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Spatially clustered type I interferon responses at injury borderzones [scRNA-Seq]

ABSTRACT: Sterile inflammation post-myocardial infarction was thought to be driven by myeloid cells, however, we show that borderzone cardiomyocytes are the critical initators of the Type I Interferon response through spatial, single-cell, and single-nuclei transcriptomics.

ORGANISM(S): Mus musculus

PROVIDER: GSE268876 | GEO | 2024/08/06

REPOSITORIES: GEO

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Spatially clustered type I interferon responses at injury borderzones

Project description:Sterile inflammation after myocardial infarction (MI) is classically credited to myeloid cells interacting with dead cell debris in the infarct zone (IZ). Here, we show that borderzone cardiomyocytes are the dominant initiators of a novel type I interferon (IFN) response in the infarct borderzone zone (BZ). Using spatial transcriptomics analysis of mice and humans, we find that MI induces colonies of interferon induced cells (IFNICs) expressing interferon stimulated genes (ISGs) decorating the BZ, where cardiomyocytes experience mechanical stress, nuclear rupture, and escape of chromosomal DNA. Cardiomyocyte-selective deletion of interferon regulatory factor 3 (Irf3) abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils, or endothelial cells; Ccr2-deficient mice; or plasmacytoid dendritic cell-depleted mice did not. IFNs blunted the protective matricellular programs and contractile function of BZ fibroblasts, and increased vulnerability to pathologic remodeling. In mice that died after MI, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival. Together, these results reveal a pathologic BZ niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of Irf3 activation in non-immune cells of the borderzone could limit ischemic cardiomyopathy while avoiding broad immunosuppression.

2024-08-06 | GSE269054 | GEO

Spatially clustered type I interferon responses at injury borderzones.

Project description:Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

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Single-nuclei RNA sequencing analysis of myocardial infarction in WT and PDGFRb EC-specific KO mouse

Project description:To investigate the transcriptome change in myocardial infarction (MI)-associated cells, we prepared single nuclei derived from mouse injured infarcted heart tissues and performed RNA sequencing analysis. Considering that adult cardiomyocytes are limited for 10XGenomics scRNA-seq due to large size not compatible with microfluidic channels, we prepared nuclei from the tissues. Particularly, cardiac nuclei were harvested from PDGFRb fl/fl control or Cdh5-Cre; PDGFRb fl/fl KO mouse.

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Transcriptional characterization of cardiomyocyte nuclei from the infarct border zone [RNA-Seq]

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Epigenetic characterization of cardiomyocyte nuclei from the infarct border zone [Cut & Run]

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Gene expression profile at single cell level of non-myocytic cells of the heart (NCM) from TRPM4 WT and KO mice 24h or 72h after SHAM intervention or LAD ligation

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Human myocardial ischemia/reperfusion injury model to study cardiac stem cells activation and regeneration mechanisms

Project description:The importance of regenerative potential of cardiac stem/progenitor cells (CSCs) after acute myocardial infarction (AMI) has been emphasized in the last decade. Several studies have demonstrated that this cell population has a relevant role in myocardial repair, supported by the establishment of a paracrine cross-talk between CSCs and the injured tissue. However, the majority of current in vitro strategies to study these cells fails to include important modulators of CSC activity, such as the paracrine effect of cardiomyocytes (CMs) and the physicochemical changes occurring in tissue during Ischemia/Reperfusion (I/R) injury. In this work, we established the first human in vitro heterotypic model of myocardial I/R injury with human CSCs (hCSCs) and human induced pluripotent cell-derived cardiomyocytes (hiPSC-CMs) using transwell inserts. hCSCs response to I/R was characterized using advanced whole proteomic mass spectrometry-based tools that allowed us to propose new pathways in hCSCs regenerative process, including: cell cycle regulation inhibition, proliferation through EGF signaling, gluthathione-mediated reactive oxygen species detoxification, and signaling through several paracrine growth factors. The model established in this work contributes with new insights regarding hCSC biology in response to AMI and provides an important tool to study and modulate molecular mechanisms involved in the regenerative potential of CSCs.

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Spatially clustered type I interferon responses at injury borderzones

Project description:Spatially clustered type I interferon responses at injury borderzones

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Ckmt2 for Evaluating Reperfusion Injury in Acute Myocardial Infarction

Project description:Mitochondrial Creatine Kinase 2 (Ckmt2) as a Plasma-Based Biomarker for Evaluating Reperfusion Injury in Acute Myocardial Infarction

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Pitx2 promotes heart repair by transcriptionally activating the antioxidant response after cardiac injury

Project description:Myocardial infarction results in compromised myocardial function with heart failure due to insufficient cardiomyocyte self-renewal. Unlike lower vertebrates, mammalian hearts only have a transient neonatal renewal capacity. Reactivating the primitive reparative ability in the fully mature heart requires an intimate knowledge of the molecular mechanisms promoting early heart repair. Here we identified a novel factor that can sufficiently promote heart muscle repair. By screening an established Hippo-deficient heart regeneration model for renewal promoting factors, we found that PITX2 protein expression in ventricles was induced after cardiomyocyte injury. Moreover, Pitx2-deficient neonatal hearts failed to repair after apex resection. Pitx2-gain-of-function in ventricular cardiomyocytes conferred reparative ability to the adult mouse heart after myocardial infarction. Integrated genomic analyses indicated that Pitx2 activated genes encoding electron transport chain components and reactive oxygen species scavengers. Pitx2 mutant myocardium had elevated reactive oxygen species levels while supplement of antioxidants suppressed the Pitx2-loss-of-function phenotype. Furthermore, PITX2 directly binds NFE2L2 and translocates from cytoplasm to nucleus upon oxidative stress.

2016-05-19 | GSE70413 | GEO

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