Background: Through genome-wide transcriptional comparisons, this study interrogates the capacity of in vitro differentiation of induced pluripotent stem cells (iPSCs) to accurately model pathogenic signatures of developmental cardiac defects. Methods and results: Herein, we studied the molecular etiology of cardiac defects in Nos3<sup>-/-</sup> mice via transcriptional analysis of stage-matched embryonic tissues and iPSC-derived cells. In vitro comparisons of differentiated cells were calibrated to in utero benchmarks of health and disease. Integrated systems biology analysis of WT and Nos3<sup>-/-</sup> transcriptional profiles revealed 50% concordant expression patterns between in utero embryonic tissues and ex vivo iPSC-derived cells. In particular, up-regulation of glucose metabolism (p-value=3.95×10<sup>-12</sup>) and down-regulation of fatty acid metabolism (p-value=6.71×10<sup>-12</sup>) highlight a bioenergetic signature of early Nos3 deficiency during cardiogenesis that can be recapitulated in iPSC-derived differentiated cells. Conclusions: The in vitro concordance of early Nos3<sup>-/-</sup> disease signatures supports the utility of iPSCs as a cellular model of developmental heart defects. Moreover, this study supports the use of iPSCs as a platform to pinpoint initial stages of congenital cardiac pathogenesis.
- Cardiac development
- Disease modeling
- Induced pluripotent stem cell
- Nos3 knock-out
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine