Cardiomyocyte progenitors generated by direct reprogramming and molecular beacon selection attenuate ventricular remodelling after experimental myocardial infarction
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ABSTRACT:
PROVIDER: PRJNA668353 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12802417.fastq.gz | Fastqsanger.gz | |||
| SRR12802418.fastq.gz | Fastqsanger.gz | |||
| SRR12802419.fastq.gz | Fastqsanger.gz | |||
| SRR12802420.fastq.gz | Fastqsanger.gz | |||
| SRR12802421.fastq.gz | Fastqsanger.gz |
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Project description:Both naturally occurring and artificially engineered multipotent cardiac progenitor cells (CPCs) are associated with highly variable cardiomyocyte (CM) differentiation efficiencies, resulting in unpredictable and/or low CM yields. Therefore, CM-committed progenitors may be a more reliable cell product for therapeutic use. Here, we demonstrate that unipotent progenitors are part of the phenotype spectrum arising during direct reprogramming of neonatal cardiac fibroblasts towards CMs using lentiviral transduction of Gata4, Mef2c, Tbx5, and Myocd. Induced CM progenitors (iCMPs) simultaneously express CPC- and CM-specific proteins and can be selected via hairpin oligonucleotide molecular beacons targeting Myh6/7-mRNA–expressing cells. Purified iCMPs can be expanded extensively with preserved phenotype using ascorbic acid and give rise to CM-like cells in differentiation assays. When transplanted into infarcted mouse hearts, iCMPs prevent CM loss, attenuate fibrotic scarring, and preserve ventricular function. Given the clinical failure of conventional cardiac cell therapy using adult stem cells, further translational development of this iCMP approach is warranted.
2023-06-20 | GSE159315 | GEO
Project description:Background: Direct cardiac reprogramming is currently being investigated for the generation of cells with a true cardiomyocyte (CM) phenotype. Based on the original approach of cardiac transcription factor-induced reprogramming of fibroblasts into CM-like cells, various modifications of that strategy have been developed. However, they uniformly suffer from poor reprogramming efficacy and a lack of translational tools for target cell expansion and purification. Therefore, our group has developed a unique approach to generate proliferative cells with a pre-CM phenotype that can be expanded in vitro to yield substantial cell doses. Methods: Cardiac fibroblasts were reprogrammed toward CM fate using lentiviral transduction of cardiac transcriptions factors (GATA4, MEF2C, TBX5, and MYOCD). The resulting cellular phenotype was analyzed by RNA sequencing and immunocytology. Live target cells were purified based on intracellular CM marker expression using molecular beacon technology and fluorescence-activated cell sorting. CM commitment was assessed using 5-azacytidine–based differentiation assays and the therapeutic effect was evaluated in a mouse model of acute myocardial infarction using echocardiography and histology. The cellular secretome was analyzed using mass spectrometry. Results: We found that proliferative CM precursor-like cells were part of the phenotype spectrum arising during direct reprogramming of fibroblasts toward CMs. These induced CM precursors (iCMPs) expressed CPC- and CM-specific proteins and were selectable via hairpin-shaped oligonucleotide hybridization probes targeting Myh6/7-mRNA–expressing cells. After purification, iCMPs were capable of extensive expansion, with preserved phenotype when under ascorbic acid supplementation, and gave rise to CM-like cells with organized sarcomeres in differentiation assays. When transplanted into infarcted mouse hearts, iCMPs prevented CM loss, attenuated fibrotic scarring, and preserved ventricular function, which can in part be attributed to their substantial secretion of factors with documented beneficial effect on cardiac repair. Conclusions: Fibroblast reprogramming combined with molecular beacon-based cell selection yields an iCMP-like cell population with cardioprotective potential. Further studies are needed to elucidate mechanism-of-action and translational potential.
2023-06-24 | PXD042806 | Pride
Project description:A human ventricular electromechanical modelling and simulation framework is constructed and validated with rich experimental and clinical datasets. Abnormalities caused by scar and border zone ionic remodeling are introduced in varying degrees as reported in experimental data obtained in acute and chronic infarction. Simulations enabled reproducing and explaining clinical phenotypes post-MI, from ionic remodelling to ECGs and pressure-volume loops.
2025-03-24 | BIOMD0000001101 | BioModels
Project description:BackgroundDirect cardiac reprogramming is currently being investigated for the generation of cells with a true cardiomyocyte (CM) phenotype. Based on the original approach of cardiac transcription factor-induced reprogramming of fibroblasts into CM-like cells, various modifications of that strategy have been developed. However, they uniformly suffer from poor reprogramming efficacy and a lack of translational tools for target cell expansion and purification. Therefore, our group has developed a unique approach to generate proliferative cells with a pre-CM phenotype that can be expanded in vitro to yield substantial cell doses.MethodsCardiac fibroblasts were reprogrammed toward CM fate using lentiviral transduction of cardiac transcriptions factors (GATA4, MEF2C, TBX5, and MYOCD). The resulting cellular phenotype was analyzed by RNA sequencing and immunocytology. Live target cells were purified based on intracellular CM marker expression using molecular beacon technology and fluorescence-activated cell sorting. CM commitment was assessed using 5-azacytidine-based differentiation assays and the therapeutic effect was evaluated in a mouse model of acute myocardial infarction using echocardiography and histology. The cellular secretome was analyzed using mass spectrometry.ResultsWe found that proliferative CM precursor-like cells were part of the phenotype spectrum arising during direct reprogramming of fibroblasts toward CMs. These induced CM precursors (iCMPs) expressed CPC- and CM-specific proteins and were selectable via hairpin-shaped oligonucleotide hybridization probes targeting Myh6/7-mRNA-expressing cells. After purification, iCMPs were capable of extensive expansion, with preserved phenotype when under ascorbic acid supplementation, and gave rise to CM-like cells with organized sarcomeres in differentiation assays. When transplanted into infarcted mouse hearts, iCMPs prevented CM loss, attenuated fibrotic scarring, and preserved ventricular function, which can in part be attributed to their substantial secretion of factors with documented beneficial effect on cardiac repair.ConclusionsFibroblast reprogramming combined with molecular beacon-based cell selection yields an iCMP-like cell population with cardioprotective potential. Further studies are needed to elucidate mechanism-of-action and translational potential.
| S-EPMC10577947 | biostudies-literature
Project description:Background: Myocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an ECM protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown. Methods: Three microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast–macrophage co-culture model in vitro. Results: ITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast–macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages. Conclusions: ITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.
2025-03-05 | GSE273243 | GEO
Project description:Our findings suggest that FtMt serves as a protective function in myocardial infarction by limiting infarct size, reducing the incidence of ventricular arrhythmias, and inhibiting ferroptosis both in vivo and in vitro. Our results also indicate that FtMt could be a promising therapeutic target for myocardial infarction.
2025-09-17 | GSE277680 | GEO
Project description:Aims: We investigate sex differences and the role of oestrogen receptor beta (ERbeta) in a mouse model of pressure overload-induced myocardial hypertrophy. Methods and results: We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ER knockout (ERbeta-/-) C57Bl6 mice. All mice were characterised by echocardiography and haemodynamic measurements and were sacrificed nine weeks after surgery. Left ventricular (LV) samples were analysed by microarray profiling, real-time RT-PCR and histology. After nine weeks, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. These sex differences were abolished in ERbeta-/- mice. ERbeta deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that male WT hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than female hearts. ERbeta-/- mice exhibited a different transcriptome. Induction of pro-apoptotic genes after TAC occurred in ERbeta-/- mice of both sexes with a stronger expression in ERbeta-/- males. Histological analysis revealed, that cardiac fibrosis was more pronounced in male WT TAC than in female mice. This was abolished in ERbeta-/- mice. Apoptosis was significantly induced in both sexes of ERbeta-/- TAC mice, but it was most prominent in males. Conclusion: Female sex offers protection against ventricular chamber dilation in the TAC model. Both the female sex and ER attenuate the development of fibrosis and apoptosis; thus slowing the progression to heart failure. The influence of sex (male/female) and estrogen receptor beta expression (ERbeta knockout/wildtype) on cardiac hypertrophy (transverse aortic constriction/sham operated) was investigated. The left ventricular transcriptome of four individual mice for each combination of the three factors (sex, genotype, surgery) was detected with Affymetrix RAE 430 2.0 GeneChip arrays.
2010-01-19 | E-GEOD-18224 | biostudies-arrayexpress
Project description:To induce myocardial infarction, ligation of left anterior descending (LAD) coronary artery was performed for 5d. After 5d heart tisse was collected from the infarct zone of MI-mice and left ventricular tissue of sham operated mice.
2025-12-17 | GSE307268 | 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:ITIH5-mediated fibroblast/macrophage crosstalk exacerbates cardiac remodelling after myocardial infarction
| PRJNA1140853 | ENA