Crosslinked elastin-like polypeptides mediate direct cardiac differentiation of mouse embryonic and induced pluripotent stem cells without use of cardiac differentiation factors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE145623 | GEO | 2024/02/12
REPOSITORIES: GEO
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Project description:Elastin wild type Eln+/+ and Eln+/- mouse aorta and aortic valve tissue. In the study, we demonstrated differential gene expression in juvenile elastin deficient mouse valve tissue. In the study, we hybridized RNA from Elastin wild type (Eln+/+) aorta tissue, elastin wild type (Eln+/+) aortic valve tissue, elastin (Eln+/-) aorta tissue and elastin (Eln+/-) aortic valve tissue to Affymetrix GeneChip Mouse Genome 430 2.0 Array
2009-11-30 | E-GEOD-16012 | biostudies-arrayexpress
Project description:Background: In the remodeling process of the volume-overloaded heart, the extracellular matrix (ECM) may be dynamically modified to adapt to hemodynamic stress. We investigated the expression of ECM-related genes and modification of the elastin network in the remodeling process of the left ventricles (LVs) of rats with aortocaval fistulae. Methods and Findings: Gene array analysis identified 36 upregulated and 11 downregulated ECM-related genes during evolution from the compensated to the late decompensated phase. Ingenuity Pathway Analysis identified the formation of elastic fibers as an important biological function. Real-time PCR confirmed persistent upregulation of elastogenesis-associated genes, including elastin, lysyl oxidase, lysyl oxidase like-1, fibrillin 1, fibulin 2, versican and latent transforming growth factor beta binding protein 2 at various intervals. The expression levels and enzymatic activities of potent elastases, cathepsin S and cathepsin K increased during the early phase. Immunofluorescence confocal microscopy showed that the microstructure of the elastin network was preserved during the early phase, degraded during the compensated phase, partially repaired during the early decompensated phase, and reinforced during the late decompensated phase. Assessment of elastin concentrations in the LVs showed a consistent temporal pattern throughout the course. Conclusions: In the volume-overloaded heart, upregulation of potent elastases during the early phase and persistent upregulation of elastogenesis-related genes result in early degradation followed by repair and reinforcement of the elastin network of the LV. Remodeling of the elastin network may contribute to changes in the mechanical property of the volume-overloaded heart.
2018-03-31 | GSE97044 | GEO
Project description:Elastin wild type Eln+/+ and Eln+/- mouse aorta and aortic valve tissue. In the study, we demonstrated differential gene expression in juvenile elastin deficient mouse valve tissue.
2009-11-30 | GSE16012 | GEO
Project description:Semilunar valve leaflets have a well-described trilaminar histoarchitecture with a sophisticated elastic fiber network. It was previously proposed that elastin-containing fibers play a subordinate role in early human cardiac valve development; however, this assumption was based on data obtained from mouse models and human second and third trimester tissues. Here, we systematically analyzed tissues from human fetal first (4-12 weeks) and second (13-18 weeks) trimester, adolescent (14-19 years) and adult (50-55 years) hearts to monitor the temporal and spatial distribution of elastic fibers, focusing on semilunar valves. Global gene expression analyses revealed that the transcription of genes essential for elastic fiber formation starts early within the first trimester. These data were confirmed by quantitative PCR and immunohistochemistry employing antibodies that recognize fibronectin, fibrilin-1, -2 and -3, EMILIN-1, fibulin-4 and fibulin-5, which were all expressed at the onset of cardiac cushion formation (~week 4 of development). Tropoelastin/ elastin protein expression was first detectable in leaflets of 7-week hearts. We revealed that immature elastic fibers are organized in early human cardiovascular development, and mature elastin-containing fibers first evolve in semilunar valves when blood pressure and heartbeat accelerate. Our findings provide a conceptual framework with the potential to lead to novel hypotheses in human cardiac valve development and disease. Total RNA obtained from fetal cardiac valve cushions, developed fetal heart valves, adolescent heart valves, and adult heart valves.
