BioProject

Through genome-wide transcriptional comparisons, this study interrogates the capacity of iPSCs to accurately model pathogenic signatures of structural cardiac defects. More...

Through genome-wide transcriptional comparisons, this study interrogates the capacity of iPSCs to accurately model pathogenic signatures of structural cardiac defects. Herein, we studied the molecular etiology of structural cardiac defects in Nos3-/- mice via transcriptional analysis of stage-matched embryonic and iPSC-derived tissues. In vitro comparisons of differentiated embryoid bodies were calibrated to in utero benchmarks of health and disease. Integrated systems biology analysis of WT and Nos3-/- transcriptional profiles revealed 50% concordant expression patterns between in utero embryonic and ex vivo iPSC-derived tissue. In particular, up-regulation of glucose metabolism (p-value = 3.95x10-12) and down-regulation of fatty acid metabolism (p-value = 6.71x10-12) highlight a bioenergetic signature of early Nos3 deficiency during cardiogenesis that can be recapitulated in iPSC-derived tissues. The in vitro concordance of early Nos3-/- disease signatures supports the utility of iPSCs as a cell-autonomous model of structural heart defects. Moreover, this study supports the use of iPSCs as a platform to pinpoint initial stages of cardiac pathogenesis. Overall design: The overall design of this study is transcriptome comparison of induced pluripotent stem cells (iPSCs, D0 and D11) reprogrammed from tail-tip fibroblasts of adult male CD1 and Nos3-/- (B6.129P2-Nos3tm1unc/J) mice. The study includes 31 samples (6 D0 Nos3 -/- iPSCs, 10 D0 control iPSCs, 6 D11 Nos3 -/- differentiated embryoid bodies (EBs), 9 control D11 differentiated EBs). Less...