
Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension
Author(s) -
James West,
Eric D. Austin,
Christa Gaskill,
Shennea Marriott,
Rubin Baskir,
Ganna Bilousova,
JyhChang Jean,
Anna R. Hemnes,
Swapna Me,
Nathaniel Bloodworth,
Joshua P. Fessel,
Jonathan A. Kropski,
David Irwin,
Lorraine B. Ware,
Lisa Wheeler,
Charles C. Hong,
Barbara Meyrick,
James E. Loyd,
Aaron B. Bowman,
Kevin C. Ess,
Dwight J. Klemm,
Pampee P. Young,
W. David Merryman,
Darrell N. Kotton,
Susan M. Majka
Publication year - 2014
Publication title -
american journal of physiology. cell physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.432
H-Index - 181
eISSN - 1522-1563
pISSN - 0363-6143
DOI - 10.1152/ajpcell.00057.2014
Subject(s) - wnt signaling pathway , mesenchymal stem cell , biology , induced pluripotent stem cell , cell type , stromal cell , endothelial stem cell , cell , pathology , cancer research , microbiology and biotechnology , medicine , signal transduction , in vitro , gene , genetics , embryonic stem cell
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.