenic cytokines to ischemic myocardium. This yields improved microvascular perfusion, limits infarct progression and adverse remodeling, and improves ventricular function.
| S-EPMC4175745 | biostudies-literature
Project description:An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) contributes to the left ventricle (LV) remodeling that occurs after myocardial infarction (MI). However, translation of these observations into a clinically relevant, therapeutic strategy remains to be established. The present study investigated targeted TIMP augmentation through regional injection of a degradable hyaluronic acid hydrogel containing recombinant TIMP-3 (rTIMP-3) in a large animal model. MI was induced in pigs by coronary ligation. Animals were then randomized to receive targeted hydrogel/rTIMP-3, hydrogel alone, or saline injection and followed for 14 days. Instrumented pigs with no MI induction served as referent controls. Multimodal imaging (fluoroscopy/echocardiography/magnetic resonance imaging) revealed that LV ejection fraction was improved, LV dilation was reduced, and MI expansion was attenuated in the animals treated with rTIMP-3 compared to all other controls. A marked reduction in proinflammatory cytokines and increased smooth muscle actin content indicative of myofibroblast proliferation occurred in the MI region with hydrogel/rTIMP-3 injections. These results provide the first proof of concept that regional sustained delivery of an MMP inhibitor can effectively interrupt adverse post-MI remodeling.
| S-EPMC4365799 | biostudies-literature
Project description:Objective:To assess the dynamics of serum levels of soluble isoform of suppression of tumorigenicity 2 (sST2) and N-terminal pro-brain natriuretic peptide (NT-proBNP) and their correlations with the development of adverse left ventricular remodeling (LVR) through 6?months in patients with primary myocardial infarction with ST-segment elevation (STEMI). Methods:Subjects were 31 patients with STEMI (median age: 58?years), who underwent percutaneous coronary intervention (PCI) during the first 24?hours of the onset of myocardial infarction (MI). Blood samples and parameters of echocardiography were assessed at days 1, 3, 7, and 14 and 6?months after STEMI. Results:Serum levels of sST2 and NT-proBNP decreased during the 6-month period. Levels of sST2 decreased by 48% from admission to day 7, and levels of NT-proBNP decreased by 40% from day 7 to 6?months after STEMI. Serum levels of sST2 at day 1 (r?=?0.5, P?<?.05) and day 3 (r?=?0.4, P?<?.05) were associated with adverse LVR by 6?months after STEMI. Logistic regression analysis showed that a high concentration of sST2 at day 7 increased the risk of adverse LVR (95% confidence interval [CI], 0.5-0.9; areas under curve [AUC]?=?0.8; P?=?.002), with 92% sensitivity and 70% specificity. A multivariate analysis model revealed that adverse LVR was associated with the level of sST2 (P?=?.003) and with complete revascularization (P?=?.01) at the admission. Conclusions:The dynamics of serum levels of sST2 and NT-proBNP were different. The level of sST2 normalized by the 7th day; NT-proBNP decreased only by the end of the 6-month period after MI. Increased serum levels of sST2 by the 7th day of MI were associated with the development of adverse LVR by the end of the 6-month period.
| S-EPMC6487275 | biostudies-literature