title: Fibrocytes Regulate Wilms Tumor 1-Positive Cell Accumulation in Severe Fibrotic Lung Disease.
abstract: Collagen-producing myofibroblast transdifferentiation is considered a crucial determinant in the formation of scar tissue in the lungs of patients with idiopathic pulmonary fibrosis. Multiple resident pulmonary cell types and bone marrow-derived fibrocytes have been implicated as contributors to fibrotic lesions because of the transdifferentiation potential of these cells into myofibroblasts. In this study, we assessed the expression of Wilms tumor 1 (WT1), a known marker of mesothelial cells, in various cell types in normal and fibrotic lungs. We demonstrate that WT1 is expressed by both mesothelial and mesenchymal cells in idiopathic pulmonary fibrosis lungs but has limited or no expression in normal human lungs. We also demonstrate that WT1(+) cells accumulate in fibrotic lung lesions, using two different mouse models of pulmonary fibrosis and WT1 promoter-driven fluorescent reporter mice. Reconstitution of bone marrow cells into a TGF-α transgenic mouse model demonstrated that fibrocytes do not transform into WT1(+) mesenchymal cells, but they do augment accumulation of WT1(+) cells in severe fibrotic lung disease. Importantly, the number of WT1(+) cells in fibrotic lesions was correlated with severity of lung disease as assessed by changes in lung function, histology, and hydroxyproline levels in mice. Finally, inhibition of WT1 expression was sufficient to attenuate collagen and other extracellular matrix gene production by mesenchymal cells from both murine and human fibrotic lungs. Thus, the results of this study demonstrate a novel association between fibrocyte-driven WT1(+) cell accumulation and severe fibrotic lung disease.
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Biochemistry, National Institute of Nutrition, Hyderabad 500007, India;
authors.forename: Vishwaraj
authors.initials: V
authors.lastname: Sontake
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors.forename: Shiva K
authors.initials: SK
authors.lastname: Shanmukhappa
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors.forename: Betsy A
authors.initials: BA
authors.lastname: DiPasquale
authors.affiliation: Department of Biochemistry, National Institute of Nutrition, Hyderabad 500007, India;
authors.forename: Geereddy B
authors.initials: GB
authors.lastname: Reddy
authors.affiliation: Laboratory for Statistical Genomics and Systems Biology, University of Cincinnati, Cincinnati, OH 45267; and.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors.forename: William D
authors.initials: WD
authors.lastname: Hardie
authors.affiliation: Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; satish.madala@cchmc.org.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Madala
mesh_terms: D000818:Animals; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000276:immunology; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D016326:Extracellular Matrix Proteins; D012097:Repressor Proteins; D016211:Transforming Growth Factor alpha; D025721:WT1 Proteins; C583751:WT1 protein, human; C000602896:WT1 protein, mouse