학술논문
Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension.
Document Type
Academic Journal
Author
West JD; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Vanderbilt Vascular Biology Center, Nashville, Tennessee;; Austin ED; Department of Pediatrics, Vanderbilt University, Nashville, Tennessee;; Gaskill C; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;; Marriott S; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;; Baskir R; 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;; Bilousova G; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado;; Jean JC; Boston University, Boston, Massachusetts.; Hemnes AR; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Vanderbilt Vascular Biology Center, Nashville, Tennessee;; Menon S; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;; Bloodworth NC; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee;; Fessel JP; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Vanderbilt Vascular Biology Center, Nashville, Tennessee;; Kropski JA; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;; Irwin D; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado;; Ware LB; 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;; Wheeler L; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;; Hong CC; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Veterans Administration Hospital, Nashville, Tennessee;; Meyrick B; 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;; Loyd JE; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee;; Bowman AB; Department of Neurology, Vanderbilt Brain Institute, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;; Ess KC; Department of Pediatrics, Vanderbilt University, Nashville, Tennessee; Department of Neurology, Vanderbilt Brain Institute, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;; Klemm DJ; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado;; Young PP; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Stem Cell Biology, Nashville, Tennessee;; Merryman WD; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee;; Kotton D; Boston University, Boston, Massachusetts.; Majka SM; 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.
Source
Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901225 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1563 (Electronic) Linking ISSN: 03636143 NLM ISO Abbreviation: Am J Physiol Cell Physiol Subsets: MEDLINE
Subject
Language
English
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.