Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA266836 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1647911_1.fastq.gz | Fastqsanger.gz | |||
| SRR1647911_2.fastq.gz | Fastqsanger.gz | |||
| SRR1647912_1.fastq.gz | Fastqsanger.gz | |||
| SRR1647912_2.fastq.gz | Fastqsanger.gz | |||
| SRR1647913_1.fastq.gz | Fastqsanger.gz |
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Project description:iPSC-derived cardiomyocyotes reveal abnormal TGFβ signaling in left ventricular non-compaction cardiomyopathy
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Project description:Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and has a unique phenotype with characteristically extensive hypertrabeculation of the left ventricle, similar to the embryonic left ventricle, suggesting a developmental defect of the embryonic myocardium. However, studying this disease has been challenging due to the lack of an animal model that can faithfully recapitulate the clinical phenotype of LVNC. To address this, we show that patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs) generated from a family with LVNC recapitulated a developmental defect consistent with the LVNC phenotype at the single-cell level. We then utilized hiPSC-CMs to show that increased transforming growth factor beta (TGFβ) signaling is one of the central mechanisms underlying the pathogenesis of LVNC. LVNC hiPSC-CMs demonstrated decreased proliferative capacity due to abnormal activation of TGFβ signaling. Exome sequencing demonstrated a mutation in TBX20, which regulates TGFβ signaling, contributing to the LVNC phenotype. Our results demonstrate that hiPSC-CMs are a useful tool for the exploration of novel mechanisms underlying poorly understood cardiomyopathies such as LVNC. Here we provide the first evidence of activation of TGF signaling as playing a role in the pathogenesis of LVNC.
2016-07-13 | GSE63161 | GEO
Project description:Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. The developmental origins and mechanistic basis of varying severity of this pathology are unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as a marker upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.
2018-04-18 | GSE113251 | GEO
Project description:Truncating variants in titin can cause dilated cardiomyopathy, however, the role of missense titin variants is less clear. In humans the heterozygous titin A178D variant is associated with dilated cardiomyopathy with left ventricular non-compaction. Using CRISPR-Cas9 mediated homology-directed repair the A178D titin variant was introduced into a mouse model. Homozygous A178D mice showed features of dilated cardiomyopathy. Total RNA was extracted from the left ventricles of WT and homozygous A178D littermate control mice and RNA-sequencing performed. Different patterns of gene expression were identified in wildtype and homozygous A178D left ventricles.
2021-02-26 | GSE154504 | GEO
Project description:During mammalian development, the left and right ventricles arise from early populations of cardiac progenitors known as the first and second heart fields, respectively. While these populations have been extensively studied in non-human model systems, their identification and study in vivo human tissues have been limited due to the ethical and technical limitations of accessing gastrulation stage human embryos. Human induced pluripotent stem cells (hiPSCs) present an exciting alternative for modeling early human embryogenesis due to their well-established ability to differentiate into all embryonic germ layers. Here, we describe the development of a TBX5/MYL2 lineage tracing reporter system that allows for the identification of FHF- progenitors and their descendants including left ventricular cardiomyocytes. Furthermore, using single cell RNA sequencing (scRNA-seq) with oligonucleotide-based sample multiplexing, we extensively profiled differentiating hiPSCs across 12 timepoints in two independent iPSC lines. Surprisingly, our reporter system and scRNA-seq analysis revealed a predominance of FHF differentiation using the small molecule Wnt-based 2D differentiation protocol. We compared this data with existing murine and 3D cardiac organoid scRNA-seq data and confirmed the dominance of left ventricular cardiomyocytes (>90%) in our hiPSC-derived progeny. Together, our work provides the scientific community with a powerful new genetic lineage tracing approach as well as a single cell transcriptomic atlas of hiPSCs undergoing cardiac differentiation.
2023-06-05 | GSE202398 | GEO
Project description:Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta1. Although the mechanisms of disease pathogenesis remain elusive due to a paucity of candidate genes and animal models, prevailing paradigm suggests that HLHS is a multigenic disease of co-occurring phenotypes2,3. Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene previously linked to HLHS in humans4,5, display cardiovascular defects overlapping those in HLHS patients. In contrast to current models, we demonstrate that co-existing ventricular, valve, and aortic deficiencies in rbfox mutant zebrafish arise secondary to impaired myocardial function as all three phenotypes are rescued when Rbfox is expressed specifically in the myocardium. On a molecular and cellular level, we find diminished expression and alternative splicing of sarcomere and mitochondrial components in rbfox-deficient hearts that compromise sarcomere assembly and mitochondrial respiration, respectively. Injection of human RBFOX2 mRNA restores ventricular structure and function in rbfox mutant zebrafish, while HLHS-linked RBFOX2 variants fail to rescue. Taken together, our data suggest that mutations in RBFOX2 are causal for HLHS pathogenesis and provide a complimentary paradigm for HLHS emergence where co-existing ventricular, valve, and aortic deficiencies have a monogenic etiology caused by myocardial dysfunction.
2022-07-12 | MTBLS4176 | MetaboLights
Project description:Arterial pulmonary hypertension is a rare disease, with little knowledge regarding its etiology, and high mortality. Development of right and later on also left ventricular heart insufficiency, secondary to pulmonary hypertension, is a negative predictive factor. Genetic and molecular processes underlying left heart ventricle remodeling over the course of pulmonary hypertension remain unknown. In particular, there is no knowledge regarding the mechanisms of left heart ventricle atrophy which was completely avoided by researchers until recently.The aim of this study was to assess changes in protein abundance in left and right heart ventricle free wall of rats in monocrotaline model of PAH.
2020-09-07 | PXD015896 | Pride
Project description:Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We explore the endothelial cell-specific deletion of the chromatin remodeler gene Ino80, which results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. We observed a pathological endocardial cell population in the non-compacted hearts, and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behavior.
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Project description:Left ventricular noncompaction (LVNC) Causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction. RNA was isolated from the ventricles of 16 WT and 16 Mib1flox; CTnT-cre hearts at E14.5 and then pooled into four replicates.
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