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A developmental model of human early cardiac valvulogenesis (I)

ABSTRACT: One third of cardiac congenital diseases affect cardiac valves. Genetically modified mice have advanced our understanding of valve development and related pathologies. However, little is known with regard to human valve development.We aimed to derive a novel human pluripotent stem cell model in order to decode the early steps of human valvulogenesis. Human MesP1+mesodermal cells were differentiated toward the fate of second heart field progenitors and then to a selected population of pre-valvular endocardial cells. Gene arrays revealed that these human prevalvular cells (HPVC) express patterns of genes similar to those expressed in the atrioventricular canal (AVC) endocardium of E9.0 mouse embryos. In mice this developmental time precedes endocardial mesenchymal transition (EndoMT),which is required for mature valve formation. HPVC treated with BMP2, cultured onto chick or mouse AVC cushions, or transplanted into the outflow tract or AVC of embryonic chick and mouse hearts, underwent EndoMTin both a Notch-dependent and independent-manner and expressed markers of valve mesenchymal cells and fibroblasts. Similar to the previously described valve interstitial cells (VICs), HPVC also differentiate into tendinous/chondrogenic cells. Our study indicates tha thuman pluripotent stem cells canrecapitulate early valvulogenesis and thus provide a powerful model to further decipher the origin and lineage contribution of different valvular cell types in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73546 | GEO | 2019/01/22

REPOSITORIES: GEO

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Project description:Malformations of the cardiovascular system are the most common type of birth defect in humans, affecting predominantly the formation of valves and septa. During heart valve and septa formation, cells from the atrio-ventricular canal (AVC) and outflow tract (OFT) regions of the heart undergo an epithelial-to-mesenchymal transformation (EMT) and invade the underlying extracellular matrix to give rise to endocardial cushions. Subsequent maturation of newly formed mesenchyme cells leads to thin stress-resistant leaflets. TWIST1 is a basic helix-loop-helix transcription factor expressed in newly formed mesenchyme cells of the AVC and OFT that has been shown to play roles in cell survival, cell proliferation and differentiation. However, the role and downstream targets of TWIST1 during heart valve formation remain unclear. To identify genes important for heart valve development downstream of Twist1 we performed global gene expression profiling of AVC, OFT, atria and ventricles of the embryonic day 10.5 mouse heart by tag-sequencing (Tag-seq). Using this resource we identified a novel set of 1246 genes, including 201 regulators of transcription, enriched in the valve forming regions of the heart. We compared these genes to a Tag-seq library from the Twist1 null developing valves revealing significant gene expression changes. These changes were consistent with a role of TWIST1 in controlling differentiation of mesenchymal cells following their transformation from endothelium in the mouse. To study the role of TWIST1 at the DNA level we performed chromatin immunoprecipitation and identified novel direct targets of TWIST1 in the developing heart valves. Our findings are consistent with a role for TWIST1 in the differentiation of AVC mesenchyme post-EMT in the mouse, and suggest that TWIST1 exerts its function by direct DNA binding to activate valve specific gene expression. Profiled the AVC, OFT, atria and ventricles of the embryonic day 10.5 mouse heart by tag-sequencing (Tag-seq) (no replicates). We also produced a Tag-seq library from Twist1 null developing valves to reveal the gene expression changes associated with loss of this gene.

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A developmental model of human early cardiac valvulogenesis (I)

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