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

1 Citation (Scopus)

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

Fingerprint

Induced Pluripotent Stem Cells
Benchmarking
Systems Biology
Energy Metabolism
Up-Regulation
Fatty Acids
Down-Regulation
Genome
Glucose
Health
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Nos3<sup>-/-</sup> iPSCs model concordant signatures of in utero cardiac pathogenesis. / Campbell, Katherine A.; Li, Xing; Biendarra, Sherri M.; Terzic, Andre; Nelson, Timothy J.

In: Journal of Molecular and Cellular Cardiology, Vol. 87, 8180, 01.10.2015, p. 228-236.

Research output: Contribution to journalArticle

@article{316c7741ed324106802a3a6ee4e178c8,
title = "Nos3-/- iPSCs model concordant signatures of in utero cardiac pathogenesis",
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-/- 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.",
keywords = "Cardiac development, Disease modeling, Induced pluripotent stem cell, Nos3 knock-out",
author = "Campbell, {Katherine A.} and Xing Li and Biendarra, {Sherri M.} and Andre Terzic and Nelson, {Timothy J}",
year = "2015",
month = "10",
day = "1",
doi = "10.1016/j.yjmcc.2015.08.021",
language = "English (US)",
volume = "87",
pages = "228--236",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Nos3-/- iPSCs model concordant signatures of in utero cardiac pathogenesis

AU - Campbell, Katherine A.

AU - Li, Xing

AU - Biendarra, Sherri M.

AU - Terzic, Andre

AU - Nelson, Timothy J

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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-/- 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.

AB - 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-/- 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.

KW - Cardiac development

KW - Disease modeling

KW - Induced pluripotent stem cell

KW - Nos3 knock-out

UR - http://www.scopus.com/inward/record.url?scp=84941277305&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941277305&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2015.08.021

DO - 10.1016/j.yjmcc.2015.08.021

M3 - Article

VL - 87

SP - 228

EP - 236

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

M1 - 8180

ER -