Nos3-/- iPSCs model concordant signatures of in utero cardiac pathogenesis.
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.


RESULTS
Herein, we studied the molecular etiology of cardiac defects in Nos3(-/-) 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(-/-) 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(-12)) and down-regulation of fatty acid metabolism (p-value=6.71×10(-12)) 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(-/-) 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.
Department of Molecular Pharmacology and Experimental Therapeutics, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Center for Regenerative Medicine, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Division of General Internal Medicine, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA.
Katherine A
KA
Campbell
Department of Health Sciences Research, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Division of Biomedical Statistics and Informatics, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA.
Xing
X
Li
Department of Molecular Pharmacology and Experimental Therapeutics, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA.
Sherri M
SM
Biendarra
Department of Molecular Pharmacology and Experimental Therapeutics, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Center for Regenerative Medicine, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Division of Cardiovascular Diseases, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Department of Medical Genetics, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA.
Andre
A
Terzic
Department of Molecular Pharmacology and Experimental Therapeutics, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Center for Regenerative Medicine, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Division of Cardiovascular Diseases, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Division of General Internal Medicine, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Center for Transplantation and Clinical Regeneration, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA; Division of Pediatric Cardiology,200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: nelson.timothy@mayo.edu.
Timothy J
TJ
Nelson
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D065150:Cellular Reprogramming / Q000235:genetics; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics
D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
Cardiac development; Disease modeling; Induced pluripotent stem cell; Nos3 knock-out