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Am J Physiol Cell Physiol. 2014 Sep 1;307(5):C415-30. doi: 10.1152/ajpcell.00057.2014. Epub 2014 May 28.

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension.

Author information

1
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Vanderbilt Vascular Biology Center, Nashville, Tennessee;
2
Department of Pediatrics, Vanderbilt University, Nashville, Tennessee;
3
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
4
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee;
5
Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado;
6
Boston University, Boston, Massachusetts.
7
Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee;
8
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee;
9
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Veterans Administration Hospital, Nashville, Tennessee;
10
Department of Neurology, Vanderbilt Brain Institute, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;
11
Department of Pediatrics, Vanderbilt University, Nashville, Tennessee; Department of Neurology, Vanderbilt Brain Institute, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;
12
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;
13
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee; Vanderbilt Vascular Biology Center, Nashville, Tennessee; Pulmonary Vascular Research Institute, Kochi, and AnalyzeDat Consulting Services, Kerala, India; and susan.m.majka@vanderbilt.edu.

Abstract

Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH.

KEYWORDS:

Wnt signaling; endothelial cell; gene array; heritable pulmonary arterial hypertension; idiopathic pulmonary arterial hypertension; induced pluripotent stem cell; mesenchymal stromal cell; pulmonary arterial hypertension

PMID:
24871858
PMCID:
PMC4154073
DOI:
10.1152/ajpcell.00057.2014
[Indexed for MEDLINE]
Free PMC Article
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