Nos3-/- iPSCs model concordant signatures of in utero cardiac pathogenesis [tissue]. Mus musculus

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 is transcriptome comparison of heart ventricular tissues between CD1 and Nos3-/- mice. The study includes 12 samples (3 left ventricle samples and 3 right ventricle samples from wild type (WT) CD1 and Nos3-/- (B6.129P2-Nos3tm1unc/J) mice. At 14.5 days post coitum (dpc, E14.5), WT and Nos3-/- embryos were harvested from timed matings (15-30 embryos per triplicate sample). Left and right ventricular tissues (LV and RV) were microdissected and RNA was extracted with the RNeasy kit for microarray experiments.