2013-04-06 | E-GEOD-45821 | biostudies-arrayexpress
Project description:Extracellular elastic fibres apply structure and mechanical elasticity to organs such as large arteries, lungs and skin 1. Elastic fibres are assembled through polymerization of tropoelastin monomers and loss of elastin is associated with aneurysmal degeneration of the aorta 2. The Fibulins are a six-member protein family hypothesized to function as intermolecular bridges that stabilize the organization of extracellular matrix structures such as elastic fibres and basement membranes 3. Fibulin-4 is found in the medial layers of arteries and moderately expressed in heart valves 4. To examine a potential role of Fibulin-4 in elastic fibre assembly and cardio-vascular disease we generated a mouse model underexpressing Fibulin-4. To get insight into the underlying molecular pathways involved in aneurysm formation, we determined the aorta transcriptome of Fibulin-4R/R animals and identified biological processes that were significantly overrepresented including apoptosis and cell death as well as several novel gene targets implicated in the response to aortic failure. We conclude that decreased Fibulin-4 expression causes aberrant composition of the elastin layers in the aorta and valvular leaflets, resulting in aortic aneurysms and heart abnormalities.
2007-01-01 | E-MEXP-840 | biostudies-arrayexpress
Project description:Expression level polymorphisms (ELPs) often result in cis-acting expression quantitative trait loci (cis-eQTL), which are important QTL and association mapping tools and account significantly for phenotypic variability. Generally, it is assumed that such stably heritable ELP represent regulatory element polymorphisms in the respective genes. However, comprehensive genome-wide analyses linking expression level, regulatory sequence and gene structure variation are missing, preventing definite verification of this assumption. Here we analyzed heritability of ELP observed between Arabidopsis thaliana accessions Eil-0 and Lc-0 by comparing genotyped recombinant inbred lines (RIL) to their parents in microarray analyses. Keywords: expression level polymorphism, Arabidopsis thaliana accessions, recombinant inbred lines
2008-11-18 | GSE13628 | GEO
Project description:Semilunar valve leaflets have a well-described trilaminar histoarchitecture with a sophisticated elastic fiber network. It was previously proposed that elastin-containing fibers play a subordinate role in early human cardiac valve development; however, this assumption was based on data obtained from mouse models and human second and third trimester tissues. Here, we systematically analyzed tissues from human fetal first (4-12 weeks) and second (13-18 weeks) trimester, adolescent (14-19 years) and adult (50-55 years) hearts to monitor the temporal and spatial distribution of elastic fibers, focusing on semilunar valves. Global gene expression analyses revealed that the transcription of genes essential for elastic fiber formation starts early within the first trimester. These data were confirmed by quantitative PCR and immunohistochemistry employing antibodies that recognize fibronectin, fibrilin-1, -2 and -3, EMILIN-1, fibulin-4 and fibulin-5, which were all expressed at the onset of cardiac cushion formation (~week 4 of development). Tropoelastin/ elastin protein expression was first detectable in leaflets of 7-week hearts. We revealed that immature elastic fibers are organized in early human cardiovascular development, and mature elastin-containing fibers first evolve in semilunar valves when blood pressure and heartbeat accelerate. Our findings provide a conceptual framework with the potential to lead to novel hypotheses in human cardiac valve development and disease.
