title: Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension.
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.
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Vanderbilt Vascular Biology Center, Nashville, Tennessee;
authors.forename: James D
authors.initials: JD
authors.lastname: West
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee;
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
authors.forename: Christa
authors.initials: C
authors.lastname: Gaskill
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
authors.forename: Shennea
authors.initials: S
authors.lastname: Marriott
authors.affiliation: 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;
authors.forename: Rubin
authors.initials: R
authors.lastname: Baskir
authors.affiliation: Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado;
authors.forename: Ganna
authors.initials: G
authors.lastname: Bilousova
authors.affiliation: Boston University, Boston, Massachusetts.
authors.forename: Jyh-Chang
authors.initials: JC
authors.lastname: Jean
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Vanderbilt Vascular Biology Center, Nashville, Tennessee;
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
authors.forename: Swapna
authors.initials: S
authors.lastname: Menon
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee;
authors.forename: Nathaniel C
authors.initials: NC
authors.lastname: Bloodworth
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Vanderbilt Vascular Biology Center, Nashville, Tennessee;
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Fessel
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
authors.forename: Johnathan A
authors.initials: JA
authors.lastname: Kropski
authors.affiliation: Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado;
authors.forename: David
authors.initials: D
authors.lastname: Irwin
authors.affiliation: 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;
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
authors.forename: Lisa
authors.initials: L
authors.lastname: Wheeler
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Veterans Administration Hospital, Nashville, Tennessee;
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.affiliation: 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;
authors.forename: Barbara
authors.initials: B
authors.lastname: Meyrick
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.affiliation: Department of Neurology, Vanderbilt Brain Institute, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee; Department of Neurology, Vanderbilt Brain Institute, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Ess
authors.affiliation: Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado;
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;
authors.forename: Pampee P
authors.initials: PP
authors.lastname: Young
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee;
authors.forename: W David
authors.initials: WD
authors.lastname: Merryman
authors.affiliation: Boston University, Boston, Massachusetts.
authors.forename: Darrell
authors.initials: D
authors.lastname: Kotton
authors.affiliation: 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.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Majka
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology*; D039904:Pluripotent Stem Cells / Q000473:pathology* / Q000502:physiology; D020545:Respiratory Mucosa / Q000473:pathology / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000235:genetics*
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