Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA390616 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5687233_1.fastq.gz | Fastqsanger.gz | |||
| SRR5687233_2.fastq.gz | Fastqsanger.gz | |||
| SRR5687234_1.fastq.gz | Fastqsanger.gz | |||
| SRR5687234_2.fastq.gz | Fastqsanger.gz |
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Project description:Background—Mesenchymal stem cells (MSCs) have shown therapeutic potency for treating cardiovascular diseases, but their therapeutic efficacy shows significant heterogeneity depending on their tissue of origin. We herein sought to identify the optimal source of MSCs for cardiovascular disease therapy. Methods—Heart- and bone marrow (BM)-derived GFP+ cells positive for the MSCs marker, Nestin, were flow cytometrically sorted from 7-day-postnatal Nestin-GFP transgenic mice. To study their biological characteristics in vitro, we characterized their self-renewal capacity, multi-lineage differentiation ability, and surface markers. To investigate their therapeutic potential in vivo, we intramyocardially injected Nestin+ cells (3×105) into the infarct border zone of mice subjected to acute myocardial infarction (MI), and performed echocardiography and Masson’s-Trichrome staining at 1 and 3 weeks post-MI. We characterized gene profiles with RNA-sequencing analysis, and analyzed the putative reparative mechanism, that of Periostin-mediated M2 macrophages polarization, by immunofluorescence staining, qPCR, ELISA, and flow cytometry in vivo and in vitro. Results—In vitro, the heart- and BM-derived Nestin+ cells (Nes+cMSCs and Nes+bmMSCs, respectively) were found to possess self-renewal ability, show similar tri-lineage differentiation potentials, and express some MSCs-related surface markers. Importantly, Nes+cMSCs significantly improved cardiac function, attenuated left ventricular (LV) remodeling, and decreased infarct size in the mouse MI model, compared with Nes+bmMSCs- or saline-treated MI controls. Nes+cMSC treatment notably reduced the total number of CD68+ pan-macrophages while inducing the polarization of macrophages toward an anti-inflammatory M2 phenotype in ischemic myocardium, compared with the saline-treated MI control. Periostin, which was highly expressed in Nes+cMSCs, could promote the polarization of M2-subtype macrophages in vitro and in vivo. Finally, Periostin knockdown remarkably reduced the therapeutic effects of Nes+cMSCs, inhibiting the survival and LV remodeling of MI model mice and significantly decreasing the number of M2 macrophages at lesion sites. Conclusions—Nestin+ cMSCs have greater efficacy than Nestin+ bmMSCs for cardiac repair following acute MI, using a reparative mechanism that acts at least partly through Periostin-mediated M2 macrophage polarization.
2020-12-31 | GSE100064 | GEO
Project description:Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial pro-inflammatory response followed by an anti-inflammatory or reparative response post-MI is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and essential for cardiac repair as they can adopt both pro-inflammatory (M1) or anti-inflammatory/reparative (M2) phenotypes to modulate inflammatory and reparative response, respectively. YAP and TAZ are the key mediators of the Hippo signaling pathway and essential for cardiac regeneration and repair. However, their role in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing M1 or M2 polarization. Genetic deletion of YAP/TAZ leads to impaired M1 polarization and enhanced M2 polarization. Consistently, YAP activation/overexpression enhanced M1 and impaired M2 polarization. We show that YAP/TAZ promote M1 polarization by increasing IL6 expression, and impede M2 polarization by decreasing Arg1 expression through interaction with the HDAC3-NCoR1 repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, and hypertrophy and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro- and anti-inflammatory responses post-MI.
2020-10-02 | GSE158889 | GEO
Project description:Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell-type in terms of their origins and functional effects in vivo. Methods: Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen inducible Cre for cellular lineage tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Results: Lineage tracing with 4 additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after myocardial infarction. Periostin-traced myofibroblasts also revert back to a less activated state upon injury resolution. Conclusions: Our results define the myofibroblast as a periostin-expressing cell-type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts. Fluidigm C1 whole genome transcriptome analysis of lineage mapped cardiac myofibroblasts
2016-06-14 | E-GEOD-83337 | biostudies-arrayexpress
Project description:Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell-type in terms of their origins and functional effects in vivo. Methods: Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen inducible Cre for cellular lineage tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Results: Lineage tracing with 4 additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after myocardial infarction. Periostin-traced myofibroblasts also revert back to a less activated state upon injury resolution. Conclusions: Our results define the myofibroblast as a periostin-expressing cell-type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts.