2013-04-06 | GSE45821 | GEO
Project description:Valve remodeling is a complex process involving extracellular matrix organization, development of trilaminar structures, and physical elongation of valve leaflets. However, the cellular and molecular mechanisms regulating valve remodeling and their roles in congenital valve disorders remain poorly understood. Semilunar valves and atrioventricular valves from healthy and age-matched human fetal hearts with pulmonary stenosis (PS) were collected. Single-Cell RNA-sequencing (scRNA-seq) was performed to determine the transcriptomic landscape of multiple valvular cell subtypes in valve remodeling and disease. Spatial localization of newly-identified cell subtypes was determined via immunofluorescence and RNA in situ hybridization. The molecular mechanisms mediating valve development was investigated utilizing primary human fetal valve interstitial cells (VICs) and endothelial cells (VECs). scRNA-seq analysis of healthy human fetal valves identified a novel APOE+ elastin-producing VIC subtype (Elastin-VIC) spatially located underneath VECs sensing the unidirectional flow. Knockdown of APOE in fetal VICs resulted in significant elastogenesis defects. In pulmonary valve with PS, we observed decreased expression of APOE and other genes regulating elastogenesis such as EMILIN1 and LOXL1, as well as elastin fragmentation. These findings suggested the crucial role of APOE in regulating elastogenesis during valve remodeling. Furthermore, cell-cell interaction analysis revealed that JAG1 from unidirectional VECs activates NOTCH signaling in Elastin-VICs through NOTCH3. In vitro Jag1 treatment in VICs increased the expression of elastogenesis-related genes and enhanced contractile functions with related gene expression. This was accompanied by activation of NOTCH signaling and elastogenesis observed in VICs co-cultured with VECs in the presence of unidirectional flow. Notably, we found that the JAG1-NOTCH3 signaling pair was drastically reduced in the PS valves. Lastly, we demonstrated that APOE is indispensable for JAG1-induced NOTCH activation in VICs, reinforcing the presence of a synergistic intrinsic and external regulatory network involving APOE and NOTCH signaling that is responsible for regulating elastogenesis during human valve remodeling. scRNA-seq analysis of human fetal valves identified a novel Elastin-VIC subpopulation, and revealed mechanism of intrinsic APOE and external NOTCH signaling from VECs sensing unidirectional flow in regulating elastogenesis during valve remodeling. These mechanisms may contribute to the pathogenesis of elastic malformation in congenital valve disease.
2024-01-10 | GSE228638 | GEO
Project description:Fibulin-4 plays an essential role in elastic fiber formation, though it's exact function is unclear. Mice lacking the fibulin-4 gene develop cutis laxa with thoracic aortic aneurysms and have narrowed descending aortic diamaters, dying shortly after birth. Another model that disrupt elastic fiber formation, elastin gene knockeds, are also perinatally lethal and have narrowed descending aortas but do not develop thoracic aneurysms. We hypothesized that there may be altered gene expression to explain the altered anatomy based on aortic tissue location we observed, which may provide therapeutic target(s) Ascending and descending aortas of p0 mouse pups were dissected, pooled in groups of eight, and homogenized to isolate RNA and we used microarrays on the pooled samples to identify genes that had expression significantly changed.
2015-04-10 | E-GEOD-67707 | biostudies-arrayexpress
Project description:Elastic fibers provide reversible elasticity to the large arteries and are assembled during development when hemodynamic forces are increasing. Mutations in elastic fiber genes are associated with cardiovascular disease. Mice lacking expression of the elastic fiber genes elastin (Eln-/-), fibulin-4 (Efemp2-/-), or lysyl oxidase (Lox-/-) die at birth with severe cardiovascular malformations. All three genetic knockout models have elastic fiber defects, aortic wall thickening, and arterial tortuosity. However, Eln-/- mice develop arterial stenoses, while Efemp2-/- and Lox-/- mice develop ascending aortic aneurysms. We performed comparative gene array analyses of these three genetic models for two vascular locations and developmental stages to determine differentially expressed genes and pathways that may explain the common and divergent phenotypes. We first examined arterial morphology and wall structure in newborn mice to confirm that the lack of elastin, fibulin-4, or lysyl oxidase expression provided the expected phenotypes. We then compared gene expression levels for each genetic model by three-way ANOVA for genotype, vascular location, and developmental stage. We found three genes upregulated by genotype in all three models, Col8a1, Igfbp2, and Thbs1, indicative of a common response to severe elastic fiber defects in developing mouse aorta. Genes that are differentially regulated by vascular location or developmental stage in all three models suggest mechanisms for location or stage specific disease pathology. Comparison of signaling pathways enriched in all three models shows upregulation of integrins and matrix proteins involved in early wound healing, but not of mature matrix molecules such as elastic fiber proteins or fibrillar collagens.
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