Transferrin improved the generation of cardiomyocyte from human pluripotent stem cells for myocardial infarction repair
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ABSTRACT:
PROVIDER: PRJNA645819 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12207311_1.fastq.gz | Fastqsanger.gz | |||
| SRR12207311_2.fastq.gz | Fastqsanger.gz | |||
| SRR12207312_1.fastq.gz | Fastqsanger.gz | |||
| SRR12207312_2.fastq.gz | Fastqsanger.gz | |||
| SRR12207313_1.fastq.gz | Fastqsanger.gz |
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Project description:Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for the repair of the injured heart, but optimal cell production in a fully chemically defined and cost-effective system is essential for the efficacy and safety of cell transplantation therapies. In this study, we provided a simple and efficient strategy for cardiac differentiation from hPSCs and performed functional evaluation in a rat model of myocardial infarction. Using a chemically defined medium including four components, recombinant human albumin, ascorbic acid, human transferrin, and RPMI 1640, we developed a manageable and cost-effective protocol for robust generation of CMs from hPSCs. Interestingly, the addition of transferrin helped hPSCs to transit from TeSR-E8 medium to the simple cardiac differentiation medium and successfully initiated mesoderm differentiation without significant cell death. The CM generation efficiency was up to 85% based on cTnT expression. We performed transcriptome profiling from differentiation day 0 to 35, and characterized interesting dynamic change of cardiac genes. CMs derived from transferrin supplemented simple medium have similar transcriptome and the maturation level compared to cardiomyocytes generated in B27 minus insulin medium as well as their in vivo counterparts. Importantly, after transplantation, hPSC derived CMs survived in the infarcted rat heart, significantly improved the physiological function and reduced fibrosis. Our study offers an easy-to-use and cost-effective method for cardiac differentiation and facilitates the translational application of hPSC-derived CMs for heart repair.
2021-01-13 | GSE154294 | GEO
Project description:Myocardial infarction (MI) contributes to cardiac mortality and morbidity. After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Post-translational regulation of cytokine / chemokine signaling occurs via ectodomain shedding through a disintegrin and metalloproteases (ADAMs). Here, we address the value of targeting a previously unknown ADAM10 / CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in biopsies from patients with ischemia-driven cardiomyopathy and correlates with heart failure progression. Intriguingly, upon MI in mice, pharmacological treatment with the ADAM10 inhibitionor GI254023X as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, this is driven by abolished ADAM10-mediated CX3CL1 ectodomain shedding followed by diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Genetic cardiomycyte-specific ADAM10 deletion confirmes the small-molecule data and leads to improved cardiac function and reduction in inflammatory markers after ischemic myocardial injury. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes.
2022-11-10 | GSE217268 | GEO
Project description:The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal (P) day 7. How to stimulate the adult cardiomyocyte to re-enter the cell cycle is still unknown. Accumulating evidence suggests that cardiomyocyte proliferation depends on its metabolic state. Due to the tight connection between the tricarboxylic acid cycle (TCA) and cell proliferation, we analyzed the TCA metabolites between P0.5 and P7 mouse hearts and found that α-ketoglutarate (α-KG) ranked first among the decreased metabolites. The intraperitoneal injection of exogenous α-KG extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction (MI) by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-KG levels. Mechanistically, α-KG activates Jmjd3, a histone lysine demethylase, that decreases H3K27me3 expression and deposition of H3K4me3 at the promoters of cell cycle and structural maturation genes in cardiomyocytes. Our present study shows that α-KG promotes cardiomyocyte proliferation by Jmjd3-dependent demethylation and inactivation of H3K27me3 andH3K4me3, which is a potential therapeutic approach for treating MI and heart failure.
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Project description:Affymetrix microarray analysis of molecular changes after myocardial infarction. Samples of heart tissue were analyzed after myocardial infarction from WT and reg3beta knock-out mice. Samples from scar tissue and samples adjacent to the scar were analyzed. In the experiment we primarily compared infarction zone of wild-type to infarction zone of knock-out animals, and remote zone of wild-type to remote zone of knock-outs.