2016-06-14 | GSE83337 | GEO
Project description:infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin 4 (TMSB4) and Prothymosin (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
2021-03-23 | PXD022212 | Pride
Project description:Mesenchymal stromal cells (MSC) are promising stem cell therapy for treating cardiovascular and other degenerative diseases. Diabetes affects the functional capability of MSC and impedes cell-based therapy. Despite numerous studies, the impact of diabetes on MSC myocardial reparative activity, metabolic fingerprint, and the mechanism of dysfunction remains inadequately understood. We demonstrated that the transplantation of diabetic-MSC (db/db-MSC) into the ischemic myocardium of mice does not confer cardiac benefit post-MI. Metabolomic studies identified defective energy metabolism in db/db-MSC. Furthermore, we found that glypican-3 (GPC3), a heparan sulfate proteoglycan, is highly upregulated in db/db-MSC and is involved in metabolic alterations in db/db-MSC via pyruvate kinase M2 activation. GPC3-knockdown reprogrammed-db/db-MSC restored their energy metabolic rates, immunomodulation, angiogenesis, and cardiac reparative activities. Together, these data indicate that GPC3-metabolic reprogramming in diabetic MSC may represent a strategy to enhance MSC based therapeutics for myocardial repair in diabetic patients
2024-09-04 | PXD055228 | Pride
Project description:The cardiac stroma contains multipotent mesenchymal progenitors. However, lineage relationships within cardiac stromal cells are poorly defined. Here, we identify heart-resident PDGFRa+ SCA-1+ cells as cardiac Fibro/Adipogenic Progenitors (cFAPs) and show that they respond to ischemic damage by generating SCA-1- fibrogenic cells. Pharmacological blockade of this differentiation step with an anti-fibrotic tyrosine kinase inhibitor decreases post-myocardial infarction (MI) remodeling and leads to improvement in heart function.
2020-01-23 | GSE141928 | GEO
Project description:The cardiac stroma contains multipotent mesenchymal progenitors. However, lineage relationships within cardiac stromal cells are poorly defined. Here, we identify heart-resident PDGFRa+ SCA-1+ cells as cardiac Fibro/Adipogenic Progenitors (cFAPs) and show that they respond to ischemic damage by generating SCA-1- fibrogenic cells. Pharmacological blockade of this differentiation step with an anti-fibrotic tyrosine kinase inhibitor decreases post-myocardial infarction (MI) remodeling and leads to improvement in heart function.
2020-01-23 | GSE141927 | GEO
Project description:Small extracellular vesicles (sEVs) play a critical role in cardiac cell therapy by delivering molecular cargo and mediating cellular signaling. Among sEV cargo molecule types, microRNA (miRNA) is particularly potent and highly heterogenous. However, not all miRNAs in sEV are beneficial. Two previous studies utilizing computational modeling identified miR-192-5p and miR-432-5p as potentially deleterious in cardiac function and repair. Here, we show that knocking down miR-192-5p and miR-432-5p in cardiac c-kit+ cell-derived sEVs enhances the therapeutic capabilities of sEVs in vitro and in a rat in vivo model of cardiac ischemia reperfusion. miR-192-5p and miR-432-5p depleted CPC-sEVs enhance cardiac function by reducing fibrosis, enhancing mesenchymal stromal cell-like cell mobilization, and inducing macrophage polarization to the M2 phenotype. Knocking down deleterious miRNAs from sEV could be a promising therapeutic strategy for treatment of chronic myocardial infarction.
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Project description:In the adult heart, the epicardium becomes activated after injury, contributing to cardiac healing by secretion of paracrine factors. Here we analyzed by single-cell RNA sequencing combined with RNA in situ hybridization and lineage tracing of WT1+ cells the cellular composition, location, and hierarchy of epicardial stromal cells (EpiSC) in comparison to activated myocardial fibroblasts/stromal cells in infarcted mouse hearts. We identified 11 transcriptionally distinct EpiSC populations, that can be classified in three groups each containing a cluster of proliferating cells. Two groups expressed cardiac specification makers and sarcomeric proteins suggestive of cardiomyogenic potential. Transcripts of HIF-1α and HIF-responsive genes were enriched in EpiSC consistent with the epicardium being a hypoxic niche. Expression of paracrine factors was not limited to WT1+ cells but was a general feature of activated cardiac stromal cells. Our findings provide the cellular framework by which myocardial ischemia may trigger in EpiSC the formation of cardioprotective/regenerative responses.
2021-06-21 | E-MTAB-10035 | biostudies-arrayexpress