Nos3<sup>-/-</sup> iPSCs model concordant signatures of in utero cardiac pathogenesis

Katherine A. Campbell, Xing Li, Sherri M. Biendarra, Andre Terzic, Timothy J Nelson

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number8180
Pages (from-to)228-236
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume87
DOIs
StatePublished - Oct 1 2015

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Keywords

  • Cardiac development
  • Disease modeling
  • Induced pluripotent stem cell
  • Nos3 knock-out

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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