2015-06-29 | E-MTAB-2561 | biostudies-arrayexpress
Project description:α-Ketoglutarate Promotes Cardiomyocyte Proliferation and Heart Regeneration after Myocardial Infarction
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Project description:Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction
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Project description:The use of anthracycline antibiotics such as doxorubicin (DOX) has greatly improved the mortality and morbidity of cancer patients. However, the associated risk of cardiomyopathy has limited their clinical application. DOX-associated cardiotoxicity is irreversible and progresses to heart failure (HF). For this reason, a better understanding of the molecular mechanisms underlying these adverse cardiac effects is essential to develop improved regimes that include cardioprotective strategies. MicroRNAs (miRNAs) are short non-coding RNAs that are able to post-trascriptionally regulate gene expression. MiRNAs have been demonstrated to be involved in both cancer and cardiovascular disease. Therefore, we were interested in unveiling the potential role of miRNAs in chemotherapy-induced HF. We used a combination of three different models to recreate this cardiac toxicity (acute in vitro DOX treatment, DOX-induced HF in vivo and a myocardial infarction -MI- leading to failure model) to study the pattern of dysregulated miRNAs. Using RNA from all three conditions, miRNA microarray profiling was performed and a common miRNA signature was identified. Interestingly, these dysregulated miRNAs have been previously identified as involved in the failing heart. Our results suggest that DOX is able to alter the expression of miRNAs implicated in HF, in vitro as well as in vivo. The present study is a microRNA profiling of the damaged cardiac muscle (cardiomyocyte cell population), following either myocardial infarction (MI) induction or doxorubicin (DOX) treatment. Two DOX-treated models were included: ARC exposed to DOX in vitro and a validated DOX-induced heart failure model generated by repeated administration of DOX injections.
2013-01-29 | E-GEOD-36239 | biostudies-arrayexpress
Project description:Inhibition of DYRK1A promotes cardiomyocyte proliferation and heart repair after myocardial infarction
| PRJNA834827 | ENA
Project description:In the severity of myocardial infarction, Toll-like receptor (TLR) 9 plays a pivotal role in the inflammatory responses induced through damage-associated molecular patterns involving mitochondrial DNA and HMGB1. However, the therapeutic agents currently available for myocardial infarction substantially lack any association with the effects on immune responses. In this study, we applied a comprehensive drug discovery approach, which integrates in silico, in vitro, and in vivo processes, as well as determined therapeutic effects and mechanisms free from side effects. In an animal model of myocardial infarction, conditioned based on pharmacological properties, improved effects compared to the FDA-approved Rosuvastatin were detected. In summary, a small molecular inhibitor, ETA53 (endosomal Toll-like receptor antagonist 53), which selectively acts on TLR9 in nano-molar units, was developed. ETA53 was found to be effective for treating myocardial infarction caused by permanent ligation of the left anterior descending coronary artery, based on indicators such as cardiac function, inflammation, infarct size, and fibrosis. The results offered insights that varied from those of conventional drug development perspectives; consequently, the novel inhibitor may provide an alternative treatment with a mechanism different from that of the commercially available drugs for myocardial infarction.
2023-11-12 | GSE247311 | GEO
Project description:Myocardial infarction is a leading cause of mortality worldwide 1 . While advances have been made
in acute treatment, an incomplete understanding of remodelling processes has limited the
effectiveness of therapies to reduce late-stage mortality 2 . Here, we generate an integrative high-
resolution map of human cardiac remodelling after myocardial infarction using single-cell gene
expression, chromatin accessibility, and spatial transcriptomic profiling of multiple physiological
zones at distinct time points in myocardium from myocardial infarction and control patients.
Multimodal data integration allowed us to evaluate cardiac cell-type compositions at increased
resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the
identification of distinct tissue structures of injury, repair and remodelling. We identified and
validated disease-specific cardiac cell-states of major cell-types and analysed them in their spatial
context, evaluating their dependency on other cell-types. Our data elucidates molecular principles
of human myocardial tissue organisation, recapitulating a gradual cardiomyocyte and myeloid
continuum following ischemic injury. In total, our study provides an integrative molecular map of
human myocardial infarction and represents an essential reference for the field and paves the way
for advanced mechanistic and therapeutic studies of cardiac disease.
| EGAS00001006330 | EGA